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INTEgRATINg CEllS INTO TISSuES
34
1
NOITCES
Fig. 2.7 An electron
micrograph of a
neuroendocrine cell
between two absorptive
cells in the colon
K
(rat tissue). Dense
neurosecretory granules
are seen in the basal
cytoplasm, apposed
to the basal lamina K
(arrows). (Courtesy of
Michael Crowder MD.)
Fig. 2.8 The basal lamina as seen in an electron micrograph, underlying
the basal epithelial layer of human skin (see Fig. 7.3). The finely fibrillar
dense layer (long arrows) corresponds to the lamina densa, and fine
collagen fibrils (*) lie in the subjacent connective tissue. These contribute
to the appearance of the basement membrane in light microscope
preparations stained for carbohydrate-rich structures. The two cells seen
Feedback loops and endocrine axes in the upper field are basal keratinocytes (K), joined by desmosomes
(short arrow), with dense keratin filaments in their cytoplasm. (Courtesy of
J McMillan MD, St John’s Institute of Dermatology, St Thomas’ Hospital,
The pituitary gland, in particular the adenohypophysis, is often termed
London.)
the master gland because of its central role in endocrine physiological
processes. It provides the means by which the central nervous system
regulates and integrates, by non-neural mechanisms, the widespread plasma membrane proteins, e.g. keratinocyte hemidesmosomes are
functions of the body, including the activities of other endocrine glands anchored into the lamina densa in the basal lamina of the epidermis.
and, often indirectly, exocrine glands such as the breast. Regulatory The basal lamina is a delicate felt-like network composed largely of two
hormones from the adenohypophysis stimulate synthesis and secretion glycoprotein polymers, laminin and type IV collagen, which self-
in target cells of many endocrine glands; these glands therefore respond assemble into two-dimensional sheets interwoven with each other.
to, as well as generate, hormonal signals. Early embryonic basal lamina is formed only of the laminin polymer.
The hypothalamus and the adenohypophysis in the brain are central Two other molecules cross-link and stabilize the network: entactin
to most regulatory feedback loops within the endocrine system. Loops (nidogen) and perlecan (a large heparan sulphate proteoglycan).
can be either positive or negative, e.g. the hypothalamus stimulates Although all basal laminae have a similar form, their thickness and
release of follicle stimulating hormone (FSH) by the adenohypophysis, precise molecular composition vary between tissues and even within a
which in turn stimulates ovarian follicular maturation and secretion of tissue, e.g. between the crypts and villi of the small intestine. The iso-
oestradiol, which acts on breast and endometrial target tissues. Oestra- forms of laminin and collagen type IV differ in various tissues; thus
diol, in this case, also acts back on the adenohypophysis and hypotha- Schwann cells and muscle cells express laminin-2 (merosin) rather than
lamus to reinforce their function positively in a feedback loop. In the prototypical laminin-1. Laminin-5, although not itself a basal
contrast, hypothalamic and adenohypophysial stimulation of testicular lamina component, is found in the hemidesmosomes of the basal
production of testosterone, which acts on targets such as skeletal epidermis and links the basal lamina with epidermal transmembrane
muscle, is negatively regulated in a feedback loop generated by circulat- proteins, αβ integrin and collagen type XVII (BPAG2, bullous pem-
6 4
ing testosterone. Such negative feedback regulation is a widely utilized phigoid antigen 2, one of the targets of the autoimmune blistering skin
physiological mechanism. disease, bullous pemphigoid). The particular isoform of collagen type
IV in the basal lamina of different tissues is reflected in tissue-specific
disease patterns. Mutations in a collagen expressed by muscle and
BASEMENT MEMBRANE AND BASAL LAMINA
kidney glomeruli cause Alport’s syndrome, a form of renal failure. Renal
failure also occurs in Goodpasture’s syndrome, in which renal basal
There is a narrow layer of extracellular matrix, which stains strongly for lamina collagen is targeted by autoantibodies.
carbohydrates, at the interface between connective and other tissues, In Descemet’s membrane in the cornea, collagen type VIII replaces
e.g. between epithelia and their supporting connective tissues. In early collagen type IV in the much thickened (increasing with age, up to
histological texts this layer was termed the basement membrane. 10 µm,) endothelial basal lamina. The basal lamina of the neuromus-
As almost all of its components are synthesized by the epithelium or cular junction contains agrin, a heparan sulphate proteoglycan, which
other tissues, rather than the adjacent connective tissue, it will be dis- plays a part in the clustering of muscle acetylcholine receptors in the
cussed here. plasma membrane at these junctions.
Electron microscopy revealed that the basement membrane is com-
posed of two distinct components. A thin, finely fibrillar layer, the basal
lamina, is associated closely with the basal cell surface (Fig. 2.8). A RETICULAR LAMINA
variable reticular lamina of larger fibrils and glycosaminoglycans of the
extracellular matrix underlies this layer and is continuous with the con- The reticular lamina consists of a dense extracellular matrix that con-
nective tissue proper, although it is much reduced or largely absent in tains collagen. In skin, it contains fibrils of type VII collagen (anchoring
some tissues, e.g. surrounding muscle fibres, Schwann cells and capil- fibrils), which bind the lamina densa to the adjacent connective tissue.
lary endothelia. In other tissues, the basal lamina separates two layers The high concentration of proteoglycans in the reticular lamina is
of cells and there are no intervening typical connective tissue elements. responsible for the positive reaction of the entire basement membrane
This occurs in the thick basal lamina of the renal glomerular filter and to stains for carbohydrates, which is seen in sections prepared for light
the basal lamina of the thin portions of the lung interalveolar septa microscopy.
across which gases exchange between blood and air.
The basal lamina is usually about 80 nm thick, varying between 40
and 120 nm, and consists of a sheet-like fibrillar layer, the lamina densa FUNCTIONS OF BASAL LAMINA
(20–50 nm wide), separated from the plasma membrane of the cell it
supports by a narrow electron-lucent zone, the lamina lucida. The Basal laminae perform a number of important roles (Iozzo 2005). They
lamina lucida is absent from tissues prepared by rapid freezing and so form selectively permeable barriers (anionic filters) between adjacent
may be an artefact. In many tissues this zone is crossed by integral tissues, e.g. in the glomerular filter of the kidney; anchor epithelial and | 78 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Connective and supporting tissues
35
2
RETPAHC
Fig. 2.10 An electron
micrograph of a
fibroblast in human
connective tissue,
surrounded by bundles
of finely banded
C BV collagen fibrils (shown
at high magnification in
the insert), which they
secrete. (Courtesy
of Dr Bart Wagner,
Histopathology
Department, Sheffield
BV Teaching Hospitals,
UK.)
Fig. 2.9 General loose connective tissue (human), with bundles of
collagen fibres (C) within an amorphous ground substance, penetrated by
a neurovascular bundle of blood vessels (BV), lymphatics and nerves. A
small autonomic ganglion is arrowed. (Courtesy of Mr Peter Helliwell and
the late Dr Joseph Mathew, Department of Histopathology, Royal
Cornwall Hospitals Trust, UK.)
connective tissues, and so stabilize and orientate the tissue layers; may to demand. Embryologically, fibroblasts and adipocytes arise from mes-
exert instructive effects on adjacent tissues, and so determine their polar- enchymal stem cells, some of which may remain in the tissues to
ity, rate of cell division, cell survival, etc.; and regulate angiogenesis. In provide a source of replacement cells postnatally. As noted above, the
addition, they may act as pathways for the migration and pathfinding cells of haemopoietic origin migrate into the tissue from bone marrow
activities of growing cell processes, both in development and in tissue and lymphoid tissue.
repair, e.g. in guiding the outgrowth of axons and the re-establishment
of neuromuscular junctions during regeneration after injury in the Resident cells
peripheral nervous system. Changes in basal lamina thickness are often
associated with pathological conditions, e.g. the thickening of the Fibroblasts
glomerular basal lamina in glomerulonephritis and diabetes.
Fibroblasts are usually the most numerous resident cells. They are flat-
tened and irregular in outline, with extended processes, and in profile
CONNECTIVE AND SUPPORTING TISSUES they appear fusiform or spindle-shaped (Fig. 2.10; see also Fig. 2.12).
Fibroblasts synthesize most of the extracellular matrix of connective
tissue (see Fig. 2.10); accordingly, they have all the features typical of
The connective tissues are defined as those composed predominantly
cells active in the synthesis and secretion of proteins. Their nuclei are
of intercellular material, the extracellular matrix, which is secreted
relatively large and euchromatic, and possess prominent nucleoli. In
mainly by the connective tissue cells. The cells are therefore usually
young, highly active cells, the cytoplasm is abundant and basophilic
widely separated by their matrix, which is composed of fibrous proteins
(reflecting the high concentration of rough endoplasmic reticulum),
and a relatively amorphous ground substance (Fig. 2.9). Many of the
mitochondria are abundant and several sets of Golgi apparatus are
special properties of connective tissues are determined by the composi-
present. In old and relatively inactive fibroblasts (often termed fibro-
tion of the matrix, and their classification is also largely based on its
cytes), the cytoplasmic volume is reduced, the endoplasmic reticulum
characteristics. In some types of connective tissue, the cellular compo-
is sparse and the nucleus is flattened and heterochromatic.
nent eventually dominates the tissue, even though the tissue originally
Fibroblasts are usually adherent to the fibres of the matrix (collagen
has a high matrix : cell ratio, e.g. adipose tissue. Connective tissues are
and elastin), which they lay down. In some highly cellular structures,
derived from embryonic mesenchyme or, in the head region, largely
e.g. liver, kidney and spleen, and in most lymphoid tissue, fibroblasts
from neural crest.
and delicate collagenous fibres (type III collagen; reticular fibres) form
Connective tissues have several essential roles in the body. These may
fibrocellular networks, which are often called reticular tissue. The
be subdivided into structural roles, which largely reflect the special
fibroblasts may then be termed reticular cells or reticulocytes.
mechanical properties of the extracellular matrix components, and
Fibroblasts are particularly active during wound repair following
defensive roles, in which the cellular component has the dominant role.
traumatic injury or inflammation, when tissue mass is lost through cell
Connective tissues often also play important trophic and morphoge-
death. They proliferate and lay down a fibrous matrix that becomes
netic parts in organizing and influencing the growth and differentiation
invaded by numerous blood vessels (granulation tissue). Contraction
of surrounding tissues, e.g. in the development of glands from an epi-
of wounds is, at least in part, caused by the shortening of myofibrob-
thelial surface.
lasts, specialized contractile fibroblast-like cells (Hinz et al 2012) with
Structural connective tissues are divided into ordinary (or general)
properties similar to smooth muscle cells. It was thought that myofi-
types, which are widely distributed, and special skeletal types, i.e. car-
broblasts differentiated from fibroblasts (reviewed in McAnulty (2007))
tilage and bone, which are described in Chapter 5. A third type, haemo-
or their progenitor mesenchymal stem cells (see below) in granulation
lymphoid tissues, consists of peripheral blood cells, lymphoid tissues
tissue. However, recent evidence suggests that in wound healing and in
and their precursors; these tissues are described in Chapter 4. They are
many fibrotic disease processes, including hepatic cirrhosis, the myofi-
often grouped with other types of connective tissue because of their
broblast precursor is the vascular pericyte or a closely related cell
similar mesenchymal origins and because the various defensive cells of
(reviewed in Duffield (2012)). In cases where the specialized cells of
the blood also form part of a typical connective tissue cell population.
the damaged region cannot divide and regenerate functional tissue, e.g.
They reach connective tissues via the blood circulation and migrate into
cardiac muscle cells after infarction, connective tissue fibroblasts and
them through the endothelial walls of vessels.
their extracellular matrix fill the void to form a scar. An exception is the
central nervous system, where glial scars are formed after injury. Fibrob-
CELLS OF GENERAL CONNECTIVE TISSUES
last activity is influenced by various factors such as steroid hormone
concentration, dietary content and prevalent mechanical stresses. Col-
Cells of general connective tissues can be separated into the resident lagen formation is impaired in vitamin C deficiency.
cell population (fibroblasts, adipocytes, mesenchymal stem cells, etc.)
Adipocytes (lipocytes, fat cells)
and a population of migrant cells with various defensive functions
(macrophages, lymphocytes, mast cells, neutrophils and eosinophils), Adipocytes occur singly or in groups in many, but not all, connective
which may change in number and moderate their activities according tissues. They are numerous in adipose tissue (Fig. 2.11). Individually, | 79 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
INTEgRATINg CEllS INTO TISSuES
36
1
NOITCES
M
BV
A L P
P
P
M
L
BV
A
BV
Fig. 2.12 Macrophages (M) in chronically inflamed human connective
tissue, showing prominent pigmented, haemosiderin-containing
Fig. 2.11 Adipose tissue (human, from a lymph node specimen). cytoplasmic granules derived from ingested erythrocytes. Many are
Adipocytes (A) are distended polygonal cells filled with lipid, which has multinucleate. Also seen are plasma cells (P), small lymphocytes (L) and
been extracted by the tissue processing. This leaves only the plasma other haemopoietic cells. (Courtesy of Mr Peter Helliwell and the late Dr
membranes with scant cytoplasm and nuclei (arrows), occasionally visible Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals
compressed against the cell periphery. Small blood vessels (BV) penetrate Trust, UK.)
the adipose tissue; larger vessels are seen on the right. (Courtesy of Mr
Peter Helliwell and the late Dr Joseph Mathew, Department of
Histopathology, Royal Cornwall Hospitals Trust, UK.)
nerve endings in adipose tissue is particularly important in this respect.
No new adipose tissue is thought to form after the immediate postnatal
period, and accumulation of body fat, as in obesity, is due to excessive
the cells are oval or spherical in shape, but when packed together they
accumulation of lipid in existing adipocytes, which become very large.
are polygonal. They vary in diameter, averaging 50 µm. Each cell con-
Conversely, weight loss results from the mobilization and metabolism
sists of a peripheral rim of cytoplasm, in which the nucleus is embed-
of lipid from adipocyte stores, with the consequent shrinkage of the
ded, surrounding a single large central globule of fat, which consists of
cells.
glycerol esters of oleic, palmitic and stearic acids. There is a small accu-
mulation of cytoplasm around the oval nucleus, which is typically Mesenchymal stem cells
compressed against the cell membrane by the lipid droplet, together
Mesenchymal stem cells are normally inconspicuous cells in connective
with the Golgi complex. Many cytoskeletal filaments, some endoplas-
tissues. They are derived from embryonic mesenchyme and are able to
mic reticulum and a few mitochondria lie around the lipid droplet,
differentiate into the mature cells of connective tissue during normal
which is in direct contact with the surrounding cytoplasm and not
growth and development, in the turnover of cells throughout life and,
enclosed within a membrane. In sections of tissue not specially treated
most conspicuously, in the repair of damaged tissues in wound healing.
to preserve lipids, the lipid droplet is usually dissolved out by the sol-
There is emerging evidence that, even in mature tissues, mesenchymal
vents used in routine preparations, so that only the nucleus and the
stem cells remain pluripotent and able to give rise to all the resident
peripheral rim of cytoplasm surrounding a central empty space remain.
cells of connective tissues in response to local signals and cues. The
Another form of adipose tissue, brown fat, occurs in the interscapu-
potential therapeutic use of mesenchymal stem cell-based therapy for
lar region of neonates, a location it shares with the classic brown fat of
a wide range of autoimmune disorders and degenerative diseases is
rodents. Brown fat is characterized by the presence of large cells, each
reflected in a burgeoning literature in the field of translational medi-
of which contains several separate droplets of fat (multilocular adipose
cine. (See, for example, Ankrum and Karp (2010), Jackson et al (2012)
tissue) rather than a single globule (typical of unilocular adipose tissue;
and Ren et al (2012)).
see above), and by mitochondria in which the cristae are unusually
large and numerous. White fat cells are specialized to store chemical
Migrant cells
energy, whereas the physiological role of brown adipose tissue (BAT)
cells is to metabolize fatty acids and generate heat; BAT cells uncouple
cellular respiration via the mitochondrial uncoupling protein UCP1. It Macrophages
had been thought that brown fat disappears during postnatal growth, Macrophages are numerous in connective tissues, where they are either
but significant deposits of UCP1-positive brown fat have been detected attached to matrix fibres or are motile and migratory (Fig. 2.12). They
by positron emission tomography (PET) scanning methods in adults, are relatively large cells, 15–20 µm in diameter, with indented and rela-
mainly in the supraclavicular region, in the neck and along the spine. tively heterochromatic nuclei and a prominent nucleolus. Their cyto-
Recent evidence suggests that these human UCP1-positive cells may not plasm is slightly basophilic, contains many lysosomes and typically has
be classic brown fat cells but a distinct type of thermogenic fat cell called a foamy appearance under the light microscope. Macrophages are
a beige fat cell, thought to be derived from precursor cells in white fat important phagocytes and form part of the mononuclear phagocyte
(Wu et al 2012). Such cells may represent an evolutionarily conserved system. They can engulf and digest particulate organic materials, such
cellular mechanism to provide flexibility in adaptive thermogenesis. as bacteria, and are able to clear dead or damaged cells from a tissue
It has long been recognized that adipose tissue is central to the too. They are also the source of a number of secreted cytokines that
control of energy balance and lipid homeostasis. There is a growing have profound effects on many other cell types. Macrophages are able
view that it may play a similarly important role as an endocrine organ, to proliferate in connective tissues to a limited extent, but are derived
secreting a class of peptides called adipokines (Trayhurn and Wood and replaced primarily from haemopoietic stem cells in the bone
2004), which may enter the blood via capillaries or lymph. Different marrow, which circulate in the blood as monocytes before migrating
types of adipose tissue display functional and regional heterogeneity through vessel walls into connective tissues, where they differentiate.
and differ in their involvement with disease processes (reviewed in Many properties of macrophages in general connective tissue are
Hassan et al (2012)). The mobilization of fat is under nervous or hor- similar to those of related cells in other sites. These include: circulating
monal control; noradrenaline (norepinephrine) released at sympathetic monocytes, from which they are derived; alveolar macrophages in the | 80 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Connective and supporting tissues
37
2
RETPAHC
lungs, which take up inhaled particles not cleared by the mucociliary CELLS OF SPECIALIZED CONNECTIVE TISSUES
rejection current; phagocytic cells in the lymph nodes, spleen and bone
marrow; Kupffer cells of the liver sinusoids; and microglial cells of the Skeletal tissues – namely, cartilage and bone – are generally classified
central nervous system. with the connective tissues, but their structure and functions are highly
specialized and they are described in Chapter 5. As with the general
Lymphocytes
connective tissues, these specialized types are characterized by their
Lymphocytes are normally present in small numbers; they are numer- extracellular matrix, which forms the major component of the tissues
ous in general connective tissue only in pathological states, when they and is responsible for their properties. The resident cells are different
migrate in from adjacent lymphoid tissue or from the circulation. The from those in general connective tissues. Cartilage is populated by
majority are small cells (6–8 µm) with highly heterochromatic nuclei chondroblasts, which synthesize the matrix, and by mature chondro-
but they enlarge when stimulated. Two major functional classes exist, cytes. Bone matrix is elaborated by osteoblasts. Their mature progeny,
termed B and T lymphocytes. B lymphocytes originate in the bone osteocytes, are embedded within the matrix, which they help to min-
marrow, then migrate to various lymphoid tissues, where they prolifer- eralize, turn over and maintain. A third cell type, the osteoclast, has a
ate. When antigenically stimulated, they undergo further mitotic divi- different lineage origin and is derived from haemopoietic tissue; osteo-
sions, then enlarge as they mature, commonly in general connective clasts are responsible for bone degradation and remodelling in collabo-
tissues, to form plasma cells that synthesize and secrete antibodies ration with osteoblasts.
(immunoglobulins). Mature plasma cells are rounded or ovoid, up to
15 µm across, and have an extensive rough endoplasmic reticulum.
Their nuclei are spherical, often eccentrically situated, and have a char- EXTRACELLULAR MATRIX
acteristic ‘clock-face’ configuration of heterochromatin (see Fig. 4.12)
that is regularly distributed in peripheral clumps. The prominent Golgi The term extracellular matrix is applied collectively to the extracellular
complex is visible with a light microscope as a pale region to one side components of connective and supporting tissues. Essentially, it con-
of the nucleus and the remaining cytoplasm is deeply basophilic sists of a system of insoluble protein fibres, adhesive glycoproteins and
because of the abundant rough endoplasmic reticulum. Mature plasma soluble complexes composed of carbohydrate polymers linked to
cells do not divide. protein molecules (proteoglycans and glycosaminoglycans), which
T lymphocytes originate from precursors in bone marrow haemo- bind water. The extracellular matrix distributes the mechanical stresses
poietic tissue but later migrate to the thymus, where they develop T-cell on tissues and also provides the structural environment of the cells
identity, before passing into the peripheral lymphoid system, where embedded in it, forming a framework to which they adhere and on
they continue to multiply. When antigenically stimulated, T cells which they can move (reviewed in Even-Ram and Yamada (2005) and
enlarge and their cytoplasm becomes filled with free polysome clusters. Wolf and Friedl (2011)). With the exception of bone matrix, it provides
The functions of T lymphocytes are numerous: different subsets recog- a highly hydrated medium, through which metabolites, gases and nutri-
nize and destroy virus-infected cells, tissue and organ grafts, or interact ents can diffuse freely between cells and the blood vessels traversing it
with B lymphocytes and several other defensive cell types. or, in the case of cartilage, passing nearby.
There are many complex interactions between connective tissue cells
Mast cells
and the extracellular matrix. The cells continually synthesize, secrete,
Mast cells are important defensive cells. They occur particularly in loose
modify and degrade extracellular matrix components, and respond to
connective tissues and in the fibrous capsules of certain organs such as
contact with the matrix in the regulation of cell metabolism, prolifera-
the liver, and are numerous around blood vessels. Mast cells are round
tion and motility. Degradation of the matrix is an important feature of
or oval, approximately 20 µm in diameter, with many filopodia extend-
embryonic development, morphogenesis, angiogenesis, tissue repair
ing from the cell surface. The nucleus is centrally placed and relatively
and remodelling (Mott and Werb 2004). Various types of proteinase are
small. The cytoplasm contains large numbers of prominent vesicles and
involved, principally metalloproteinases such as matrix metalloprotei-
a well-developed Golgi apparatus, but scant endoplasmic reticulum.
nases (MMPs), and those with a disintegrin and metalloproteinase
The vesicles have a high content of glycosaminoglycans and show a
domain (ADAMs) that include ADAMs with a thrombospondin domain
strongly positive reaction with the PAS stain for carbohydrates. They are
(ADAMTS). Tissue remodelling depends on the controlled degradation
membrane-bound, vary in size and shape (mean diameter 0.5 µm) and
of the extracellular matrix by secreted MMPs, regulated by their specific
also have a rather heterogeneous content of dense, lipid-containing
inhibitors, as occurs, for instance, during involution of the postpartum
material, which may be finely granular, lamellar or in the form of
uterus or during menstrual lysis and shedding of the endometrium
membranous whorls.
(Gaide Chevronnay et al 2012). In the process of matrix degradation,
The major granule components, many of them associated with
bioactive peptides are liberated that act as growth factors, cytokines and
inflammation (Frenzel and Hermine 2013), are the proteoglycan
other signalling molecules to change the behaviour of cells in the vicin-
heparin, histamine, tryptase, superoxide dismutase, aryl sulphatase,
ity. While precisely regulated under physiological conditions, patho-
β-hexosaminidase and various other enzymes, including chymase in
logically dysregulated extracellular matrix degradation is a cause of
connective tissue but not mucosal mast cells, together with chemotactic
many diseases, such as atherosclerosis, emphysema, osteoarthritis and
factors for neutrophil and eosinophil granulocytes. There are functional
diabetic vascular complications.
differences between mast cells found in different tissues.
The insoluble fibres are mainly of two types of structural pro-
Mast cells may be stimulated to release some or all of their contents,
tein: members of the collagen family, and elastin (Fig. 2.13). The
either by direct mechanical or chemical trauma, or after contact with
particular antigens to which the body has previously been exposed. The
consequences of granule release include alteration of capillary perme-
ability, smooth muscle contraction, and activation and attraction to the
locality of various other defensive cells. Responses to mast cell degranu-
lation may be localized, e.g. urticaria, or there may occasionally be a
generalized response to the release of large amounts of histamine into
the circulation (anaphylactic shock). Mast cells closely resemble
basophil granulocytes of the general circulation but are thought to
develop as distinct descendants of an earlier myeloid lineage precursor.
It is believed that they are generated in the bone marrow and circulate
to the tissues as immature basophil-like cells, migrating through the
capillary and venule walls to their final destination. For further reading,
see Bischoff (2007) and Collington et al (2011).
Granulocytes (polymorphonuclear
leukocytes)
Neutrophil and eosinophil granulocytes are immigrant cells from the
circulation. Relatively infrequent in normal connective tissues, their
numbers may increase dramatically in infected tissues, where they are
important components of cellular defence. Neutrophils are highly Fig. 2.13 Elastic fibres, seen as fine, dark, relatively straight fibres in a
phagocytic, especially towards bacteria. The functions of eosinophils are whole-mount preparation of mesentery, stained for elastin. The wavy pink
less well understood. These cells are described further in Chapter 4. bands are collagen bundles and oval grey nuclei are mainly of fibroblasts. | 81 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
INTEgRATINg CEllS INTO TISSuES
38
1
NOITCES
interfibrillar matrix (ground substance) includes a number of adhesive
glycoproteins that perform a variety of functions in connective tissues,
including cell–matrix adhesion and matrix–cell signalling. These glyco-
proteins include fibronectin, laminin, tenascin and vitronectin, in
addition to a number of other less well characterized proteins. The
glycosaminoglycans of the interfibrillar matrix are, with one notable
exception, post-translationally modified proteoglycan molecules in H
which long polysaccharide side chains are added to short core proteins S
during transit through the secretory pathway between the rough endo- S
plasmic reticulum and the trans-Golgi network. The exception, the poly- H
meric disaccharide, hyaluronan, has no protein core and is synthesized
entirely by cell surface enzymes. For further reading on extracellular
matrix molecules, see Pollard et al (2008). Functional attributes of con-
nective tissues vary and depend on the abundance of its different com-
ponents. Collagen fibres resist tension, whereas elastin provides a
measure of resilience to deformation by stretching. The highly hydrated,
soluble polymers of the interfibrillar material (proteoglycans and gly-
cosaminoglycans, mainly hyaluronan) generally form a stiff gel resisting
compressive forces. Thus tissues that are specialized to resist tensile
forces (e.g. tendons) are rich in collagen fibrils; tissues that accommo- Fig. 2.14 Reticular fibres (type III collagen; reticulin demonstrated by
date changes in shape and volume (e.g. mesenteries) are rich in elastic silver-staining) in human liver, forming a delicate meshwork within the
space of Disse between hepatocytes (H), plasma membranes and the
fibres; and those that absorb compressive forces (e.g. cartilages) are rich
sinusoidal endothelia (S). (Courtesy of Mr Peter Helliwell and the late Dr
in glycosaminoglycans and proteoglycans. In bone, mineral crystals take
Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals
the place of most of the soluble polymers and endow the tissue with
Trust, UK.)
incompressible rigidity.
ency. Tendons, aponeuroses and ligaments are also highly ordered
Fibrillar matrix
tissues (Ch. 5).
Collagens Types II, III, V and XI collagens
Types II, III, V and XI collagens can also aggregate to form linear fibrils.
Collagens make up a very large proportion (approximately 30%) of all
Type II collagen occurs in extremely thin (10 nm), short fibrils in the
the proteins of the body. They consist of a wide range of related mol-
vitreous humour and in very thick fibrils in ageing human cartilage. The
ecules that have various roles in the organization and properties of
amino-acid sequence and banding pattern are very similar to those of
connective (and some other) tissues. The first collagen to be character-
type I collagen, as are the post-translational modifications of the triple
ized was type I, the most abundant of all the collagens and a constituent
helical protein molecule. The fine fibrils in the vitreous may fuse into
of the dermis, fasciae, bone, tendon, ligaments, blood vessels and the
thicker aggregates in older tissue.
sclera of the eyeball. The characteristic collagen of cartilage and the
Type III collagen is very widely distributed, particularly in young and
vitreous body of the eye, with a slightly different chemical composition,
repairing tissues. It usually co-localizes with type I collagen, and cova-
is type II, whereas type III is present in several tissues, including the
lent links between type I and type III collagen have been demonstrated.
dermis and blood vessels, and type IV is in basal lamina. The other
In skin, many fibrils are probably composites of type I and type III
types are widely distributed in various tissues. Five of the collagens,
collagens.
types I, II, III, V and XI, form fibrils; types IV, VIII and X form sheets or
meshworks; types VI, VII, IX, XII, XIV and XVIII have an anchoring or
Reticular fibres
linking role; and types XIII and XVII are transmembrane proteins.
Fine branching and anastomosing reticular fibres form the supporting
Biochemically, all collagens have a number of features in common.
mesh framework of many glands, including the liver (Fig. 2.14), the
Unlike most other proteins, they contain high levels of hydroxyproline
kidney and lymphoreticular tissue (lymph nodes, spleen, etc.). Classi-
and all are composed of three polypeptides that form triple helices and
cally, these fibres stained intensely with silver salts, although they are
are substantially modified post-translationally. After secretion, indi-
poorly stained using conventional histological techniques. They associ-
vidual molecules are further cross-linked to form stable polymers. Func-
ate with basal laminae and are often found in the neighbourhood of
tionally, collagens are structural proteins with considerable mechanical
collagen fibre bundles. Reticular fibres are formed principally of type
strength. Just a few of their distinguishing structural features are
III collagen.
described below. For further reading on the molecular structure and
functions of the collagens, see Pollard et al (2008). Elastin
Elastin is a 70 kDa protein, rich in the hydrophobic amino acids valine
Type I collagen
and alanine. Elastic fibrils, which also contain fibrillin, are highly cross-
Type I collagen is very widely distributed. It forms inextensible fibrils
linked via two elastin-specific amino acids, desmosine and iso-
in which collagen molecules (triple helices) are aligned side by side in
desmosine, which are formed extracellularly from lysine residues. They
a staggered fashion, with three-quarters of the length of each molecule
are less widely distributed than collagen, yellowish in colour, typically
in contact with neighbouring molecules. The fibril has well-marked
cross-linked and usually thinner (10–20 nm) than collagen fibrils. They
bands of charged and uncharged amino acids arranged across it; these
can be thick, e.g. in the ligamenta flava and ligamentum nuchae. Unlike
stain with heavy metals in a banding pattern that repeats every 65 nm
collagen type I, they show no banding pattern in the electron micro-
in longitudinal sections viewed in the electron microscope (see Fig. 2.10
scope. They stain poorly with routine histological stains but are stained
insert).
with orcein-containing preparations (see Fig. 2.13). They sometimes
Fibril diameters vary between tissues and with age. Developing
appear as sheets, as in the fenestrated elastic lamellae of the aortic wall.
tissues often have thinner fibrils than mature tissues. Corneal stroma
Elastin-rich structures stretch easily with almost perfect recoil, although
fibrils are of uniform and thin diameter, whereas tendon fibrils may be
they tend to calcify with age and lose elasticity. Elastin is highly resistant
up to 20 times thicker and quite variable. Tissues in which the fibrils
to attack by acid and alkali, even at high temperatures.
are subject to high tensile loading tend to have thicker fibrils. Thick
fibrils are composites of uniform thin fibrils with a diameter of 8–12 nm.
Interfibrillar matrix
The fibrils themselves are relatively flexible, but when mineralized (as
in bone) or surrounded by high concentrations of proteog lycan (as in
Glycosaminoglycans
cartilage), the resulting fibre-reinforced composite materials are rigid.
Fresh type I collagen fibres are tightly packed assemblies of parallel The structural soluble polymers characteristic of the extracellular matrix
fibrils and are white and glistening. They form variably wavy (crimped) are the acidic glycosaminoglycans, which are unbranched chains of
bundles of various sizes that are generally visible at the light microscope repeating disaccharide units, each unit carrying one or more negatively
level. The component fibres may leave one bundle and interweave with charged groups (carboxylate or sulphate esters, or both). The anionic
others. In some situations, collagen fibrils are laid down in precise geo- charge is balanced by cations (Na+, K+, etc.) in the interstitial fluid. Their
metrical patterns, in which successive layers alternate in direction, e.g. polyanionic character endows the glycosaminoglycans with high
corneal stroma, where the high degree of order is essential for transpar- osmotic activity, which helps to keep the fibrils apart, confers stiffness | 82 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Connective and supporting tissues
39
2
RETPAHC
on the porous gel that they collectively create, and gives the tissue a Tenascin
varying degree of basophilia. Glycosaminoglycans are named according Tenascin is large glycoprotein composed of six subunits that are joined
to the tissues in which they were first found, e.g. hyaluronan (vitreous at one end to form a structure that resembles the spokes of a wheel.
body), chondroitins (cartilage), dermatan (skin), keratan (cornea), There is a family of tenascin molecules, generated by alternative splicing
heparan (liver). This terminology is no longer relevant, as most gly- of the tenascin gene transcript. Tenascin is abundant in embryonic
cosaminoglycans are very widely distributed, whereas, conversely, some tissues but its distribution is restricted in the adult. It appears to be
corneas contain little or no keratan sulphate. Of the glycosaminogly- important in guiding cell migration and axonal growth in early develop-
cans, all except hyaluronan have short protein cores and are highly ment: it may either promote or inhibit these activities, depending on
variable in their carbohydrate side-chain structure. the cell type and tenascin isoform.
Hyaluronan
Hyaluronan was formerly called hyaluronic acid (or hyaluronate, as CLASSIFICATION OF CONNECTIVE TISSUES
only the salt exists at physiological pH). It is a very large, highly hydrated
molecule (25,000 kDa). Hyaluronan is found in all extracellular matri-
Connective and supporting tissues differ considerably in appearance,
ces and in most tissues, and is a prominent component of embryonic
consistency and composition in different regions. These differences
and developing tissues.
reflect local functional requirements and are related to the predomi-
Hyaluronan is important in the aggregation of proteoglycans and
nance of the cell types; the concentration, arrangement and types of
link proteins that possess specific hyaluronan binding sites (e.g.
fibre; and the characteristics of the interfibrillar matrix. On these
laminin). Indeed, the very large aggregates that are formed may be the
bases, general connective tissues can be classified into irregular and
essential compression-resisting units in cartilage. Hyaluronan also
regular types, according to the degree of orientation of their fibrous
forms very viscous solutions, which are probably the major lubricants
components.
in synovial joints. Because of its ability to bind water, it is often present
in semi-rigid structures (e.g. vitreous humour in the eye), where it
cooperates with sparse but regular meshworks of thin collagen fibrils. Irregular connective tissues
Proteoglycans
Irregular connective tissues can be further subdivided into loose, dense
Proteoglycans have been classified according to the size of their protein and adipose connective tissue.
core; their nomenclature is under review. The same core protein can
bear different glycosaminoglycan side chains in different tissues. The Loose (areolar) connective tissue
functions of many proteoglycans are poorly understood. Some of the Loose connective tissue is the most generalized form and is extensively
better-known proteoglycans are: aggrecan in cartilage, perlecan in basal distributed. Its chief function is to bind structures together, while still
laminae, decorin associated with fibroblasts in collagen fibril assembly, allowing a considerable amount of movement to take place. It consti-
and syndecan in embryonic tissues. tutes the submucosa in the digestive tract and other viscera lined by
mucosae, and the subcutaneous tissue in regions where this is devoid
Adhesive glycoproteins
of fat (e.g. eyelids, penis, scrotum and labia), and it connects muscles,
These proteins include molecules that mediate adhesion between cells vessels and nerves with surrounding structures. It is present in the inte-
and the extracellular matrix, often in association with collagens, proteo- rior of organs, where it binds together the lobes and lobules of glands,
glycans or other matrix components. All of them are glycosylated and forms the supporting layer (lamina propria) of mucosal epithelia and
they are, therefore, glycoproteins. General connective tissue contains the vascular endothelia, and lies within and between fascicles of muscle
well-known families of fibronectins (and osteonectin in bone), lam- and nerve fibres.
inins and tenascins; there is a rapidly growing list of other glycoproteins Loose connective tissue consists of a meshwork of thin collagen and
associated with extracellular adhesion (Pollard et al 2008). They possess elastin fibres interlacing in all directions (see Fig. 2.13) to give a measure
binding sites for other extracellular matrix molecules and for cell adhe- of both elasticity and tensile strength. The large meshes contain the soft,
sion molecules, especially the integrins; in this way they enable cells semi-fluid interfibrillar matrix or ground substance, and different con-
selectively to adhere to and migrate through, appropriate matrix struc- nective tissue cells, which are scattered along the fibres or in the meshes.
tures (reviewed in Jacquemet et al (2013)). They also function as signal- It also contains adipocytes, usually in small groups, and particularly
ling molecules, which are detected by cell surface receptors and initiate around blood vessels.
changes within the cytoplasm (e.g. to promote the formation of A variant of loose connective tissue occurs in the choroid and the
hemidesmosomes or other areas of strong adhesion; reorganize the sclera of the eye, where large numbers of pigment cells (melanocytes)
cytoskeleton; and promote or inhibit locomotion and cell division). are also present.
Fibronectin Dense irregular connective tissue
Fibronectin is a large glycoprotein consisting of a dimer joined by Dense irregular connective tissue is found in regions that are under
disulphide links. Each subunit is composed of a string of large repetitive considerable mechanical stress and where protection is given to
domains linked by flexible regions. Fibronectin subunits have binding ensheathed organs. The matrix is relatively acellular and contains a high
sites for collagen, heparin and cell surface receptors, especially integrins, proportion of collagen fibres organized into thick bundles interweaving
and so can promote adhesion between all these elements. In connective in three dimensions and imparting considerable strength. There are few
tissues, the molecules are able to bind to cell surfaces in an orderly active fibroblasts, which are usually flattened with heterochromatic
fashion, to form short fibronectin filaments. The liver secretes a related nuclei. Dense irregular connective tissue occurs in: the reticular layer of
protein, plasma fibronectin, into the circulation. The selective adhesion the dermis; the superficial connective tissue sheaths of muscle and
of different cell types to the matrix during development and in postna- nerves, and the adventitia of large blood vessels; and the capsules of
tal life is mediated by numerous isoforms of fibronectin generated by various glands and organs (e.g. testis, sclera of the eye, periostea and
alternative splicing. Isoforms found in embryonic tissues are also perichondria).
expressed during wound repair, when they facilitate tissue proliferation
and cell movements; the adult form is re-expressed once repair is Adipose tissue
complete. A few adipocytes occur in loose connective tissue in most parts of the
body. However, they constitute the principal component of adipose
laminin tissue (see Fig. 2.11), where they are embedded in a vascular loose con-
Laminin is a large (850 kDa) flexible molecule composed of three nective tissue, usually divided into lobules by stronger fibrous septa
polypeptide chains (designated α, β and γ). There are many isoforms carrying the larger blood vessels. Adipose tissue only occurs in certain
of the different chains, and at least 18 types of laminin. The prototypical regions. In particular it is found: in subcutaneous tissue; in the mesenter-
molecule has a cruciform shape, in which the terminal two-thirds are ies and omenta; in the female breast; in bone marrow; as retro-orbital
wound round each other to form the stem of a cross, and the shorter fat behind the eyeball; around the kidneys; deep to the plantar skin of
free ends form the upright and transverse members. Laminin bears the foot; and as localized pads in the synovial membrane of many
binding sites for other extracellular matrix molecules such as heparan joints. Its distribution in subcutaneous tissue shows characteristic age
sulphate, type IV collagen and entactin, and also for laminin receptor and sex differences. Fat deposits serve as energy stores, sources of meta-
molecules (integrins) situated in cell plasma membranes. Laminin mol- bolic lipids, thermal insulation (subcutaneous fat) and mechanical
ecules can assemble themselves into flat regular meshworks, e.g. in the shock-absorbers (e.g. soles of the feet, palms of the hands, gluteal
basal lamina. region and synovial membranes). | 83 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
INTEgRATINg CEllS INTO TISSuES
40
1
NOITCES
Mucosa
Epithelium
Lamina propria
Muscularis mucosae
Muscularis
externa
Submucosa
Serosa
Fig. 2.15 Dense regular connective tissue in a tendon. Thick parallel Duct of extrinsic
gland or organ
bundles of type I collagen (here stained pink) give tendon its white colour
in life. The elongated nuclei of inactive fibroblasts (tendon cells) are visible
between collagen bundles.
Submucosal gland
Regular connective tissues Fig. 2.16 A generalized mucosa and supporting tissues. For details and
variations, see text.
Regular connective tissues include highly fibrous tissues in which fibres
are regularly orientated, either to form sheets such as fasciae and
foci of stratified squamous metaplasia in response to irritants in ciga-
aponeuroses, or as thicker bundles such as ligaments or tendons (Fig.
rette smoke. Mesenchymal (osseous) metaplasia can occur, for example,
2.15). The direction of the fibres within these structures is related to
in the fibrous connective tissue of muscles subjected to repeated
the stresses that they undergo: fibrous bundles display considerable
damage, where trabeculi of bone develop. It is thought that stem cells
interweaving, even within tendons, which increases their structural sta-
(rather than the differentiated cells) in the affected tissue respond to
bility and resilience.
changes in their environment by altering their differentiation pathway,
The fibroblasts that secrete the fibres may eventually become trapped
a process that may be reversible if the stimulus is removed.
within the fibrous structure, where they become compressed, relatively
inactive cells with stellate profiles and small heterochromatic nuclei;
these cells are called tendon cells. Fibroblasts on the external surface MUCOSA (MUCOUS MEMBRANE)
may be active in continued fibre formation and they constitute a pool
of cells available for repair of injured tissue.
A mucosa or mucous membrane (Fig 2.16) lines many internal hollow
Although regular connective tissue is predominantly collagenous,
organs in which the inner surfaces are moistened by mucus, such as the
some ligaments contain significant amounts of elastin, e.g. the liga-
intestines, conducting portions of the airway, and the genital and
menta flava of the vertebral laminae and the vocal folds. The collagen
urinary tracts. A mucosa proper consists of an epithelial lining, which
fibres may form precise geometrical patterns, as in the cornea.
may have the ducts of mucosal, submucosal or extrinsic glands opening
on to its surface, an underlying loose connective tissue, the lamina
Mucoid tissue
propria, and a thin layer of smooth muscle, the muscularis mucosae.
This last layer either may be absent from some mucosae, or may be
Mucoid tissue is found chiefly as a stage in the development of connec- replaced by a layer of elastic fibres. The term mucous membrane reflects
tive tissue from mesenchyme. It exists in Wharton’s jelly, which forms the fact that these tissues can all be peeled away as a sheet or membrane
the bulk of the umbilical cord, and consists substantially of extracellular from underlying structures; the plane of separation occurs along the
matrix, largely made up of hydrated mucoid material and a fine mesh- muscularis mucosae.
work of collagen fibres, in which nucleated, fibroblast-like cells with Submucosa is a layer of supporting connective tissue that usually lies
branching processes are found. Fibres are usually rare in typical mucoid below the muscularis mucosae. It may contain mucous or seromucous
tissue, although the full-term umbilical cord contains perivascular col- submucosal glands. Inflammation of the viscera involves, primarily, the
lagen fibres. Postnatally, mucoid tissue is seen in the pulp of a develop- connective tissues of the submucosa and lamina propria, and is char-
ing tooth, the vitreous body of the eye (a persistent form of mucoid acterised by dilated vessels, oedema, and accumulations of extravasated
tissue that contains few fibres or cells) and the nucleus pulposus of the immune defence cells. Most mucosae are also supported by one or more
intervertebral disc. layers of smooth muscle, the muscularis externa. Contraction of this
muscle may constrict the mucosal lumen (e.g. in the airway) or, where
there are two or more muscle layers orientated in opposing directions
TRANSDIFFERENTIATION AND METAPLASIA
(e.g. in the intestines), cause peristaltic movement of the viscus and the
contents of its lumen. The outer surface of the muscle may be covered
Transitions occur between populations of cells forming an epithelium by a serosa or, where the structure is retroperitoneal or passes through
(sheets of polarized cells) and mesenchymal types (where the cells lack the pelvic floor, by a connective tissue adventitia.
polarity) during normal development (see Thiery et al (2009)). In post-
natal life, most well-described transitions between morphologically dif-
ferent cell types do not cross an epithelial–mesenchymal boundary but MUCUS
are transitions between types of epithelial cell or, less frequently,
between mesenchymal (connective tissue) cell types. Most instances Mucus is a viscous suspension of complex glycoproteins (mucins) of
of such transdifferentiation (metaplasia, see Commentary 1.4) are various kinds, and is secreted by scattered individual epithelial (goblet)
adaptive, to changing environmental conditions or trauma, and almost cells, a secretory surface epithelium (e.g. the stomach lining) or mucous
all are pathological; the altered cells are termed metaplastic. A very and seromucous glands. The precise composition of the mucus varies
common and physiologically normal example is the squamous meta- with the tissue and secretory cells that produce it. All mucins consist of
plasia of columnar secretory epithelium of the distal endocervical canal, filamentous core proteins to which are attached carbohydrate chains,
when exposed to the hormonally stimulated vaginal environment. usually branched; salivary mucus contains nearly 600 chains. Carbohy-
Gastric metaplasia of the lower oesophagus may occur when chronic drate residues include glucose, fucose, galactose and N-acetylglucosamine
reflux of gastric juices exposes its stratified squamous epithelial lining (sialic acid). The terminals of some carbohydrate chains are identical
to acid, and the original epithelium is replaced by a mucus-secreting to the blood group antigens of the ABO group in the majority of the
columnar epithelium typical of the stomach (Barrett’s oesophagus); this population (secretors, bearing the secretor gene Se), and can be detected
is pathological and susceptible to malignant change. Similarly, the res- in salivary mucus by means of appropriate clinical tests. The long poly-
piratory epithelium (see Fig. 2.2D) of the upper airway often develops meric carbohydrate chains bind water and protect surfaces against | 84 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
41
2
RETPAHC
Key references
drying; they also provide good lubricating properties. In concentrated
FASCIA
form, mucins form viscous layers that protect the underlying tissues
against damage.
Synthesis of mucus starts in the rough endoplasmic reticulum. It is Fascia is a generic term applied to sheaths, sheets or other dissectible
then passed to the Golgi complex, where it is conjugated with sulphated masses of connective tissue that are large enough to be visible to the
carbohydrates to form the glycoprotein, mucinogen, and this is exported unaided eye. The terms superficial fascia and deep fascia, widely used
in small, dense, membrane-bound vesicles that swell as they approach to describe the connective tissue between the skin and underlying
the cell surface, with which they fuse before releasing their contents. muscle, and the connective tissue surrounding muscles, viscera and
related structures, respectively, are no longer included in the Terminolo-
gia Anatomica, although they remain in common usage in the English
SEROSA (SEROUS MEMBRANE)
language. Tela subcutanea, hypodermis and subcutaneous tissue are
the recommended synonymous terms that replace superficial fascia.
Serosa consists of a single layer of squamous mesothelial cells, express- Deeper-lying condensations of connective tissue have been defined
ing keratin intermediate filaments, supported by an underlying layer of according to their location, e.g. investing muscles (fascia musculorum)
loose connective tissue that contains numerous blood and lymphatic or viscera (fascia visceralis). Loosely packed connective tissue surrounds
vessels. Serosa lines the pleural, pericardial and peritoneal cavities, and peripheral nerves, blood and lymph vessels as they pass between
covers the external surfaces of organs lying within those cavities and, in other structures, often linking them together as neurovascular bundles.
the abdomen, the mesenteries that envelop them. A potential space, Some large vessels, e.g. the common carotid and femoral arteries, are
filled with a small amount of protein-containing serous fluid – largely invested by a dense connective tissue sheath that may be functionally
an exudate of interstitial fluid – exists between the outer parietal and significant, aiding venous return by approximating large veins to pulsat-
the inner visceral layers of the serosa. ing arteries.
KEY REFERENCES
Collington SJ, Williams TJ, Weller CL 2011 Innate immune cell trafficking: A review of the biology of connective tissue fibroblasts and related
mechanisms underlying the localisation of mast cells in tissues. Trends mesenchymal cells.
Immunol 32:478–85.
Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin
A discussion of recent advances in understanding the recruitment of mast
intermediate filaments in normal and diseased epithelia. Curr Opin Cell
cells to tissues.
Biol 25:1–10.
Duffield JS 2012 The elusive source of myofibroblasts: problem solved? Nat A discussion of the current understanding of the keratin intermediate
Med 18:1178–80. filament family, specific to epithelia, and the roles of keratins in epithelial
A review of recent evidence for a perivascular cell (pericyte) origin for functions and selected diseases.
myofibroblasts and fibrotic tissue in a number of disease states.
Pollard TD, Earnshaw WC, Lippincott-Schwartz J 2008 Cell Biology, 2nd ed.
Frenzel L, Hermine O 2013 Mast cells and inflammation. Joint Bone Spine Philadelphia: Elsevier, Saunders; Ch. 29 Extracellular matrix molecules,
80:141–5. pp. 531–52.
A description of the role of mast cells in inflammatory processes and A comprehensive text on the molecular structures and functions of matrix
prospects for therapeutic intervention in inflammatory diseases. molecules.
Hassan M, Latif N, Yacoub M 2012 Adipose tissue: friend or foe? Nature Rev Thiery JP, Acloque H, Huang RYJ et al 2009 Epithelial–mesenchymal transi-
Cardiol 9:689–702. tions in development and disease. Cell 139:871–90.
A review of the status of adipose tissue, its structural and functional A description of these processes in normal development and the contribution
variations and roles in health and disease. of epithelial–mesenchymal transitions to carcinoma progression and
metastasis.
Hinz B, Phan SH, Thannickal VJ et al 2012 Recent developments in myofi-
broblast biology. Am J Path 180:1340–55. Wolf K, Friedl P 2011 Extracellular matrix determinants of proteolytic and
A review of recent work on myofibroblasts, their origins, molecular non-proteolytic cell migration. Trends Cell Biol 21:736–44.
regulation of differentiation from precursor cells and roles in organ-specific A review of cell migration through extracellular matrices in wound healing
fibrotic disease processes. and pathological processes, using proteolytic and other mechanisms.
McAnulty RJ 2007 Fibroblasts and myofibroblasts: their source, function and
role in disease. Int J Biochem Cell Biol 39:666–71. | 85 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Integrating cells into tissues
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RETPAHC
REFERENCES
Ankrum J, Karp JM 2010 Mesenchymal stem cell therapy: two steps forward, Jacquemet G, Humphries MJ, Caswell PT 2013 Role of adhesion receptor
one step back. Trends in Mol Med 16:203–9. trafficking in 3D cell migration. Curr Opin Cell Biol 25:1–6.
Bischoff SC 2007 Role of mast cells in allergic and non-allergic immune McAnulty RJ 2007 Fibroblasts and myofibroblasts: their source, function and
responses: comparison of human and murine data. Nat Rev Immunol role in disease. Int J Biochem Cell Biol 39:666–71.
7:93–104. A review of the biology of connective tissue fibroblasts and related
Blanpain C, Horsley V, Fuchs E 2007 Epithelial stem cells: turning over new mesenchymal cells.
leaves. Cell 128:445–8. Mott JD, Werb Z 2004 Regulation of matrix biology by matrix metallopro-
Collington SJ, Williams TJ, Weller CL 2011 Innate immune cell trafficking: teinases. Curr Opin Cell Biol 16:558–64.
mechanisms underlying the localisation of mast cells in tissues. Trends Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin
Immunol 32:478–85. intermediate filaments in normal and diseased epithelia. Curr Opin Cell
A discussion of recent advances in understanding the recruitment of mast Biol 25:1–10.
cells to tissues. A discussion of the current understanding of the keratin intermediate
Duffield JS 2012 The elusive source of myofibroblasts: problem solved? Nat filament family, specific to epithelia, and the roles of keratins in epithelial
Med 18:1178–80. functions and selected diseases.
A review of recent evidence for a perivascular cell (pericyte) origin for Pollard TD, Earnshaw WC, Lippincott-Schwartz J 2008 Cell Biology, 2nd ed.
myofibroblasts and fibrotic tissue in a number of disease states. Philadelphia: Elsevier, Saunders; Ch. 29 Extracellular matrix molecules,
Even-Ram S, Yamada KM 2005 Cell migration in 3D matrix. Curr Opin Cell pp. 531–52.
Biol 17:524–32. A comprehensive text on the molecular structures and functions of matrix
molecules.
Frenzel L, Hermine O 2013 Mast cells and inflammation. Joint Bone Spine
80:141–5. Ren G, Chen X, Dong F et al 2012 Concise review: mesenchymal stem cells
A description of the role of mast cells in inflammatory processes and and translational medicine: emerging issues. Stem Cells Transl Med
prospects for therapeutic intervention in inflammatory diseases. 1:51–8.
Gaide Chevronnay HP, Selvais C, Emonard H et al 2012 Regulation of matrix Stoeckelhuber M, Schubert C, Kesting MR et al 2011 Human axillary apo-
metalloproteinases activity studied in human endometrium as a para- crine glands: proteins involved in the apocrine secretory mechanism.
digm of cyclic tissue breakdown and regeneration. Biochim Biophys Histol Histopathol 26:177–84.
Acta 1824:146–56. Thiery JP, Acloque H, Huang RYJ et al 2009 Epithelial–mesenchymal transi-
Hassan M, Latif N, Yacoub M 2012 Adipose tissue: friend or foe? Nature Rev tions in development and disease. Cell 139:871–90.
Cardiol 9:689–702. A description of these processes in normal development and the contribution
A review of the status of adipose tissue, its structural and functional of epithelial–mesenchymal transitions to carcinoma progression and
variations and roles in health and disease. metastasis.
Hinz B, Phan SH, Thannickal VJ et al 2012 Recent developments in myofi- Trayhurn P, Wood IS 2004 Adipokines: inflammation and the pleiotropic
broblast biology. Am J Path 180:1340–55. role of white adipose tissue. Br J Nutr 92:347–55.
A review of recent work on myofibroblasts, their origins, molecular Wolf K, Friedl P 2011 Extracellular matrix determinants of proteolytic and
regulation of differentiation from precursor cells and roles in organ-specific non-proteolytic cell migration. Trends Cell Biol 21:736–44.
fibrotic disease processes. A review of cell migration through extracellular matrices in wound healing
and pathological processes, using proteolytic and other mechanisms.
Iozzo RV 2005 Basement membrane proteoglycans: from cellar to ceiling.
Nat Rev Mol Cell Biol 6:646–56. Wu J, Bostro P, Sparks LM et al 2012 Beige adipocytes are a distinct type of
Jackson WM, Nesti LJ, Tuan RS 2012 Concise review: clinical translation of thermogenic fat cell in mouse and human. Cell 150:366–76.
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42
1
NOITCES
CHAPTER
3
Nervous system
The nervous system has two major divisions, the central nervous system with neurones in many different ways; their two-way communication
(CNS) and the peripheral nervous system (PNS). The CNS consists of is essential for normal brain activity.
the brain, spinal cord, optic nerve and retina, and contains the majority It was thought for many years that glia outnumbered neurones by
of neuronal cell bodies. The PNS includes all nervous tissue outside the 10 times in the CNS, but recent studies using the isotropic fractionator
CNS and consists of the cranial and spinal nerves, the peripheral auto- method have challenged that popular view, suggesting instead that the
nomic nervous system (ANS) and the special senses (taste, olfaction, two cell populations are rather similar in size (Azevedo et al 2009). That
vision, hearing and balance). It is composed mainly of the axons of said, the glia : neurone ratio has been reported to be as high as 17 : 1 in
sensory and motor neurones that pass between the CNS and the body. the thalamus (Pakkenberg and Gundersen 1988).
The ANS is subdivided into sympathetic and parasympathetic compo- The glial population in the CNS consists of microglia and macroglia;
nents. It consists of neurones that innervate secretory glands and cardiac the latter are subdivided into oligodendrocytes and astrocytes. The
and smooth muscle, and is concerned primarily with control of the principal glial cell in the PNS is the Schwann cell. Satellite cells sur-
internal environment. Neurones in the wall of the gastrointestinal tract round each neuronal soma in ganglia.
form the enteric nervous system (ENS) and are capable of sustaining For further reading on the nervous system, see Finger (2001), Kandel
local reflex activity that is independent of the CNS. The ENS contains et al (2012), Kettenmann and Ransom (2012), Levitan and Kaczmarek
as many intrinsic neurones in its ganglia as the entire spinal cord and (2001), Nicholls et al (2011) and Squire et al (2012).
is often considered as a third division of the nervous system (Gershon
1998).
NEURONES
In the CNS, the cell bodies of neurones are often grouped together
in discrete areas termed nuclei, or they may form more extensive layers
or masses of cells; collectively they constitute the grey matter. Neuronal Most of the neurones in the CNS are either clustered into nuclei,
dendrites and synaptic contacts are mostly confined to areas of grey columns or layers, or dispersed within grey matter. Neurones in the PNS
matter and form part of its meshwork of neuronal and glial processes, are confined to ganglia. Irrespective of location, neurones share many
termed the neuropil. Their axons join bundles of nerve fibres that tend general features, which are discussed here in the context of central
to be grouped separately to form tracts. In the spinal cord, cerebellum, neurones. Special characteristics of ganglionic neurones and their adja-
cerebral cortices and some other areas, concentrations of tracts consti- cent tissues are discussed on page 57.
tute the white matter, so called because the axons are often ensheathed Neurones exhibit great variability in their size (cell bodies range
in lipid-rich sheaths of myelin, which is white when fresh (Fig. 3.1; see from 5 to 100 µm diameter) and shape (Spruston 2008). Their surface
Fig. 16.9). areas are extensive because most neurones display numerous branched
The PNS is composed of the efferent axons (fibres) of motor neu- cell processes. They usually have a rounded or polygonal cell body
rones situated inside the CNS, and the cell bodies of sensory neurones (perikaryon or soma). This is a central mass of cytoplasm that encloses
(grouped together as ganglia) and their afferent processes. Sensory cells a nucleus and gives off long, branched extensions with which most
in dorsal root ganglia give off both centrally and peripherally directed intercellular contacts are made. Typically, one of these processes, the
processes; there are no synapses on their cell bodies. Also included are axon, is much longer than the others, the dendrites (Fig. 3.2). Gener-
ganglionic neurones of the ANS, which receive synaptic contacts from ally, dendrites conduct electrical signals towards a soma whereas axons
the peripheral fibres of preganglionic autonomic neurones whose cell conduct impulses away from it.
bodies lie within the CNS. For further details of the organization of the Neurones can be classified according to the number and arrange-
nervous system, see Chapter 16. ment of their processes (Bota and Swanson 2007). Multipolar neurones
When the neural tube is formed during prenatal development (Sanes (Fig. 3.3) are common; they have an extensive dendritic tree that arises
et al 2011), its walls thicken greatly but do not completely obliterate either from a single primary dendrite or directly from the soma, and a
the cavity within. The latter remains in the spinal cord as the narrow single axon. Bipolar neurones, which typify neurones of the special
central canal and becomes greatly expanded in the brain to form a series sensory systems, have only a single dendrite that emerges from the soma
of interconnected cavities called the ventricular system. In the fore- and opposite the axonal pole. Unipolar neurones, which transmit general
hindbrains, parts of the neural tube roof do not generate neurones but sensation, e.g. dorsal root ganglion neurones, have a single short process
become thin, folded sheets of secretory tissue, which are invaded by that bifurcates into a peripheral and a central process. This arrangement
blood vessels and are called the choroid plexuses. The latter secrete arises by the fusion of the proximal axonal and dendritic processes of
cerebrospinal fluid (CSF), which fills the ventricles and subarachnoid a bipolar neurone during development, and so such neurones may also
spaces, and penetrates the intercellular spaces of the brain and spinal be termed pseudounipolar. Neurones may also be classified according
cord to create their interstitial fluid. The CNS has a rich blood supply, to whether their axons terminate locally on other neurones (interneu-
which is essential to sustain its high metabolic rate. The blood–brain rones), or transmit impulses over long distances, often to distinct ter-
barrier places considerable restrictions on the substances that are able ritories via defined tracts (projection neurones).
to diffuse from the blood stream into the neuropil. Neurones are postmitotic cells and, with few exceptions, they are not
Neurones encode information, conduct it over considerable dis- replaced when lost.
tances, and then transmit it to other neurones or to various non-neural
targets such as muscle cells. The propagation of this information within
the nervous system depends on rapid electrical signals, the action SOMA
potentials. Transmission to other cells is mediated by secretion of neu-
rotransmitters at special junctions, either with other neurones (syn- The plasma membrane of the soma is generally unmyelinated and
apses), or with cells outside the nervous system, e.g. muscle cells at is contacted by both inhibitory and excitatory axosomatic synapses;
neuromuscular junctions, gland cells or adipose tissue, and causes very occasionally, somasomatic and dendrosomatic contacts may be
changes in the behaviour of the target cells. made. The non-synaptic surface may contain gap junctions and is partly
The nervous system contains large populations of non-neuronal covered by either astrocytic or satellite oligodendrocyte processes.
cells, termed neuroglia or glia. These cells do not generate action poten- The cytoplasm of a typical soma (see Fig. 3.2) is rich in rough and
tials, but convey information encoded as transient changes in intracel- smooth endoplasmic reticulum and free polyribosomes, indicating
lular calcium concentration, termed calcium signalling. Glia interact a high level of protein synthetic activity. Free polyribosomes often | 87 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Nervous system
42.e1
3
RETPAHC
WM
GM
Fig. 3.1 A section through the human cerebellum stained to show the
arrangement in the brain of the central white matter (WM, deep pink) and
the highly folded outer grey matter (GM). In the cerebellum, GM consists
of an inner granular layer of tightly packed small neurones (blue) and an
outermost molecular layer (pale pink), where neuronal processes make
synaptic contacts. (Courtesy of Mr Peter Helliwell and the late Dr Joseph
Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust,
UK.) | 88 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Neurones
43
3
RETPAHC
tide subunits, NF-L (68 kDa), NF-M (160 kDa) and NF-H (200 kDa).
NF-M and NF-H have long C-terminal domains that project as side arms
from the assembled neurofilament and bind to neighbouring filaments.
They can be heavily phosphorylated, particularly in the highly stable
neurofilaments of mature axons, and are thought to give axons their
tensile strength. Some axons are almost filled by neurofilaments.
Soma Microtubules are important in axonal transport, although dendrites
Nucleolus usually have more microtubules than axons. Centrioles persist in
Nucleus mature postmitotic neurones, where they are concerned with the gen-
eration of microtubules rather than cell division. Centrioles are associ-
ated with cilia on the surfaces of developing neuroblasts. Their
significance, other than at some sensory endings (e.g. the olfactory
Axon hillock mucosa), is not known.
Pigment granules (Fig. 3.5) appear in certain regions, e.g. neurones
Dendrite of the substantia nigra contain neuromelanin, which is probably a
waste product of catecholamine synthesis. A similar pigment gives a
bluish colour to the neurones in the locus coeruleus. Some neurones
are unusually rich in metals, which may form components of enzyme
Axon systems, e.g. zinc in the hippocampus and iron in the red nucleus.
Ageing neurones, especially in spinal ganglia, accumulate granules of
Myelin sheath lipofuscin (senility pigment) in residual bodies, which are lysosomes
packed with partially degraded lipoprotein material.
DENDRITES
Axodendritic
synapse
Dendrites are highly branched, usually short processes that project from
Axosomatic the soma (see Fig. 3.2; Shah et al 2010). The branching patterns of many
synapse
dendritic arrays are probably established by random adhesive interac-
Axon collateral tions between dendritic growth cones and afferent axons that occur
during development. There is an overproduction of dendrites in early
Axo-axonal
synapse development, and this is pruned in response to functional demand as
the nervous system matures and information is processed through the
dendritic tree. There is evidence that dendritic trees may be plastic
structures throughout adult life, expanding and contracting as the traffic
of synaptic activity varies through afferent axodendritic contacts (for a
Synaptic
review, see Wong and Ghosh (2002)). Groups of neurones with similar
terminals
functions have a similar stereotypic tree structure (Fig. 3.6), suggesting
that the branching patterns of dendrites are important determinants of
the integration of the afferent inputs that converge on the tree. For a
Fig. 3.2 A schematic view of typical neurones featuring one with the review of current research on dendritic trees in the normal and patho-
soma cut away to show the nucleus and cytoplasmic organelles, dendritic logical brain, see Kulkarni and Firestein (2012).
trees with synaptic contacts, other types of synapse, the axon hillock and Dendrites differ from axons in many respects. They represent the
a myelinated axon.
afferent rather than the efferent system of the neurone, and receive both
excitatory and inhibitory axodendritic contacts. They may also make
dendrodendritic and dendrosomatic connections (see Fig. 3.9), some
congregate in large groups associated with the rough endoplasmic retic- of which are reciprocal. Synapses occur either on small projections
ulum. These aggregates of RNA-rich structures are visible by light micro- called dendritic spines or on the smooth dendritic surface. Dendrites
scopy as basophilic Nissl bodies or granules. They are distributed contain ribosomes, smooth endoplasmic reticulum, microtubules, neu-
throughout the cell body and large dendrites; the axon hillock is con- rofilaments, actin filaments and Golgi complexes. Their neurofilament
spicuously ribosome-free. Nissl bodies are more obvious in large, highly proteins are poorly phosphorylated and their microtubules express the
active cells, such as spinal motor neurones (Fig. 3.4), which contain microtubule-associated protein (MAP)-2 almost exclusively in compari-
large stacks of rough endoplasmic reticulum and polyribosome aggre- son with axons.
gates. Maintenance and turnover of cytoplasmic and membranous com- The shapes of dendritic spines range from simple protrusions to
ponents are necessary activities in all cells; the huge total volume of structures with a slender stalk and expanded distal end. Most spines are
cytoplasm within the soma and processes of many neurones requires a not more than 2 µm long, and have one or more terminal expansions;
considerable commitment of protein synthetic machinery. Neurones they can also be short and stubby, branched or bulbous. Large mush-
also synthesize other proteins (enzyme systems, G-protein coupled room spines are assumed to have differentiated in response to afferent
receptors, scaffold proteins) involved in the production of neurotrans- activity (‘memory spines’; Matsuzaki et al 2004). These large spines
mitters and in the reception and transduction of incoming stimuli. often contain a spine apparatus, an organelle consisting of small
Various transmembrane channel proteins and enzymes are located at sacs of endoplasmic reticulum interleaved by electron-dense bars (Gray
the surfaces of neurones, where they are associated with movements 1959, Segal et al 2010). Mouse mutants deficient in these organelles
of ions. show memory deficits (Deller et al 2003). Free ribosomes and polyri-
The nucleus is characteristically large and euchromatic, and contains bosomes are concentrated at the base of the spine. Ribosomal accumu-
at least one prominent nucleolus; these are features typical of all cells lations near synaptic sites provide a mechanism for activity-dependent
engaged in substantial levels of protein synthesis. The cytoplasm con- synaptic plasticity through the local regulation of protein synthesis.
tains many mitochondria and moderate numbers of lysosomes. Golgi
complexes are usually close to the nucleus, near the bases of the main
dendrites and opposite the axon hillock. AXONS
The neuronal cytoskeleton is a prominent feature of its cytoplasm
and gives shape, strength and support to the dendrites and axons. A The axon originates either from the soma or from the proximal segment
number of neurodegenerative diseases are characterized by abnormal of a dendrite at a specialized region free of Nissl granules, the axon
aggregates of cytoskeletal proteins (reviewed in Cairns et al (2004)). hillock (see Fig. 3.2). Action potentials are initiated here, at the junction
Neurofilaments (the intermediate filaments of neurones) and microtu- with the proximal axon (axon initial segment). The axonal plasma
bules are abundant in the soma and along dendrites and axons; the membrane (axolemma) is undercoated at the hillock by a concentration
proportions vary with the type of neurone and cell process. Bundles of of cytoskeletal molecules, including spectrin and actin fibrils, which are
neurofilaments constitute neurofibrils, which can be seen by light important in anchoring numerous voltage-sensitive channels to the
microscopy in silver-stained or immunolabelled sections. Neurofila- membrane. For details, see Bender and Trussell (2012), and for neural
ments are heteropolymers of proteins assembled from three polypep- electrophysiological techniques, see Sakmann and Neher (2009). The | 89 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
44
1
NOITCES
Sensory Integrative Motor
Dendrites
Apical
dendrites
Sensory endings
e.g. in skin Nissl bodies
in soma
Pyramidal cell
soma
Unipolar
neurone
Purkinje cell
soma
Basal Large motor
dendrites neurone
Axon
Axon
Soma
Peripheral Bipolar
axon neurone
Presynaptic
autonomic
neurone Axon
Soma
Soma
Axon
Soma
Postsynaptic
autonomic
neurone
Axon
Central
axon
Smooth muscle
Axon e.g intestine
Soma
Interneurone Interneurone
Axon
Striated (skeletal)
muscle
Fig. 3.3 The variety of shapes of neurones and their processes. The inset shows a human multipolar retinal ganglion cell, filled with fluorescent dye by
microinjection. (Inset, Courtesy of Drs Richard Wingate, James Morgan and Ian Thompson, King’s College, London.)
Fig. 3.5 Neurones in
the substantia nigra of
the human midbrain,
S showing cytoplasmic
granules of
neuromelanin pigment.
(Courtesy of Mr Peter
Helliwell and the late
Dr Joseph Mathew,
Department of
N Histopathology, Royal
G P Cornwall Hospitals
Trust, UK.)
P
Fig. 3.4 Spinal motor neurones (toluidine blue stained resin section, rat
tissue) showing a group of cell bodies (somata, S), some with the
proximal parts of axonal and dendritic processes (P) visible. Their nuclei
(N) typically have prominent, deeply staining nucleoli, indicative of
metabolically highly active cells; two are visible in the plane of section.
Nissl granules (G) are seen in the cytoplasm. Surrounding the neuronal
somata is the neuropil, consisting of the interwoven processes of these
and other neurones and of glial cells. | 90 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Neurones
45
3
RETPAHC
Fig. 3.6 A Purkinje role in Alzheimer’s disease (Cairns et al 2004): formation of tau oli-
neurone from the gomers and the subsequent pathological filament arrays are critical
cerebellum of a rat steps in the aetiopathogenesis of this condition. Neurofilament proteins
stained by the ranging from high to low molecular weights are highly phosphorylated
Golgi–Cox method, in mature axons, whereas growing and regenerating axons express a
showing the extensive calmodulin-binding membrane-associated phosphoprotein, growth-
two-dimensional array associated protein-43 (GAP-43), as well as poorly phosphorylated
of dendrites. (Courtesy
neurofilaments.
of Dr Martin Sadler and
Neurones respond differently to injury, depending on whether the
Professor M Berry,
damage occurs in the CNS or the PNS. The glial microenvironment of
Division of Anatomy
a damaged central axon does not facilitate axonal regrowth; conse-
and Cell Biology, GKT
quently, reconnection with original synaptic targets does not normally
School of Medicine,
occur. In marked contrast, the glial microenvironment in the PNS is
London.)
capable of facilitating axonal regrowth. However, functional outcome
of clinical repair of a large mixed peripheral nerve, especially if the
injury occurs some distance from the target organ, or produces a long
defect in the damaged nerve, is frequently unsatisfactory (Birch 2011;
see also Commentary 1.6).
Axoplasmic flow
Neuronal organelles and cytoplasm are in continual motion. Bidirec-
tional streaming of vesicles along axons results in a net transport of
materials from the soma to the terminals, with more limited movement
in the opposite direction. Two major types of transport occur, one slow
and one relatively fast. Slow axonal transport is a bulk flow of axoplasm
only in the anterograde direction, carrying cytoskeletal proteins and
soluble, non-membrane-bound proteins from the soma to the termi-
axon hillock is unmyelinated and often participates in inhibitory axo-
nals at a rate of approximately 0.1–3 mm a day. In contrast, fast axonal
axonal synapses. It is unique because it contains ribosomal aggregates
transport carries membrane-bound vesicular material (endosomes and
immediately below the postsynaptic membrane (Kole and Stuart 2012).
lysosomal autophagic vacuoles) and mitochondria at approximately
In the CNS, small, unmyelinated axons lie free in the neuropil,
200 mm a day in the retrograde direction (towards the soma) and
whereas in the PNS they are embedded in Schwann cell cytoplasm.
approximately 40 mm per day anterogradely (in particular, synaptic
Myelin, which is formed around almost all axons of >2 µm diameter
vesicles containing neurotransmitters).
by oligodendrocytes in the CNS and by Schwann cells in the PNS,
Rapid flow depends on microtubules. Vesicles with side projections
begins at the distal end of the axon hillock. Nodes of Ranvier are spe-
line up along microtubules and are transported along them by their
cialized regions of myelin-free axon where action potentials are gener-
side arms. Two microtubule-based motor proteins with adenosine 5′-
ated and where an axon may branch. In both CNS and PNS, the territory
triphosphatase (ATPase) activity are involved in fast transport: kinesin
of a myelinated axon between adjacent nodes is called an internode;
family proteins are responsible for the fast component of anterograde
the region close to a node, where the myelin sheath terminates, is called
transport, and cytoplasmic dynein is responsible for retrograde trans-
the paranode; and the region just beyond that is the juxtaparanode.
port. Retrograde transport mediates the movement of neurotrophic
Myelin thickness and internodal lengths are, in general, positively cor-
viruses, e.g. herpes zoster, rabies and polio, from peripheral terminals,
related with axon diameter. The density of sodium channels in the
and their subsequent concentration in the neuronal soma. It has been
axolemma is highest at nodes of Ranvier, and very low along internodal
suggested that specific pools of endocytic organelles, signalling endo-
membranes; sodium channels are spread more evenly within the axo-
somes, mediate the long-distance axonal transport of growth factors,
lemma of unmyelinated axons. Fast potassium channels are present in
such as neurotrophins and their signalling receptors. Defects in axonal
the paranodal regions of myelinated axons. Fine processes of glial cyto-
and dendritic transport have been linked to various neurodegenerative
plasm (astrocytic in the CNS, Schwann cell in the PNS) surround the
processes. See Guzik and Goldstein (2004), Hinckelmann et al (2013)
nodal axolemma.
and Schmieg et al (2014) for reviews of axonal transport in health and
The terminals of an axon are unmyelinated. Most expand into presy-
disease.
naptic boutons, which may form connections with axons, dendrites,
neuronal somata or, in the periphery, muscle fibres, glands and lym-
phoid tissue. Exceptions include the free afferent sensory endings in,
SYNAPSES
for example, the epidermis, which are unspecialized structurally, and
the peripheral terminals of afferent sensory fibres with encapsulated
Transmission of impulses across specialized junctions (synapses)
endings (see Fig. 3.27). Axon terminals contain abundant small clear
between two neurones is largely chemical and depends on the release
synaptic vesicles and large dense-core vesicles. The former contain a
of neurotransmitters from the presynaptic terminal. These neurotrans-
neurotransmitter (e.g. glutamate, γ-aminobutyric acid (GABA), acetyl-
mitters bind to cognate receptors in the postsynaptic neuronal mem-
choline) that is released into the synaptic cleft on the arrival of an action
brane, resulting in a change of membrane conductance and leading to
potential at the terminal and which then binds to cognate receptors on
either a depolarization or a hyperpolarization (Ryan and Grant 2009).
the postsynaptic membrane. Depending on the nature of the transmit-
The patterns of axonal termination vary considerably. A single axon
ter and its receptors, the postsynaptic neurone will become excited or
may synapse with one neurone (e.g. climbing fibres ending on cere-
inhibited. The dense-core vesicles contain neuropeptides, including
bellar Purkinje neurones), or more often with many neurones (e.g.
brain-derived neurotrophic factor (BDNF; Dieni et al 2012). Axon ter-
cerebellar parallel fibres, which provide an extreme example of this
minals may themselves be contacted by other axons, forming axo-
phenomenon). In synaptic glomeruli (e.g. in the olfactory bulb), groups
axonal presynaptic inhibitory circuits. Further details of neuronal
of synapses between two or many neurones form interactive units
microcircuitry are given in Kandel et al (2012) and Haines (2006).
encapsulated by neuroglia (Fig. 3.7; Perea et al 2009).
Axons contain microtubules, neurofilaments, mitochondria, mem-
Electrical synapses (direct communication via gap junctions) are rare
brane vesicles, cisternae and lysosomes. They do not usually contain
in the human CNS and are confined largely to groups of neurones with
ribosomes or Golgi complexes, other than at the axon hillock; excep-
tightly coupled activity, e.g. the inspiratory centre in the medulla. They
tionally, the neurosecretory fibres of hypothalamo-hypophysial neu-
will not be discussed further here.
rones contain the mRNA of neuropeptides. Organelles are differentially
distributed along axons, e.g. there is a greater density of mitochondria
Classification of chemical synapses
and membrane vesicles in the axon hillock, at nodes and in presynaptic
endings. Axonal microtubules are interconnected by cross-linking
MAPs, of which tau is the most abundant. Microtubules have an intrin- Chemical synapses have an asymmetric structural organization (Figs
sic polarity, and in axons all microtubules are uniformly orientated with 3.8–3.9) in keeping with the unidirectional nature of their transmis-
their rapidly growing ends directed away from the soma towards the sion. Typical chemical synapses share a number of important features.
axon terminal. The microtubule binding protein tau plays an important They all display an area containing a presynaptic density apposed to a | 91 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
46
1
NOITCES
Axon of Golgi cell Soma of granule cell corresponding postsynaptic density; the two are separated by a narrow
(20–30 nm) gap, the synaptic cleft. Synaptic vesicles containing the
appropriate neurotransmitter are found on the presynaptic side, clus-
tered near the presynaptic density at the presynaptic membrane.
Together these define the active zone, the area of the synapse where
neurotransmission takes place (Eggermann et al 2012, Gray 1959).
Chemical synapses can be classified according to a number of dif-
ferent parameters, including the neuronal regions forming the synapse,
their ultrastructural characteristics, the chemical nature of their
neurotransmitter(s) and their effects on the electrical state of the post-
synaptic neurone. The following classification is limited to associations
– between neurones. Neuromuscular junctions share many (though not
– all) of these parameters, and are often referred to as peripheral synapses.
+
They are described separately on page 63.
+ Synapses can occur between almost any surface regions of the par-
ticipating neurones. The most common type occurs between an axon
and either a dendrite or a soma, when the axon is expanded as a small
bulb or bouton (see Figs 3.8–3.9). This may be a terminal of an axonal
branch (terminal bouton) or one of a row of bead-like endings, when
the axon makes contact at several points, often with more than one
+ neurone (bouton de passage). Boutons may synapse with dendrites,
–
including thorny protrusions named dendritic spines or the flat surface
+
of a dendritic shaft; a soma (usually on its flat surface, but occasionally
on spines); the axon hillock; and the terminal boutons of other axons.
The connection is classified according to the direction of transmis-
sion, and the incoming terminal region is named first. Most common
are axodendritic synapses, although axosomatic connections are fre-
quent. All other possible combinations are found but are less common,
i.e. axo-axonal, dendro-axonal, dendrodendritic, somatodendritic or
somatosomatic. Axodendritic and axosomatic synapses occur in all
regions of the CNS and in autonomic ganglia, including those of
the ENS. The other types appear restricted to regions of complex inter-
action between larger sensory neurones and microneurones, e.g. in the
thalamus.
Neuroglial cell Mossy fibre Dendrite of Ultrastructurally, synaptic vesicles may be internally clear or dense,
axon terminal Golgi cell
and of different size (loosely categorized as small or large) and shape
Fig. 3.7 The arrangement of a complex synaptic unit. A cerebellar (round, flat or pleomorphic, i.e. irregularly shaped). The submembra-
synaptic glomerulus with excitatory (‘+’) and inhibitory (‘−’) synapses nous densities may be thicker on the postsynaptic than on the presyn-
grouped around a central axonal bouton. The directions of transmission aptic side (asymmetric synapses), or equivalent in thickness (symmetrical
are shown by the arrows. synapses), and can be perforated or non-perforated. Synaptic ribbons
Fig. 3.8 Electron micrographs demonstrating
various types of synapse. A, A cross-section of a
dendrite (D) on which two synaptic boutons (B)
end. The upper bouton contains round vesicles,
and the lower bouton contains flattened vesicles
of the small type. A number of pre- and
BB
postsynaptic (P) thickenings mark the specialized
zones of contact. B, A type I synapse
P BB (S, postsynaptic site) containing both small, round,
clear vesicles and also large, dense-cored vesicles
** of the neurosecretory type. C, A large terminal
bouton (B) of an optic nerve afferent fibre, which
DD is making contact with a number of postsynaptic
processes, in the dorsal lateral geniculate nucleus
BBff
of the rat. One of the postsynaptic processes (*)
also receives a synaptic contact from a bouton
PP
PP (Bf) containing flattened vesicles. D, Reciprocal
synapses (S) between two neuronal processes in
the olfactory bulb. (Courtesy of Professor AR
BB
Lieberman, Department of Anatomy, University
College, London.)
C
A
SS
SS
SS
B D | 92 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Neurones
47
3
RETPAHC
A Excitatory synapses Serial synapses B Axosomatic
synapses
Bouton With small With dense Excitatory Inhibitory
de passage clear spherical catecholamine- to dendrite axo-axonal
vesicles containing vesicles synapse
Capillary
Dendrite
Nucleus
C Ribbon synapse
Axo-initial segment
Retinal synapse
rod
With small With large Inhibitory to dendrite
flattened flattened Excitatory in opposite
vesicles vesicles direction
Neurosecretory
Inhibitory synapses Reciprocal synapse ending
Fig. 3.9 The structural arrangements of different types of synaptic contact.
are found at sites of neurotransmission in the retina and inner ear. They instances, types I and II synapses are found in close proximity, orien-
have a distinctive morphology, in that the synaptic vesicles are grouped tated in opposite directions across the synaptic cleft (a reciprocal
around a ribbon- or rod-like density orientated perpendicular to the synapse).
cell membrane (see Fig. 3.9).
Mechanisms of synaptic activity
Synaptic boutons make obvious close contacts with postsynaptic
structures but many other terminals lack specialized contact zones. Synaptic activation begins with arrival of one or more action potentials
Areas of transmitter release occur in the varicosities of unmyelinated at the presynaptic bouton, which causes the opening of voltage-sensitive
axons, where effects are sometimes diffuse, e.g. the aminergic pathways calcium channels in the presynaptic membrane. The response time in
of the basal ganglia, and in autonomic fibres in the periphery. In some typical fast-acting synapses is then very rapid; classic neurotransmitter
instances, such axons may ramify widely throughout extensive areas of (e.g. ACh, glutamate or GABA) is released in less than a millisecond.
the brain and affect the behaviour of very large populations of neu- Release-ready synaptic vesicles are docked to the presynaptic membrane
rones, e.g. the diffuse cholinergic innervation of the cerebral cortices. and primed through processes not yet fully understood. On Ca2+ influx
Pathological degeneration of these pathways can therefore cause wide- through voltage-sensitive channels, their membranes fuse to open a
spread disturbances in neural function. pore through which neurotransmitter diffuses into the synaptic cleft
Neurones express a variety of neurotransmitters, either as one class (Eggermann et al 2012; Gray 1959).
of neurotransmitter per cell or more often as several. Good correlations Once the vesicle has discharged its contents, its membrane is incor-
exist between some types of transmitter and specialized structural porated into the presynaptic plasma membrane and is then recycled
features of synapses. In general, asymmetric synapses with relatively back into the bouton by endocytosis near the edges of the active zone.
small spherical vesicles are associated with acetylcholine (ACh), gluta- The recycling time for a synaptic vesicle may be in the range of a few
mate, serotonin (5-hydroxytryptamine, 5-HT) and some amines; those seconds to minutes; newly recycled vesicles may be used instantly for
with dense-core vesicles include many peptidergic synapses and the next cycle of neurotransmitter release (cycling pool of vesicles). The
other amines (e.g. noradrenaline (norepinephrine), adrenaline (epine- fusion of vesicles with the presynaptic membrane is responsible for the
phrine), dopamine). Symmetrical synapses with flattened or pleomor- observed quantal behaviour of neurotransmitter release, both during
phic vesicles have been shown to contain either GABA or glycine. neural activation and spontaneously, in the slightly leaky resting condi-
Neurosecretory endings found in various parts of the brain and in tion (Neher and Sakaba 2008; Suedhof 2012).
neuroendocrine glands and cells of the dispersed neuroendocrine Postsynaptic events vary greatly, depending on the receptor mole-
system share many features with presynaptic boutons. They all contain cules and their related molecular complexes (Murakoshi and Yasuda
peptides or glycoproteins within dense-core vesicles. The latter are of 2012). Receptors are generally classed as either ionotropic or metabo-
characteristic size and appearance: they are often ellipsoidal or irregular tropic. Ionotropic receptors are multimeric protein complexes that
in shape, and relatively large, e.g. oxytocin and vasopressin vesicles in harbour intrinsic ion channels that can be operated by conformational
the neurohypophysis may be up to 200 nm in diameter. changes induced when neurotransmitter molecules bind the receptor
Synapses may cause depolarization or hyperpolarization of the post- complex, causing a voltage change within the postsynaptic cell. Exam-
synaptic membrane, depending on the neurotransmitter released and ples are the nicotinic ACh receptor and the related GABA A receptor,
the classes of receptor molecule in the postsynaptic membrane. Depo- which are formed from five subunits, and the tetrameric ionotropic
larization of the postsynaptic membrane results in excitation of the glutamate receptors, such as the N-methyl-D-aspartate (NMDA)
postsynaptic neurone, whereas hyperpolarization has the effect of tran- receptor or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
siently inhibiting electrical activity. Subtle variations in these responses (AMPA) receptor. Alternatively, the receptor and ion channel may be
may also occur at synapses where mixtures of neuromediators are separate molecules, coupled by G-proteins, some via a complex cascade
present and their effects are integrated. For details of the synaptic organ- of chemical interactions (a second messenger system), e.g. the adenylate
ization of the brain, see Shepherd (2003). cyclase pathway. Postsynaptic effects are generally rapid and short-lived,
because the transmitter is quickly inactivated either by an extracellular
Type I and II synapses
enzyme (e.g. acetylcholinesterase, AChE), or by uptake into neurones
There are two broad categories of synapse, type I and type II. In active or glial cells. Examples of such metabotropic receptors are the mus-
zones of type I synapses the cytoplasmic density is thicker on the post- carinic ACh receptor and the dopamine receptor.
synaptic side. In type II synapses the pre- and postsynaptic densities are
thinner and more symmetrical. Type I boutons contain a predominance Neurohormones
of small spherical vesicles approximately 50 nm in diameter, and type Neurohormones are included in the class of molecules with
II boutons contain oval or flattened vesicles. Throughout the CNS, type neurotransmitter-like activity. They are synthesized in neurones and
I synapses are generally excitatory and type II are inhibitory. In a few released into the blood circulation by exocytosis at synaptic bouton-like | 93 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
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NOITCES
structures. As with classic endocrine gland hormones, they may act at lie mainly in the brainstem, although their axons ramify widely into all
great distances from their site of secretion. Neurones secrete into the parts of the nervous system. Monoaminergic cells are also present in
CSF or local interstitial fluid to affect other cells, either diffusely or at the retina.
a distance. To encompass this wide range of phenomena the general Noradrenaline is the chief transmitter present in sympathetic gangli-
term neuromediation has been used, and the chemicals involved are onic neurones with endings in various tissues, notably smooth muscle
called neuromediators. and glands, and in other sites including adipose and haemopoietic
tissues and the corneal epithelium. It is also found at widely distributed
Neuromodulators synaptic endings within the CNS, many of them the terminals of neu-
Some neuromediators do not appear to affect the postsynaptic mem- ronal somata situated in the locus coeruleus in the medullary floor. The
brane directly but they can affect its responses to other neuromediators, actions of noradrenaline depend on its site of action and vary with the
either enhancing their activity (by increasing or prolonging the immedi- type of postsynaptic receptor, e.g. it strongly inhibits neurones of
ate response), or perhaps limiting or inhibiting their action. These the submucosal plexus of the intestine and of the locus coeruleus via
substances are called neuromodulators. A single synaptic terminal may α 2-adrenergic receptors, whereas it mediates depolarization, producing
contain one or more neuromodulators in addition to a neurotransmit- vasoconstriction, via β-receptors in vascular smooth muscle. Adrenaline
ter, usually (though not always) in separate vesicles. Neuropeptides (see is present in central and peripheral nervous pathways and occurs
below) are nearly all neuromodulators, at least in some of their actions. with noradrenaline in the suprarenal medulla. Both adrenaline and
They are stored within dense granular synaptic vesicles of various sizes noradrenaline are found in dense-cored synaptic vesicles approximately
and appearances. 50 nm in diameter.
Dopamine is a neuromediator of considerable clinical importance,
Development and plasticity of synapses found mainly in neurones with cell bodies in the telencephalon,
diencephalon and mesencephalon. A major dopaminergic neuronal
population in the midbrain constitutes the substantia nigra, so called
Embryonic synapses first appear as inconspicuous dense zones flanking
because its cells contain neuromelanin, a black granular by-product
synaptic clefts. Immature synapses often appear after birth, suggesting
of dopamine synthesis. Dopaminergic endings are particularly numer-
that they may be labile, and are reinforced if transmission is function-
ous in the corpus striatum, limbic system and cerebral cortex. Structur-
ally effective, or withdrawn if redundant. This is implicit in some theo-
ally, dopaminergic synapses contain numerous dense-cored vesicles
ries of memory (Squire and Kandel 2008), which postulate that synapses
that resemble those containing noradrenaline. Pathological reduction
are modifiable by frequency of use, to establish preferential conduction
in dopaminergic activity has widespread effects on motor control,
pathways. Evidence from hippocampal neurones suggests that even
affective behaviour and other neural activities, as seen in Parkinson’s
brief synaptic activity can increase the strength and sensitivity of the
syndrome.
synapse for some hours or longer (long-term potentiation, LTP). During
Serotonin and histamine are found in neurones mainly within the
early postnatal life, the normal developmental increase in numbers and
CNS. Serotonin is typically synthesized in small midline neuronal clus-
sizes of synapses and dendritic spines depends on the degree of neural
ters in the brainstem, mainly in the raphe nuclei; the axons from these
activity and is impaired in areas of damage or functional deprivation.
neurones ramify extensively throughout the entire brain and spinal
cord. Synaptic terminals contain rounded, clear vesicles approximately
Neurotransmitter molecules 50 nm in diameter and are of the asymmetrical type. Histaminergic
neurones appear to be relatively sparse and are restricted largely to the
Until recently, the molecules known to be involved in chemical syn- hypothalamus.
apses were limited to a fairly small group of classic neurotransmitters,
Amino acids
e.g. ACh, noradrenaline (norepinephrine), adrenaline (epinephrine),
dopamine and histamine, all of which had well-defined rapid effects There are three major amino acids: GABA, glutamate and glycine, which
on other neurones, muscle cells or glands. However, many synaptic bind to specific receptors (Barrera and Edwardson 2008). GABA is a
interactions cannot be explained on the basis of classic neurotransmit- major inhibitory transmitter released at the terminals of local circuit
ters, and it is now known that other substances, particularly some neurones within the brainstem and spinal cord (e.g. the recurrent inhib-
amino acids such as glutamate, glycine, aspartate, GABA and the itory Renshaw loop), cerebellum (where it is the main transmitter of
monoamine, serotonin, also function as transmitters. Substances first Purkinje cells), basal ganglia, cerebral cortex, thalamus and subthala-
identified as hypophysial hormones or as part of the dispersed neuroen- mus. It is stored in flattened or pleomorphic vesicles within symmetrical
docrine system (see below) of the alimentary tract, can be detected synapses. GABA may be inhibitory to postsynaptic neurones, or may
widely throughout the CNS and PNS, often associated with functionally mediate either presynaptic inhibition or facilitation, depending on the
integrated systems. Many of these are peptides; more than one hundred synaptic arrangement (Gassmann and Bettler 2012).
(together with other candidates) function mainly as neuromodulators Glutamate is the major excitatory transmitter present widely within
and influence the activities of classic transmitters. the CNS, including the major projection pathways from the cortex to
the thalamus, tectum, substantia nigra and pontine nuclei. It is found
Acetylcholine in the central terminals of the auditory and trigeminal nerves, and in
Acetylcholine (ACh) is perhaps the most extensively studied neuro- the terminals of parallel fibres ending on Purkinje cells in the cerebel-
transmitter of the classic type. Its precursor, choline, is synthesized in lum. Structurally, glutamate is associated with asymmetrical synapses
the neuronal soma and transported to the axon terminals, where it is containing small (approximately 30 nm), round, clear synaptic vesicles
acetylated by the enzyme choline acetyl transferase (ChAT), and stored (Contractor et al 2011). For further reading, see Willard and Koochek-
in clear spherical vesicles 40–50 nm in diameter. ACh is synthesized by pour (2013).
motor neurones and released at all their motor terminals on skeletal Glycine is a well-established inhibitory transmitter of the CNS, par-
muscle. It is released by preganglionic fibres at synapses in parasympa- ticularly the lower brainstem and spinal cord, where it is mainly found
thetic and sympathetic ganglia, and many parasympathetic, and some in local circuit neurones. Recent evidence suggests that glycine may also
sympathetic, ganglionic neurones are cholinergic. ACh is also associ- be released from glutamatergic axon terminals to participate in activa-
ated with the degradative extracellular enzyme AChE, which inactivates tion of NMDA receptors, and from astrocytes into the synaptic cleft via
the transmitter by converting it to choline. activation of non-NMDA-type glutamatergic ionotropic receptors in
The effects of ACh on nicotinic receptors (i.e. those in which nicotine the glial cell membrane (see Harsing and Matyus (2013) for further
is an agonist) are rapid and excitatory. In the CNS, the nicotinic ACh references).
receptor mediates the effect of tobacco (for review, see Albuquerque
ATP and adenosine
et al (2009)). In the peripheral autonomic nervous system, the slower,
more sustained excitatory effects of cholinergic autonomic endings are ATP serves not only as a universal energy substrate, but also as an extra-
mediated by muscarinic receptors via a second messenger system. cellular signalling molecule. Specific ionotropic (P2X) and metabo-
tropic (P2Y) receptors are expressed in neurones and even more
Monoamines
prominently on all types of glial cell. Adenosine is a degradation
Monoamines include the catecholamines (noradrenaline (norepine- product of ATP and has specific metabotropic receptors that may be
phrine), adrenaline (epinephrine) and dopamine), the indoleamine located presynaptically (Burnstock et al 2011).
serotonin (5-hydroxytryptamine, 5-HT) and histamine (Haas et al
Nitric oxide
2008). They are synthesized by neurones in sympathetic ganglia and by
their homologues, the chromaffin cells of the suprarenal medulla and Nitric oxide (NO) is of considerable importance at autonomic and
paraganglia. Within the CNS, the somata of monoaminergic neurones enteric synapses, where it mediates smooth muscle relaxation. It | 94 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Central glia
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RETPAHC
functions in several types of synaptic plasticity, including hippocampal Subpial end-foot Neurone Tanycyte
long-term potentiation (LTP), when it may act as a retrograde messen- Perineuronal
Pia mater Astrocyte end-foot Microglial cell Ependymal cellVentricle
ger after postsynaptic NMDA receptor activation. NO is able to diffuse
freely through cell membranes, and so is not under such tight quantal
control as vesicle-mediated neurotransmission.
Neuropeptides
Many neuropeptides coexist with other neuromediators in the same
synaptic terminals. As many as three peptides often share a particular
ending with a well-established neurotransmitter, in some cases within
the same synaptic vesicles. Some peptides occur in both the CNS and
the PNS, particularly in the ganglion cells and peripheral terminals
of the ANS, whilst others are entirely restricted to the CNS. Only a
few examples are given here.
Most of the neuropeptides are classified according to the site where
they were first discovered. For example, the gastrointestinal peptides
were initially found in the gut wall, and a group that includes releasing
hormones, adenohypophysial and neurohypophysial hormones was Myelinated Oligodendrocyte Capillary Pericapillary Astrocyte
axon end-foot
first associated with the pituitary gland. Some of these peptides are
Fig. 3.10 The different types of non-neuronal cell in the CNS and their
closely related to each other in their chemistry because they are derived
structural organization and interrelationships with each other and with
from the same gene products (e.g. the pro-opiomelanocortin group),
neurones.
which are cleaved to produce smaller peptides.
Substance P (SP) was the first of the peptides to be characterized as
a gastrointestinal neuromediator and is considered to be the proto-
typic neuropeptide. It is an 11-amino-acid polypeptide that belongs to
ASTROCYTES
the tachykinin neuropeptide family, and is a major neuromediator in
the brain and spinal cord. Contained within large granular synaptic
Astrocytes are the most abundant and diverse glial cell type but their
vesicles, SP is found in approximately 20% of dorsal root and trigemi-
identity is not well defined (Matyash and Kettenmann 2010). There is
nal ganglion cells, in particular in small nociceptive neurones, and in
no common marker that labels all astrocytes, in the way that myelin
some fibres of the facial, glossopharyngeal and vagal nerves. Within
basic protein is a marker for oligodendrocytes or the calcium-binding
the CNS, SP is present in several apparently unrelated major pathways,
protein Iba1 is a marker for microglia. A commonly used marker is the
and has been described in the limbic system, basal ganglia, amygdala
expression of glial fibrillary acidic protein (GFAP), which forms inter-
and hypothalamus. Its known action is prolonged postsynaptic
mediate filaments, but GFAP is not expressed in all astrocytes.
excitation, particularly from nociceptive afferent terminals, which sus-
The morphology of astrocytes is extremely diverse. Classically, two
tains the effects of noxious stimuli. SP is one of the main neuropep-
forms were distinguished: protoplasmic and fibrous astrocytes. Proto-
tides that trigger an inflammatory response in the skin and has
plasmic astrocytes (star-shaped cells) are found in grey matter, possess
also been implicated in the vomiting reflex, changes in cardiovascular
several stem processes that branch further into a very complex network,
tone, stimulation of salivary secretion, smooth muscle contraction,
and contact synapses, both at the pre- and postsynaptic membranes.
and vasodilation.
Fibrous astrocytes are predominantly found in white matter and their
Vasoactive intestinal polypeptide (VIP), another gastrointestinal
processes are often orientated in parallel with the axons. Radial glial
peptide, is widely present in the CNS, where it is probably an excitatory
cells are found early in development and serve as stem cells for neu-
neurotransmitter or neuromodulator. It is found in distinctive bipolar
rones and glial cells. They may be categorized as astrocytes because they
neurones of the cerebral cortex; small dorsal root ganglion cells, par-
transform later in development into typical astrocytes. There are a
ticularly of the sacral region; the median eminence of the hypothala-
number of other types of astrocyte with specialized morphologies. Berg-
mus, where it may be involved in endocrine regulation; intramural
mann glial cells in the cerebellum have somata in the Purkinje cell layer,
ganglion cells of the gut wall; and sympathetic ganglia.
processes that intermingle with the dendritic trees of the Purkinje
Somatostatin (ST, somatotropin release inhibiting factor) has a
neurones and terminal end-feet at the pial surface. Müller cells in the
broad distribution within the CNS, and may be a central neurotransmit-
retina have a radial morphology and span the entire retina. Other
ter or neuromodulator. It also occurs in small dorsal root ganglion cells.
astrocytic cells are tanycytes, velate astrocytes (cerebellum) and pitui-
Beta-endorphin, leu- and metenkephalins, and the dynorphins belong
cytes (infundibulum and neurohypophysis of the pituitary gland).
to a group of peptides called the naturally occurring opiates that possess
Pituicyte processes end mostly on endothelial cells in the neurohypo-
analgesic properties. They bind to opiate receptors in the brain where,
physis and tuber cinereum.
in general, their action seems to be inhibitory. Enkephalins have been
Astrocyte complexity and morphological diversity has reached the
localized in many areas of the brain. Their particular localization in the
highest evolutionary level in humans (Fig. 3.11). A single astrocyte may
septal nuclei, amygdaloid complex, basal ganglia and hypothalamus
enwrap several neuronal somata and make contacts with tens of thou-
suggests that they are important mediators in the limbic system and in
sands of individual synapses; bipolar astrocytes located in layer 5 and
the control of endocrine function. They have also been implicated
6 of the cortex may extend processes up to 1 mm long.
strongly in the central control of pain pathways, because they are found
Astrocytes in grey matter form a syncytium in which cells are inter-
in the peri-aqueductal grey matter of the midbrain, a number of reticu-
connected by gap junctions, permitting the exchange of ions (e.g.
lar raphe nuclei, the spinal nucleus of the trigeminal nerve and the
calcium, propagated in waves) and small molecules such as ATP or
substantia gelatinosa of the spinal cord. The enkephalinergic pathways
glucose. They are the only cells in the brain capable of converting
exert an important presynaptic inhibitory action on nociceptive affer-
glucose into glycogen, which serves as an energy store. Before re-releasing
ents in the spinal cord and brainstem. Like many other neuromediators,
glucose, astrocytes convert it to lactate, which is taken up by neurones;
enkephalins also occur widely in other parts of the brain in lower
failure in glucose flow through the astrocytic network results in impair-
concentrations.
ment of neuronal function.
Astrocytes not only respond to neuronal activity but also modulate
that activity. They enwrap all penetrating and intracerebral arterioles
CENTRAL GLIA
and capillaries, control the ionic and metabolic environment of the
neuropil and mediate neurovascular coupling. They form specialized
Glial (neuroglial) cells (Fig 3.10) vary considerably in type and number structures that contact either the pial surface (as the glia limitans) or
in different regions of the CNS. There are two major groups, macroglia blood vessels; their end-feet entirely enwrap blood vessels and are
(astrocytes and oligodendrocytes) and microglia, classified according to instrumental in the induction of the blood–brain barrier.
origin. Macroglia arise within the neural plate, in parallel with neu- Traumatic injury to the CNS induces astrogliosis, seen as a local
rones, and constitute the great majority of glial cells. Their functions increase in the number and size of GFAP-positive cells and a character-
are diverse and are now known to extend beyond a passive supporting istic extensive meshwork of processes. The microenvironment of this
role (reviewed in Kettenmann and Ransom (2012)). Microglia have a glial scar, which may also include cells of oligodendrocyte lineage and
small soma (see Fig. 3.19) and are derived from a distinct lineage of myelin debris, plays an important role in inhibiting regrowth of
monocytic cells originating from the yolk sac. damaged CNS axons (Robel et al 2011, Seifert et al 2006). | 95 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Nervous system
49.e1
3
RETPAHC
Astrocytes control the diameter of the vessels they contact and can
trigger either their dilation or their contraction, depending on the sub-
stances they release and the levels of associated neuronal activity. They
express water channels (aquaporins) at the end-feet covering the capil-
laries; it has been suggested that this may represent the means by which
astrocytes control brain volume (Tait et al 2008), and it may be relevant
to understanding mechanisms of brain tissue swelling, a major clinical
complication. Astrocytes express different glutamate transporters that
efficiently maintain low levels of extracellular glutamate, which is
excitotoxic. Internalized glutamate is converted into glutamine and
released from astrocytes to be taken up by local neurones and recon-
verted to glutamate via the glutamate–glutamine cycle. They play a
similar role in controlling extracellular GABA levels via expression of
GABA transporters. Astrocytes possess both passive and active mecha-
nisms to control extracellular potassium levels at a resting level of about
3 mmol. They also express transporters that regulate pH and are thought
to play an important role in controlling extracellular pH in the brain.
For further reading on the concept of the ‘tripartite synapse’, where
astrocytic processes interact with pre- and postsynaptic neuronal ele-
ments, see Haydon and Carmignoto (2006).
It has become evident that astrocytes are involved in the modulation
of long-term potentiation (considered as a cellular mechanism of
memory formation) and heterosynaptic depression. They modulate
neuronal activity by releasing neuroactive substances such as D-serine,
ATP or glutamate; it is unclear whether they express all the elements
required for neurotransmitter release by a vesicular mechanism (Parpura
and Zorec 2010). | 96 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
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NOITCES
Fig. 3.11 Human protoplasmic astrocytes are
larger and more complicated than their rodent
counterparts. A, A typical mouse protoplasmic
astrocyte. Glial fibrillary acidic protein (GFAP)
immunostain; white. SB = 20 µm. B, A typical
human protoplasmic astrocyte to the same scale.
SB = 20 µm. (From Oberheim NA, Takano T, Han
X, et al 2009 Uniquely hominid features of adult
human astrocytes. J Neurosci 29:3276–87.)
A B
A which means that a free exchange of molecules occurs between blood
and adjacent brain. Most of these areas are situated close to the ventri-
cles and are known as circumventricular organs; these areas make up
Astrocyte end-foot
less than 1% of the total area of the brain. Elsewhere, unrestricted
Basal lamina diffusion through the blood–brain barrier is only possible for sub-
stances that can cross biological membranes because of their lipophilic
Pia mater character. Lipophilic molecules may be actively re-exported by the
(larger vessels only) brain endothelium.
Breakdown of the blood–brain barrier occurs when the brain is
Pericyte under damaged by ischaemia or infection, and is also associated with primary
the basal lamina and metastatic cerebral tumours. Reduced blood flow to a region of the
brain alters the permeability and regulatory transport functions of the
barrier locally; the increased stress on compromised endothelial cells
results in leakage of fluid, ions, serum proteins and intracellular sub-
stances into the extracellular space of the brain. The integrity of the
barrier can be evaluated clinically using computed tomography and
B functional magnetic resonance imaging. Breakdown of the blood–brain
barrier may be seen at postmortem in jaundiced patients who have had
Pericyte Astrocyte an infarction. Normally, the brain, spinal cord and peripheral nerves
end-foot remain unstained by the bile post mortem, although the choroid plexus
Perivascular cell is often stained a deep yellow. However, areas of recent infarction (1–3
(macrophage) days) will also be stained by bile pigment because of the localized
breakdown of the blood–brain barrier.
OLIGODENDROCYTES
Endothelium
Oligodendrocytes myelinate CNS axons and are most commonly seen
as intrafascicular cells in myelinated tracts (Figs 3.13–3.14). They
Basal lamina usually have round nuclei and their cytoplasm contains numerous
mitochondria, microtubules and glycogen. They display a spectrum of
Fig. 3.12 The relationship between the glia limitans, perivascular cells morphological variation, from cells with large euchromatic nuclei and
and blood vessels within the brain, in longitudinal (A) and transverse pale cytoplasm, to cells with heterochromatic nuclei and dense cyto-
(B) sections. A sheath of astrocytic end-feet wraps around the vessel and, plasm. In contrast to Schwann cells, which myelinate only one axonal
in vessels larger than capillaries, its investment of pial meninges. Vascular segment, individual oligodendrocytes myelinate up to 50 axonal seg-
endothelial cells are joined by tight junctions and supported by pericytes; ments. Some oligodendrocytes are not associated with axons, and are
perivascular macrophages lie outside the endothelial basal lamina (light either precursor cells or perineuronal (satellite) oligodendrocytes with
blue). processes that ramify around neuronal somata.
Within tracts, interfascicular oligodendrocytes are arranged in long
rows interspersed at regular intervals with single astrocytes. Since oli-
Blood–brain barrier
godendrocyte processes are radially aligned to the axis of each row,
myelinated tracts typically consist of cables of axons myelinated by a
Proteins circulating in the blood enter most tissues of the body except row of oligodendrocytes running down the axis of each cable.
those of the brain, spinal cord and peripheral nerves. This concept of a Oligodendrocytes originate from the ventricular neurectoderm and
blood–brain or a blood–nerve barrier applies to many substances – the subependymal layer in the fetus, and continue to be generated from
some are actively transported across the blood–brain barrier, others are the subependymal plate postnatally. Stem cells migrate and seed into
actively excluded. The blood–brain barrier is located at the capillary white and grey matter to form a pool of adult progenitor cells, which
endothelium within the brain and is dependent on the presence of tight can later differentiate to replenish defunct oligodendrocytes, and pos-
junctions (occluding junctions, zonulae adherentes) between endothe- sibly remyelinate axons in pathologically demyelinated regions. These
lial cells coupled with a relative lack of transcytotic vesicular transport. cells display a highly branching morphology and express a specific
The tightness of the barrier is substantially supported by the close chondroitin sulphate proteoglycan (Neuron Glia 2 (NG2) in rats and
apposition of astrocytes, which direct the formation of endothelial tight its homologue, melanoma cell surface chondroitin sulphate proteo-
junctions, to blood capillaries (reviewed in Abbott et al (2006), Cardoso glycan (MSCP), in humans). The name NG2 cell is used to describe the
et al (2010); Fig. 3.12). cells in both species: several different names have also been used since
The blood–brain barrier develops during embryonic life but may it was first recognized, including polydendrocyte (Nishiyama et al
not be fully completed by birth. There are certain areas of the adult 2009) and syantocyte (Butt et al 2005). NG2 cells express a complex
brain where the endothelial cells are not linked by tight junctions, set of voltage-gated channels and ionotropic receptors for glutamate | 97 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Central glia
51
3
RETPAHC
Oligodendrocyte Lateral loop
Node of Ranvier Nucleus Outer loop
A
N
Fig. 3.15 A node of Ranvier (N) in the central nervous system of a rat.
The pale-staining axon (A) is ensheathed by oligodendrocyte myelin
(arrow), apart from a short, exposed region at the node. Toluidine blue
stained resin section. (Courtesy of Dr Clare Farmer, King’s College,
London.)
and GABA; they form direct synapses with axons, enabling transient
activation of these receptors (Hill and Nishiyama 2014). There is con-
siderable support for the view that the NG2 cell is a distinct glial type.
Nodes of Ranvier and incisures of
Schmidt–Lanterman
The territory ensheathed by an oligodendrocyte (or Schwann cell)
process defines an internode, the interval between internodes is called
a node of Ranvier (Fig. 3.15) and the territory immediately adjacent to
the nodal gap is a paranode, where loops of oligodendrocyte cytoplasm
Axon Longitudinal Inner loop Myelin sheath abut the axolemma. Nodal axolemma is contacted by fine filopodia of
incisures perinodal cells, which have been shown in animal studies to have a
Fig. 3.13 The ensheathment of a number of axons by the processes of presumptive adult oligodendrocyte progenitor phenotype; their func-
an oligodendrocyte. The oligodendrocyte soma is shown in the centre tion is unknown. Schmidt–Lanterman incisures are helical decompac-
and its myelin sheaths are unfolded to varying degrees to show their tions of internodal myelin where the major dense line of the myelin
extensive surface area. (Modified from Morell P, Norton WT (1980, May). sheath splits to enclose a spiral of oligodendrocyte cytoplasm. Their
Myelin, Scientific American, 242(5), 88–90, 92, 96 and Raine CS (1984),
structure suggests that they may play a role in the transport of molecules
Morphology of Myelin and Myelination. In Myelin, 2nd ed. P Morell (ed)
across the myelin sheath, but their function is not known.
New York (Plenum Press), by permission.)
MYELIN AND MYELINATION
Myelin is formed by oligodendrocytes (CNS) and Schwann cells (PNS).
A single oligodendrocyte may ensheathe up to 50 separate axon seg-
ments, depending on calibre, whereas myelinating Schwann cells
ensheathe axons on a 1 : 1 basis.
In general, myelin is laid down around axons above 2 µm in diam-
eter. However, the critical minimal axon diameter for myelination is
smaller and more variable in the CNS than in the PNS (approximately
0.2 µm in the CNS compared with 1–2 µm in the PNS). There is con-
siderable overlap between the size of the smallest myelinated and the
largest unmyelinated axons, and so axonal calibre is unlikely to be the
only factor in determining myelination. Moreover, the first axons to
become ensheathed ultimately attain larger diameters than those that
are ensheathed at a later date. There is a reasonable linear relationship
between axon diameter and internodal length and myelin sheath thick-
ness: as the sheath thickens from a few lamellae to up to 200, the axon
may also grow from 1 to 15 µm in diameter. Internodal lengths increase
A about 10-fold during the same time (Nave 2010).
It is not known precisely how myelin is formed in either PNS or
CNS. Akt/mTOR (mammalian (or mechanistic) target of rapamycin)
signalling has emerged as one of the major pathways involved in myeli-
nation; it has been implicated in the regulation of several steps during
the development of myelinating Schwann cells and oligodendrocytes
(Norrmén and Suter 2013). In the CNS, myelination also depends in
part on expression of a protein (Wiskott–Aldrich syndrome protein
B family verprolin homologous; WAVE), which influences the actin
cytoskeleton, oligodendrocyte lamellipodia formation and myelination
Fig. 3.14 A, An oligodendrocyte enwrapping several axons with myelin, (Kim et al 2006). The ultrastructural appearance of myelin is usually
demonstrated in a whole-mounted rat anterior medullary velum, explained in terms of the spiral wrapping of an extensive, flat glial
immunolabelled with antibody to an oligodendrocyte membrane antigen. process (lamellipodium) around an axon, and the subsequent extrusion
B, A confocal micrograph of a mature myelin-forming oligodendrocyte in of cytoplasm from the sheath at all points other than incisures and
an adult rat optic nerve, iontophoretically filled with an immunofluorescent paranodes. In this way, the compacted external surfaces of the plasma
dye by intracellular microinjection. (A, Courtesy of Fiona Ruge. membrane of the ensheathing glial cell are thought to produce the
B, Prepared by Professor A Butt, Portsmouth, and Kate Colquhoun, minor dense lines, and the compacted inner cytoplasmic surfaces, the
formerly Division of Physiology, GKT School of Medicine, London.) major dense lines, of the mature myelin sheath (Fig. 3.16). These lines,
first described in early electron microscope studies of the myelin sheath,
correspond to the intraperiod and period lines respectively, defined in
X-ray studies of myelin. The inner and outer zones of occlusion of the
spiral process are continuous with the minor dense line and are called | 98 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
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NOITCES
Fig. 3.16 Suggested stages in
myelination of a peripheral axon by an
ensheathing Schwann cell.
Schwann cell Basal Inner Outer
cytoplasm lamina mesaxon mesaxon Axon
the inner and outer mesaxons. For further reading on aspects of myeli-
nation, see Bakhti et al (2013). V
There are significant differences between central and peripheral
myelin, reflecting the fact that oligodendrocytes and Schwann cells
express different proteins during myelinogenesis. The basic dimensions
of the myelin membrane are different. CNS myelin has a period repeat C
thickness of 15.7 nm whereas PNS myelin has a period to period line
E
thickness of 18.5 nm, and the major dense line space is approximately
1.7 nm in CNS myelin, compared with 2.5 nm in PNS myelin. Myelin
membrane contains protein, lipid and water, which forms at least 20%
of the wet weight. It is a relatively lipid-rich membrane and contains SVZ
70–80% lipid. All classes of lipid have been found; perhaps not surpris-
ingly, the precise lipid composition of PNS and CNS myelin is different.
The major lipid species are cholesterol (the most common single mol-
ecule), phospholipids and glycosphingolipids. Minor lipid species
include galactosylglycerides, phosphoinositides and gangliosides. The
major glycolipids are galactocerebroside and its sulphate ester, sul- Fig. 3.17 Ciliated columnar epithelial lining of the lateral ventricle (V),
phatide; these lipids are not unique to myelin but they are present overlying the subventricular zone (SVZ). C, cilia; E, ependymal cells.
in characteristically high concentrations. CNS and PNS myelin also Mouse tissue, toluidine blue stained resin section.
contain low concentrations of acidic glycolipids, which constitute
important antigens in some inflammatory demyelinating states. Gan-
gliosides, which are glycosphingolipids characterized by the presence ependymal lining of the ventricles but four major types have been
of sialic acid (N-acetylneuraminic acid), account for less than 1% of the described. These are: general ependymal, which overlies grey matter;
lipid in myelin. general ependymal, which overlies white matter; specialized areas of
A relatively small number of protein species account for the majority ependyma in the third and fourth ventricles; and choroidal epithelium.
of myelin protein. Some of these proteins are common to both PNS The ependymal cells overlying areas of grey matter are cuboidal.
and CNS myelin, but others are different. Proteolipid protein (PLP) Each cell bears approximately 20 central apical cilia, surrounded by
and its splice variant DM20 are found only in CNS myelin, whereas short microvilli. The cells are joined by gap junctions and desmosomes.
myelin basic protein (MBP) and myelin associated glycoprotein (MAG) Beneath them there may be a subependymal (or subventricular) zone,
occur in both. MAG is a member of the immunoglobulin supergene from two to three cells deep, consisting of cells that generally resemble
family, and is localized specifically at those regions of the myelin ependymal cells. In rodents, the subventricular zone contains neural
segment where compaction starts: namely, the mesaxons and inner progenitor cells, which can give rise to new neurones, but the existence
periaxonal membranes, paranodal loops and incisures, in both CNS of these stem cells in the adult human brain is controversial (Sanai et al
and PNS sheaths. It is thought to have a functional role in membrane 2011, Kempermann 2011). The capillaries beneath the ependymal cells
adhesion. have no fenestrations and few transcytotic vesicles, which is typical of
In the developing CNS, axonal outgrowth precedes the migration of the CNS. Where the ependyma overlies myelinated tracts of white
oligodendrocyte precursors, and oligodendrocytes associate with and matter, the cells are much flatter and few are ciliated. There are gap
myelinate axons after their phase of elongation; oligodendrocyte myelin junctions and desmosomes between these cells, but their lateral margins
gene expression is not dependent on axon association. In marked con- interdigitate, unlike their counterparts overlying grey matter. No sub-
trast, Schwann cells in the developing PNS are associated with axons ependymal zone is present.
during the entire phase of axonal growth. Myelination does not occur Specialized areas of ependymal cells called the circumventricular
simultaneously in all parts of the body in late fetal and early postnatal organs are found in four areas around the margins of the third ventricle:
development. White matter tracts and nerves in the periphery have their namely, the lining of the median eminence of the hypothalamus; the
own specific temporal patterns that relate to their degree of functional subcommissural organ; the subfornical organ; and the vascular organ
maturity. of the lamina terminalis. The area postrema, at the inferoposterior limit
Mutations of the major myelin structural proteins have now been of the fourth ventricle, has a similar structure. In all of these sites the
recognized in a number of inherited human neurological diseases. As ependymal cells are only rarely ciliated and their ventricular surfaces
would be expected, these mutations produce defects in myelination and bear many microvilli and apical blebs. They have numerous mitochon-
in the stability of nodal and paranodal architecture that are consistent dria, well-formed Golgi complexes and rather flattened basal nuclei.
with the suggested functional roles of the relevant proteins in maintain- They are joined laterally by tight junctions, which form a barrier to the
ing the integrity of the myelin sheath. passage of materials across the ependyma, and by desmosomes. Many
of the cells are tanycytes (ependymal astrocytes) and have basal
processes that project into the perivascular space surrounding the
EPENDYMA underlying capillaries. Significantly, these capillaries are fenestrated and
therefore do not form a blood–brain barrier. It is believed that neu-
Ependymal cells line the ventricles (Fig. 3.17; see Fig. 3.10) and central ropeptides can pass from nervous tissue into the CSF by active transport
canal of the spinal cord. They form a single-layered epithelium that through the ependymal cells in these specialized areas, and so access a
varies from squamous to columnar in form. At the ventricular surface, wide population of neurones via the permeable ependymal lining of
cells are joined by gap junctions and occasional desmosomes. Their the rest of the ventricle.
apical surfaces have numerous microvilli and/or cilia, the latter contrib- The ependyma is highly modified where it lies adjacent to the vas-
uting to the flow of CSF. There is considerable regional variation in the cular layer of the choroid plexuses. | 99 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Central glia
53
3
RETPAHC
Choroid plexus MICROGLIA
The choroid plexus forms the CSF and actively regulates the concentra- Microglia are the endogenous immune cells of the brain (Kettenmann
tion of molecules in the CSF. It consists of highly vascularized masses et al 2011, Eggen et al 2013). They originate from an embryonic mono-
of pia mater enclosed by pockets of ependymal cells. The ependymal cyte precursor and invade the brain early during development. While
cells resemble those of the circumventricular organs, except that they the invading cells have an ameboid morphology, microglial cells in a
do not have basal processes, but form a cuboidal epithelium that rests mature brain are highly ramified cells. They have elongated nuclei, scant
on a basal lamina adjacent to the enclosed fold of meningeal pia mater cytoplasm and several highly branched processes. They occupy a defined
and its capillaries (Fig. 3.18). The cells have numerous long microvilli territory in the brain parenchyma and are found in all areas of the CNS
with only a few cilia interspersed between them. They also have many including optic nerve, retina and spinal cord. Their density shows little
mitochondria, large Golgi complexes and basal nuclei, features consist- variation.
ent with their secretory activity; they produce most components of the Resting microglia, a term used to refer to microglia in the normal
CSF. They are linked by tight junctions forming a transepithelial barrier brain, should more accurately be described as surveying microglia.
(a component of the blood–CSF barrier), and by desmosomes. Their Microglial processes are fast-moving structures that rapidly scan their
lateral margins are highly folded. territory while the soma remains fixed in position. Microglial cells
The choroid plexus has a villous structure where the stroma is com- express receptors for neurotransmitters and thus can sense neuronal
posed of pial meningeal cells, and contains fine bundles of collagen activity. It is likely that they interact with synapses, from which it has
and blood vessels. Choroidal capillaries are lined by a fenestrated been inferred that they may influence synaptic transmission.
endothelium. During fetal life, erythropoiesis occurs in the stroma, All pathological changes in the brain result in the activation of
which is occupied by bone marrow-like cells. In adult life, the stroma microglial cells (Fig. 3.19), e.g. activated microglia are found in the
contains phagocytic cells, which, together with the cells of the choroid brain tissue of multiple sclerosis, Alzheimer’s disease and stroke
plexus epithelium, phagocytose particles and proteins from the ven- patients. The most common indication of their activation is a change
tricular lumen. from a ramified to an ameboid morphology, which may occur within
Age-related changes occur in the choroid plexus, which can be a few hours of the onset of injury or disease process.
detected by neuroimaging. Calcification of the choroid plexus can be In general, microglia respond to two types of signal: ‘on’ signals, which
detected by X-ray or CT scan very rarely in individuals in the first decade either appear de novo or are strongly upregulated, e.g. cell wall compo-
of life and in the majority in the eighth decade. The incidence of calci- nents of invading bacteria; and ‘off’ signals, which are normally present
fication rises sharply, from 35% of CT scans in the fifth decade to 75% but disappear or decrease in pathological states, e.g. defined cytokines
in the sixth decade. Visible calcification is usually restricted to the or neurotransmitters. Both types of event are interpreted as signals for
glomus region of the choroid plexus, i.e. the vascular bulge in the activation. The functional repertoire of activated microglia includes pro-
choroid plexus as it curves to follow the anterior wall of the lateral liferation; migration to the site of injury; expression of major histocom-
ventricle into the temporal horn. patibility complex (MHC) II molecules to interact with infiltrating
lymphocytes; and the release of a variety of different substances including
chemokines, cytokines and growth factors. These cells are therefore capa-
ble of significantly influencing ongoing pathological processes.
Microglial cells are the professional phagocytes of the nervous
system and actively migrate through tissue. A number of factors such as
ATP and complement factors act as chemoattractants. This behaviour is
relevant not only in pathology but also during development where
microglial cells remove apoptotic cells. After a pathological insult,
microglial cells revert to their surveying phenotype, re-acquiring a rami-
fied morphology.
Entry of inflammatory cells into the brain
Although the CNS has long been considered to be an immunologically
privileged site, lymphocyte and macrophage surveillance of the brain
may be a normal, but very low-grade, activity that is enhanced in
disease. Lymphocytes can enter the brain in response to virus infections
and as part of the autoimmune response in multiple sclerosis. Activated,
A
but not resting, lymphocytes pass through the endothelium of small
venules, a process that requires the expression of recognition and adhe-
sion molecules (induced following cytokine activation), and subse-
Arachnoid Pia mater Choroid Subarachnoid Capillary quently migrate into the brain parenchyma. Within the CNS, microglia
mater fissure space
can be induced by T-cell cytokines to act as efficient antigen-presenting
cells. After leaving the CNS, lymphocytes probably drain along lym-
phatic pathways to regional cervical lymph nodes.
CNS CNS
Choroid epithelium Choroid capillary Ependyma
B Ventricle
Fig. 3.18 A, A choroid plexus within the lateral ventricle. Frond-like
projections of vascular stroma derived from the pial meninges are Fig. 3.19 Activated microglial cells in the human central nervous system,
covered with a low columnar epithelium that secretes cerebrospinal fluid. in a biopsy from a patient with Rasmussen’s encephalitis, visualized using
Mouse tissue, toluidine blue stained resin section. B, The arrangement of MHC class II antigen immunohistochemistry. (Courtesy of Dr Norman
tissues forming the choroid plexus. Gregson, Division of Neurology, GKT School of Medicine, London.) | 100 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
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NOITCES
Monocytes enter the CNS in the early stages of infarction and fibres. B fibres are myelinated autonomic preganglionic efferent fibres.
autoimmune disease and, in particular, in pyogenic infections, probably C fibres are unmyelinated and have thermoreceptive, nociceptive and
by passing through the endothelium of local vessels. Once in the brain, interoceptive functions, including the perception of slow, burning pain
monocytes are difficult to distinguish from intrinsic microglia because and visceral pain. This scheme can be applied to fibres of both spinal
both cell types express a similar marker profile. During the inflamma- and cranial nerves except perhaps those of the olfactory nerve, where
tory phase of meningitis, polymorphonuclear leukocytes and lym- the fibres form a uniquely small and slow group. The largest somatic
phocytes pass into the CSF through the endothelium of large veins in efferent fibres (Aα) innervate extrafusal muscle fibres (at motor end-
the subarachnoid space. Recent developments in research on brain plates) exclusively and conduct at a maximum of 120 m/s. Fibres to fast
inflammatory disorders are reviewed in Anthony and Pitossi (2013). twitch muscles are larger than those to slow twitch muscle. Smaller (Aγ)
fibres of gamma motor neurones, and autonomic preganglionic (B) and
postganglionic (C) efferent fibres conduct, in order, progressively more
PERIPHERAL NERVES
slowly (40 m/s to less than 10 m/s).
A different classification, used for afferent fibres from muscles,
Afferent nerve fibres connect peripheral receptors to the CNS; they are divides fibres into groups I–IV on the basis of their calibre; groups I–III
derived from neuronal somata located either in special sense organs are myelinated and group IV is unmyelinated. Group I fibres are large
(e.g. the olfactory epithelium) or in the sensory ganglia of the cranio- (12–22 µm), and include primary sensory fibres of muscle spindles
spinal nerves. Efferent nerve fibres connect the CNS to the effector cells (group Ia) and smaller fibres of Golgi tendon organs (group Ib). Group
and tissues and are the peripheral axons of neurones with somata in II fibres are the secondary sensory terminals of muscle spindles, with
the central grey matter. diameters of 6–12 µm. Group III fibres, 1–6 µm in diameter, have free
Peripheral nerve fibres are grouped in widely variable numbers into sensory endings in the connective tissue sheaths around and within
bundles (fasciculi). The size, number and pattern of fasciculi vary in muscles and are nociceptive and, in skin, also thermosensitive. Group
different nerves and at different levels along their paths (Fig. 3.20). IV fibres are unmyelinated, with diameters below 1.5 µm; they include
Their number increases and their size decreases some distance proximal free endings in skin and muscle, and are primarily nociceptive.
to a point of branching. Where nerves are subjected to pressure, e.g.
deep to a retinaculum, fasciculi are increased in number but reduced
in size, and the amount of associated connective tissue and degree of CONNECTIVE TISSUE SHEATHS
vascularity also increase. At these points, nerves may occasionally show
a pink, fusiform dilation, sometimes termed a pseudoganglion or gan- Nerve trunks, whether uni- or multifascicular, are limited externally by
gliform enlargement. an epineurium, which is connected to surrounding tissues by mesoneu-
rium. Mesoneurium is a loose connective tissue sheath (see Ch. 2)
containing the extrinsic, segmental blood supply of the nerve, and so
CLASSIFICATION OF PERIPHERAL NERVE FIBRES
is of clinical importance in nerve injury. Individual fasciculi of the nerve
trunk are enclosed by a multilayered perineurium, which in turn sur-
Classification of peripheral nerve fibres is based on various parameters rounds the endoneurium or intrafascicular connective tissue (see
such as conduction velocity, function and fibre diameter. Of two clas- Fig. 3.20).
sifications in common use, the first divides fibres into three major
classes, designated A, B and C, corresponding to peaks in the distribu- Epineurium
tion of their conduction velocities. In humans, this classification is used
mainly for afferent fibres from the skin. Group A fibres are subdivided
Epineurium is a condensation of loose (areolar) connective tissue
into α, β, γ and δ subgroups; fibre diameter and conduction velocity
derived from mesoderm. As a general rule, the more fasciculi present
are proportional in most fibres. Group Aα fibres are the largest and
in a peripheral nerve, the thicker the epineurium. Epineurium contains
conduct most rapidly, and C fibres are the smallest and slowest.
fibroblasts, collagen (types I and III) and variable amounts of fat, and
The largest afferent axons (Aα fibres) innervate encapsulated cutane-
it cushions the nerve it surrounds. Loss of this protective layer may be
ous mechanoreceptors, Golgi tendon organs and muscle spindles, and
associated with pressure palsies seen in wasted, bedridden patients. The
some large alimentary enteroceptors. Aβ fibres form secondary endings
epineurium also contains lymphatics (which probably pass to regional
on some muscle spindle (intrafusal) fibres and also innervate cutaneous
lymph nodes) and blood vessels, vasa nervorum, that pass across the
and joint capsule mechanoreceptors. Aδ fibres innervate thermorecep-
perineurium to communicate with a network of fine vessels within the
tors, stretch-sensitive free endings, hair receptors and nociceptors,
endoneurium, forming the intrinsic system of vascular plexuses.
including those in dental pulp, skin and connective tissue. Aγ fibres are
exclusively fusimotor to plate and trail endings on intrafusal muscle
Perineurium
Perineurium extends from the CNS–PNS transition zone to the periph-
ery, where it is continuous with the capsules of muscle spindles and
encapsulated sensory endings, but ends openly at unencapsulated
endings and neuromuscular junctions. It consists of alternating layers
of flattened polygonal cells (thought to be derived from fibroblasts) and
collagen. It can often contain 15–20 layers of such cells, each layer
enclosed by a basal lamina up to 0.5 µm thick. Within each layer the
cells interdigitate along extensive tight junctions; their cytoplasm typi-
cally contains vesicles and bundles of microfilaments and their plasma
membrane often shows evidence of pinocytosis. These features are con-
sistent with the function of the perineurium as a metabolically active
E
P diffusion barrier; together with the blood–nerve barrier, the perineu-
rium is thought to play an essential role in maintaining the osmotic
milieu and fluid pressure within the endoneurium. Lymphatic vessels
Ep have not been detected in the perineurium.
Endoneurium
Strictly speaking, the term endoneurium is restricted to intrafascicular
connective tissue and excludes the perineurial partitions within fasci-
cles. Endoneurium consists of a fibrous matrix composed predomi-
Fig. 3.20 A transverse section of a biopsied human sural nerve, showing nantly of type III collagen (reticulin) fibres, characteristically organized
the arrangement of the connective tissue sheaths. Individual axons, in fine bundles lying parallel to the long axis of the nerve, and con-
myelinated and unmyelinated, are arranged in a small fascicle bounded densed around individual Schwann cell–axon units and endoneurial
by a perineurium. Abbreviations: P, perineurium; Ep, epineurium; vessels. The fibrous and cellular components of the endoneurium are
E, endoneurium. (Courtesy of Professor Susan Standring, GKT School bathed in endoneurial fluid at a slightly higher pressure than that
of Medicine, London.) outside in the surrounding epineurium. The major cellular constituents | 101 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Peripheral nerves
55
3
RETPAHC
of the endoneurium are Schwann cells and endothelial cells; minor
components are fibroblasts (constituting approximately 4% of the total
endoneurial cell population), resident macrophages and mast cells.
Schwann cell–axon units and blood vessels are enclosed within indi-
vidual basal laminae and therefore isolated from the other cellular and A
extracellular components of the endoneurium.
Endoneurial arterioles have a poorly developed smooth muscle layer
and do not autoregulate well. In sharp contrast, epineurial and perineu-
rial vessels have a dense perivascular plexus of peptidergic, serotonin-
ergic and adrenergic nerves. There are free nerve endings in all layers of
neural connective tissue sheaths and there are some encapsulated
(Pacinian) corpuscles in the endoneurium. These probably contribute
A
to the acute sensitivity of nerves trapped in fibrosis after injury or
surgery. S
SCHWANN CELLS
Schwann cells are the major glial type in the PNS. In vitro they are A
fusiform in appearance. Both in vitro and in vivo, Schwann cells ensheathe S
peripheral axons, and myelinate those greater than 2 µm in diameter.
In a mature peripheral nerve, they are distributed along the axons in
longitudinal chains; the geometry of their association depends on
whether the axon is myelinated or unmyelinated. In myelinated axons Fig. 3.21 An electron micrograph of a transverse section of biopsied
the territory of a Schwann cell defines an internode. human sural nerve, showing a myelinated axon and several unmyelinated
The molecular phenotype of mature myelin-forming Schwann cells axons (A), ensheathed by Schwann cells (S). (Courtesy of Professor Susan
is different from that of mature non-myelin-forming Schwann cells. Standring, GKT School of Medicine, London.)
Adult myelin-forming Schwann cells are characterized by the presence
of several myelin proteins, some, but not all, of which are shared with
oligodendrocytes and central myelin. In contrast, expression of the
low-affinity neurotrophin receptor (p75NTR) and GFAP intermediate et al 2008). The region under the compact myelin sheath that extends
between two juxtaparanodes is the internode. The molecular domains
filament protein (which differs from the CNS form in its post-
of myelinated axons, including that of the axon initial segment are
translational modification) characterizes adult non-myelin-forming
reviewed in Buttermore et al (2013)).
Schwann cells.
Schwann cell cytoplasm forms a continuous layer only in the peri-
Schwann cells arise from Schwann cell precursors that, in turn, are
nuclear (mid-internodal) and paranodal regions, where it forms a collar
generated from multipotent cells of the neural crest. Neuronal signals
from which microvilli project into the nodal gap substance. Elsewhere
regulate many aspects of Schwann cell behaviour in developing and
it is dispersed as a lace-like network over the inner (adaxonal) and outer
postnatal nerves. Axon-associated signals appear to control the prolif-
(abaxonal) surfaces of the myelin sheath.
eration of developing Schwann cells and their precursors; the develop-
mentally programmed death of those precursors in order to match
Nodes of Ranvier
numbers of axons and glia within each peripheral nerve bundle; the
production of basal laminae by Schwann cells; and the induction and The nodal compartment consists of a short length of exposed axo-
maintenance of myelination. Axonal neuregulin 1 signalling via ErbB2/ lemma, typically 0.8–1.1 µm long, surrounded by a nodal gap sub-
B3 receptors on Schwann cells is essential for Schwann cell myelination stance composed of various extracellular components, some of which
and also determines myelin thickness. An extensive literature supports may possess nerve growth-repulsive characteristics. Multiple processes
the view that Schwann cells are key players in the acute injury response (microvilli) protrude into the gap substance from the outer collar of
in the PNS (see Commentary 1.6), helping to provide a microenviron- Schwann cytoplasm and contact the nodal axolemma. Voltage-gated
ment that facilitates axonal regrowth (Birch 2011). Few Schwann cells Na+ channels, the cell adhesion molecules NrCAM and neurofascin-186,
persist in chronically denervated nerves. For further reading about the cytoskeletal adaptor ankyrin G25,26 and the actin-binding protein
Schwann cells, see Kidd et al (2013). spectrin βIV are clustered at nodes. The calibre of the nodal axon is
usually significantly less than that of the internodal axon, particularly
Unmyelinated axons in large-calibre fibres.
Paranodes
Unmyelinated axons are commonly 1.0 µm in diameter, although some
The axolemma on either side of a node is contacted by paranodal loops
may be 1.5 µm or even 2 µm in diameter. Groups of up to 10 or more
of Schwann cell cytoplasm via specialized septate junctions that spiral
small axons (0.15–2.0 µm in diameter) are enclosed within a chain of
around the axon. The junctions are thought to form a partial diffusion
overlapping Schwann cells that is surrounded by a basal lamina. Within barrier into the peri-axonal space; restrict the movement of K+ channels
each Schwann cell, individual axons are usually sequestered from their
from under the compact myelin; and limit lateral diffusion of mem-
neighbours by delicate processes of cytoplasm. It seems likely, on the
brane components. Caspr, contactin and their putative ligand NF155
basis of quantitative studies in subhuman primates, that axons from
(an isoform of neurofascin) are concentrated in paranodes.
adjacent cord segments may share Schwann cell columns; this phenom-
enon may play a role in the evolution of neuropathic pain after nerve Juxtaparanodes
injury. In the absence of a myelin sheath and nodes of Ranvier, action
The region of the axon lying just beyond the innermost paranodal junc-
potential propagation along unmyelinated axons is not saltatory but
tion is now recognized as a distinct domain defined by the localization
continuous, and relatively slow (0.5–4.0 m/s).
of voltage-gated K+ channels (delayed-rectifier K+ channels Kv1.1, Kv1.2
and their Kvb2 subunit). Clustering of Kv1 channels at the juxtapara-
Myelinated axons
nodal region depends on their association with the Caspr2/TAG-1 adhe-
sion complex.
Myelinated axons (Fig. 3.21) have a 1 : 1 relationship with their
Schmidt–Lanterman incisures
ensheathing Schwann cells. The territorial extent of individual Schwann
cells varies directly with the diameter of the axon they surround, from Schmidt–Lanterman incisures are helical decompactions of internodal
150 to 1500 µm. Specialized domains of axo-glial interaction define myelin that appear as funnel-like profiles in teased fibre preparations
nodes of Ranvier and their neighbouring compartments, paranodes and labelled for markers of non-compacted myelin (e.g. MAG, Cx32). At an
juxtaparanodes (Pereira et al 2012; Fig. 3.22). These domains contain incisure the major dense line of the myelin sheath splits to enclose a
multiprotein complexes characterized by unique sets of transmembrane continuous spiral band of cytoplasm passing between abaxonal and
and cytoskeletal proteins and clusters of ion channels; the mechanisms adaxonal layers of Schwann cell cytoplasm. The minor dense line of
regulating channel clustering and node formation remain a subject of incisural myelin is also split, creating a channel connecting the peri-
intense scrutiny (Peles and Salzer 2000, Poliak and Peles 2003, Horresh axonal space with the endoneurial extracellular fluid. The function of | 102 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
56
1
NOITCES
A B
BL
CM
PNL PNL PNL MV
CM
Internode Juxtaparanode Paranode Node
• Caspr 2 • Caspr • Na+ ch
EP • Kv1.1, 1.2, β2 • Contactin • ank G
• NF155 • NrCAM
• NF186
Fig. 3.22 The general plan of a peripheral myelinated nerve fibre in longitudinal section, including one complete internodal segment and two adjacent
paranodal bulbs, used as a key for the more detailed microarchitecture of specific subregions. A, A transverse electron microscope section through the
centre of a node of Ranvier, with numerous finger-like processes of adjacent Schwann cells converging towards the nodal axolemma. Many microtubules
and neurofilaments are visible within the axoplasm. B, The arrangement of the axon, myelin sheath and Schwann cell cytoplasm at the node of Ranvier,
in the paranodal bulbs and in the juxtaparanodal region. The axon is myelinated by a Schwann cell surrounded by a basal lamina (BL). Only a portion of
the internode, which is located beneath the compact myelin (CM) sheath, is shown. A spiral of paranodal (green) and juxtaparanodal (blue) proteins
extends into the internode; this spiral is apposed to the inner mesaxon of the myelin sheath (not shown). K+ channels and Caspr2 are concentrated in the
juxtaparanodal region. In the paranodal region, the compact myelin sheath opens up into a series of paranodal cytoplasmic loops (PNL) that invaginate
and closely appose the axon, forming a series of septum-like junctions that spiral around the axon. Caspr, contactin and an isoform of neurofascin
(NF155) are concentrated in this region. At the node, numerous microvilli (MV) project from the outer collar of the Schwann cell to contact the axolemma.
The axon is enormously enriched in intramembranous particles at the node that correspond to Na+ channels (Na+ ch). Ankyrin G (ank G) isoforms and the
cell adhesion molecules NrCAM and NF186 are also concentrated in this region. (A, Courtesy of Professor Susan Standring, GKT School of Medicine,
London. B, Redrawn from Peles and Salzer 2000.)
incisures is not known; their structure suggests that they may participate from horizontal basal stem cells in the olfactory epithelium (Leung et al
in transport of molecules across the myelin sheath. 2007, Forni and Wray 2012). They extend new axons through the
lamina propria and cribriform plate into the CNS environment of the
olfactory bulb, where they synapse with second-order neurones. Olfac-
SATELLITE CELLS
tory ensheathing cells (OECs, also known as olfactory ensheathing glia)
accompany olfactory axons from the lamina propria of the olfactory
Many non-neuronal cells of the nervous system have been called satel-
epithelium to their synaptic contacts in the glomeruli of the olfactory
lite cells, including small, round extracapsular cells in peripheral
bulbs and are thought to play a role in directing them to their correct
ganglia, ganglionic capsular cells, Schwann cells, any cell that is closely
position in the olfactory bulb (Higginson and Barnett 2011). This
associated with neuronal somata, and precursor cells associated with
unusual arrangement is unique; elsewhere in the nervous system the
striated muscle fibres (Hanani 2010). Within the nervous system, the
territories of peripheral and central glia are clearly demarcated at CNS–
term is most commonly reserved for flat, epithelioid cells (ganglionic
PNS transition zones. OECs and the end-feet of astrocytes lying between
glial cells, capsular cells) that surround the neuronal somata of periph-
the bundles of olfactory axons both contribute to the glia limitans at
eral ganglia (see Fig. 3.23). Their cytoplasm resembles that of Schwann
the pial surface of the olfactory bulbs.
cells, and their deep surfaces interdigitate with reciprocal infoldings in
OECs share many properties with Schwann cells and express similar
the membranes of the enclosed neurones.
antigenic and morphological properties. They ensheathe olfactory
sensory axons in a manner comparable to the relationship that exists
Enteric glia
transitorily between Schwann cells and axons in very immature periph-
eral nerves, i.e. they surround, but do not segregate, bundles of up to
Enteric nerves lack an endoneurium and so do not have the collagenous 50 fine unmyelinated axons to form approximately 20 fila olfactoria.
coats of other peripheral nerves. The enteric ganglionic neurones are Both OECs and Schwann cells can myelinate axons, even though nor-
supported by glia that closely resemble astrocytes; they contain more mally none of the axons in the olfactory nerve is myelinated. It was
GFAP than non-myelinating Schwann cells and do not produce a basal thought that OECs shared a common origin with olfactory receptor
lamina. Evidence for their roles in gut function is reviewed in Gul- neurones in the olfactory placode, but recent fate-mapping experiments
bransen and Sharkey (2012). in chicken embryos and genetic linkage-tracing studies in mice have
shown that OECs are derived from neural crest cells (Forni and Wray
Olfactory ensheathing glia
2012).
OECs have a malleable phenotype. There may be several subtypes:
The olfactory system is unusual because it supports neurogenesis some OECs express GFAP as either fine filaments or more diffusely in
throughout life. Olfactory receptor neurones are continuously renewed their cytoplasm, and some express p75NTR and the O4 antigen. | 103 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Peripheral nerves
57
3
RETPAHC
BLOOD SUPPLY OF PERIPHERAL NERVES processes; in myelinated fibres the junction occurs at a node of Ranvier.
The peripheral process terminates in a sensory ending and, because it
The blood vessels supplying a nerve, end in a capillary plexus that conducts impulses towards the soma, it functions as an elongated den-
pierces the perineurium. The branches of the plexus run parallel with drite, strictly speaking. However, it has the typical structural and func-
the fibres, connected by short transverse vessels, forming narrow, rec- tional properties of a peripheral axon, and is conventionally described
tangular meshes similar to those found in muscle. The blood supply of as an axon.
peripheral nerves is unusual. Endoneurial capillaries have atypically Each neuronal soma is surrounded by a sheath of satellite glial cells
large diameters and intercapillary distances are greater than in many (SGCs). (A notable exception is the spiral, or cochlear, ganglion, where
other tissues. Peripheral nerves have two separate, functionally inde- most neuronal somata are myelinated, presumably contributing to fast
pendent vascular systems: an extrinsic system (regional nutritive vessels electrical transmission.) The axodendritic process and its peripheral and
and epineurial vessels) and an intrinsic system (longitudinally running central divisions, ensheathed by Schwann cells, lie outside the SGC
microvessels in the endoneurium). Anastomoses between the two sheath. All the cells in the ganglion lie within a highly vascularized
systems produce considerable overlap between the territories of the connective tissue that is continuous with the endoneurium of the nerve
segmental arteries. This unique pattern of vessels, together with a high root. In dorsal root ganglia there is no clear regional mapping of the
basal nerve blood flow relative to metabolic requirements, means that innervated body regions. In contrast, each of the three nerve branches
peripheral nerves possess a high degree of resistance to ischaemia. (ophthalmic, maxillary and mandibular) of the trigeminal nerve is
mapped to a different part of the trigeminal ganglion. Although sensory
Blood–nerve barrier neurones receive no synapses, they are endowed with receptors for
numerous neurotransmitters and hormones, and can thus communi-
cate chemically amongst themselves and with SGCs.
Just as the neuropil within the CNS is protected by a blood–brain
SGCs are the main type of glial cell in sensory ganglia. They share
barrier, the endoneurial contents of peripheral nerve fibres are protected
several properties with astrocytes, including expression of glutamine
by a blood–nerve barrier and by the cells of the perineurium. The
synthetase and various neurotransmitter transporters. In addition, like
blood–nerve barrier operates at the level of the endoneurial capillary
astrocytes, the SGCs that surround a neurone are coupled by gap junc-
walls, where the endothelial cells are joined by tight junctions, and are
tions and express receptors for ATP. Unlike astrocytes, SGCs completely
non-fenestrated and surrounded by continuous basal laminae. The
surround individual sensory neurones (and more rarely two or three
barrier is much less efficient in dorsal root ganglia and autonomic
neurons) in a glial sheath. They undergo major changes as a result of
ganglia and in the distal parts of peripheral nerves.
injury to peripheral nerves, and appear to contribute to chronic pain in
a number of animal pain models.
GANGLIA
Herpes zoster Primary infection with the varicella zoster virus causes
Ganglia are aggregations of neuronal somata and are of varying form chickenpox. Following recovery, the virus remains dormant within
and size. They occur in the dorsal roots of spinal nerves; in the sensory dorsal root ganglia or trigeminal ganglia, mostly in the neurones, and
roots of the trigeminal, facial, vestibulocochlear, glossopharyngeal and less commonly in the SGCs. Reactivation of the virus leads to herpes
vagal cranial nerves; and in the peripheral autonomic nervous system zoster (shingles), which involves the dermatome(s) supplied by the
(ANS). Each ganglion is enclosed within a capsule of fibrous connective affected sensory nerve(s). Diagnostic signs are severe pain, erythema
tissue and contains neuronal somata and neuronal processes. Enteric and blistering as occurs in chickenpox, often confined to one of the
ganglia are an exception to this rule; they resemble the CNS in both divisions of the trigeminal nerve or to a spinal nerve dermatome.
structure and function, and are not covered by a connective tissue Herpes zoster involving the geniculate ganglion compresses the facial
capsule. Some ganglia, particularly in the ANS, contain axons that nerve and results in a lower motor neurone facial paralysis, known as
originate from neuronal somata that lie elsewhere in the nervous system Ramsay Hunt syndrome. Occasionally, if the vestibulocochlear nerve
and which pass through the ganglia without synapsing. becomes involved, there is vertigo, tinnitus and some deafness. The
most important complication of herpes zoster is post-herpetic neural-
Sensory ganglia gia, a severe and persistent pain that is highly refractory to treatment.
The sensory ganglia of dorsal spinal roots (Fig. 3.23) and the ganglia Autonomic ganglia
of the trigeminal, facial, glossopharyngeal and vagal cranial nerves are
enclosed in a periganglionic connective tissue capsule that resembles The main types of cell in autonomic ganglia are the ganglionic neu-
the perineurium surrounding peripheral nerves. Ganglionic neurones rones, small intensely fluorescent (SIF) cells and satellite glial cells
are unipolar (sometimes called pseudounipolar, see above). They have (SGCs). Most of the neurones have somata ranging from 25 to 50 µm
spherical or oval somata of varying size, aggregated in groups between and complex dendritic fields; dendritic glomeruli have been observed
fasciculi of myelinated and unmyelinated nerve fibres. For each neurone, in ganglia in experimental animals. Ganglionic neurones receive many
a single axodendritic process bifurcates into central and peripheral axodendritic synapses from preganglionic axons; axosomatic synapses
are less numerous. Postganglionic fibres commonly arise from the
initial stem of a large dendrite and produce few or no collateral proc-
esses. Given their close relationship to the ganglionic neurones, auto-
nomic SGCs may have the potential to influence synaptic transmission.
SIF cells are characterized by being smaller than the neurones and by
having numerous granules that contain noradrenaline (norepine-
phrine), dopamine and serotonin. They are almost completely invested
by a sheath of SGCs and receive and make synapses; their physiological
role is currently obscure, but they lend credence to the idea that auto-
S nomic ganglia are far more than simple relay stations.
N Sympathetic neurones are multipolar and their dendritic trees, on
which preganglionic motor axons synapse, are more elaborate than
those of parasympathetic neurones (Fig. 3.24). The neurones are sur-
rounded by a mixed neuropil of afferent and efferent fibres, dendrites,
S
synapses and non-neural cells. There is considerable variation in the
ratio of pre- and postganglionic fibres in different types of ganglion.
Preganglionic sympathetic axons may synapse with many postgangli-
onic neurones for the wide dissemination and perhaps amplification of
sympathetic activity, a feature not found to the same degree in para-
sympathetic ganglia. Dissemination may also be achieved by connec-
Fig. 3.23 Sensory neurones in a dorsal root ganglion (rat). Neurones (N) tions with ganglionic interneurones or by the diffusion within the
are typically variable in size but all are encapsulated by satellite cells (S). ganglion of transmitter substances produced either locally (paracrine
Myelinated axons are seen above and below the neuronal somata. effect) or elsewhere (endocrine effect). Some axons within a ganglion
Toluidine blue stained resin section. (Courtesy of Dr Clare Farmer, King’s may be efferent fibres en route to another ganglion, or afferents from
College, London.) viscera and glands. These fibres may synapse with neurones in the | 104 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
58
1
NOITCES
the neonatal period. Treatment usually consists of removing the dis-
eased intestinal segment.
The enteric plexuses consist of sensory neurones, interneurones and
a variety of motor neurones. These neurones are endowed with recep-
tors for a large number of neurotransmitters and also release a variety
of neurotransmitters. All classes of enteric neurone are equally distrib-
uted along the entire ganglionic network; consequently the ENS con-
sists of numerous repeating modules.
The myenteric plexus contains the motor neurones that control the
movements of gastrointestinal smooth muscle. The main excitatory
neurotransmitter is acetylcholine, which may be co-localized with an
excitatory peptide (usually a tachykinin, such as substance P). The main
inhibitory neurotransmitter is nitric oxide (NO), released from neu-
rones that may also release the inhibitory peptide vasoactive intestinal
peptide (VIP).
An important function of myenteric neurones is to mediate the peri-
staltic reflex, which is induced by intestinal wall distension or by
mechanical stimulation of the mucosa. These stimuli initiate contrac-
tion oral to the site of the stimulus, and relaxation anal to the site, creat-
ing a pressure gradient that propels the intestinal contents. Interstitial
cells of Cajal (ICC) are pacemaker cells believed to integrate neuronal
Fig. 3.24 A parasympathetic autonomic ganglion from a human stomach. signals with rhythmic oscillations of muscle contraction; disturbance of
Large neuronal somata, some with nuclei and prominent nucleoli in the ICC function may be a factor in a number of gastrointestinal disorders
plane of section, are encapsulated by satellite cells and surrounded by
(Huizinga et al 2009).
nerve fibres and non-neuronal cells. (Courtesy of Mr Peter Helliwell and
Enteric glia are the main type of glial cell in the ENS. In some
the late Dr Joseph Mathew, Department of Histopathology, Royal
respects they resemble astrocytes, e.g. they form end-feet with blood
Cornwall Hospitals Trust, UK.)
vessels, respond to numerous chemical mediators, and are extensively
coupled among themselves by gap junctions. They appear to play an
important role in neuroprotection and in maintaining the integrity of
the intestinal mucosal barrier.
M
DISPERSED NEUROENDOCRINE SYSTEM
Although the nervous, neuroendocrine and endocrine systems all
operate by intercellular communication, they differ in the mode, speed
and degree or localization of the effects produced (Day and Salzet
2002). The autonomic nervous system uses impulse conduction and
neurotransmitter release to transmit information, and the responses
induced are rapid and localized. The dispersed neuroendocrine system
uses only secretion. It is slower and the induced responses are less local-
ized, because the secretions, e.g. neuromediators, can act either on
contiguous cells, or on groups of nearby cells reached by diffusion, or
on distant cells via the blood stream. Many of its effector molecules
operate in both the nervous system and the neuroendocrine system.
M
The endocrine system proper, which consists of clusters of cells and
discrete, ductless, hormone-producing glands, is even slower and less
localized, although its effects are specific and often prolonged. These
regulatory systems overlap in function, and can be considered as a
Fig. 3.25 An enteric ganglion (outlined) of the myenteric (Auerbach’s)
single neuroendocrine regulator of the metabolic activities and internal
plexus between the inner circular and outer longitudinal layers of smooth
environment of the organism, acting to provide conditions in which it
muscle (M) in the wall of the human intestine. An enteric ganglionic
can function successfully. Neural and neuroendocrine axes appear to
neurone is arrowed. (Courtesy of Mr Peter Helliwell and the late Dr
cooperate to modulate some forms of immunological reaction; the
Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals
extensive system of vessels, circulating hormones and nerve fibres that
Trust, UK.)
link the brain with all viscera are thought to constitute a neuroimmune
network (Fig. 3.26).
ganglion, e.g. substance P-containing axons of dorsal root neurones
Some cells can take up and decarboxylate amine precursor com-
synapse on neurones in prevertebral ganglia, thereby enabling interac-
pounds (amine precursor uptake and decarboxylation, or APUD, cells).
tions between the sensory system and the ANS.
They are characterized by dense-core cytoplasmic granules (see Fig. 2.6),
similar to the neurotransmitter vesicles seen in some types of neuronal
Enteric ganglia
terminal. The group includes cells described as chromaffin cells (phaeo-
chromocytes), derived from neuroectoderm and innervated by pregan-
The enteric nervous system (ENS) lies within the walls of the gastroin- glionic sympathetic nerve fibres. Chromaffin cells synthesize and secrete
testinal tract (see Fig. 2.15 for the layers of a typical viscus) and includes catecholamines (dopamine, noradrenaline (norepinephrine) or adren-
the myenteric and submucosal plexuses and associated ganglia (Furness aline (epinephrine)). Their name refers to the finding that their cyto-
2012, Neunlist et al 2013). The ganglionic neurones (Fig. 3.25) serve plasmic store of catecholamines is sufficiently concentrated to give an
different functions, including the regulation of gut motility (in conjunc- intense yellow–brown colouration, the positive chromaffin reaction,
tion with interstitial cells of Cajal (Huizinga et al 2009)), mucosal when they are treated with aqueous solutions of chromium salts, par-
transport and mucosal blood flow. Unlike the other two divisions of ticularly potassium dichromate. Classic chromaffin cells include clus-
the ANS, the ENS is largely independent of the CNS, and the extrinsic ters of cells in the suprarenal medulla; the para-aortic bodies, which
autonomic fibres that supply the gut wall exert only modulatory effects secrete noradrenaline; paraganglia; certain cells in the carotid bodies;
on it. Submucosal neurones, together with sympathetic axons, regulate and small groups of cells irregularly dispersed among the paravertebral
the local blood flow. sympathetic ganglia, splanchnic nerves and prevertebral autonomic
Hirschsprung’s disease is a congenital disease in which dysfunctional plexuses.
neural crest migration means that the ganglia of both the myenteric and The alimentary tract contains a large population of cells of a similar
submucosal plexuses in the distal bowel fail to develop. The resulting type (previously called neuroendocrine or enterochromaffin cells)
lack of propulsive activity in the aganglionic bowel leads to functional in its wall. These cells act as sensory transducers, activating intrinsic
obstruction and megacolon, which can be life-threatening. Around 1 in and extrinsic primary afferent neurones via their release of 5-
5,000 infants is born with the condition and is typically diagnosed in hydroxytryptamine (5-HT, serotonin). The neonatal respiratory tract | 105 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Sensory endings
59
3
RETPAHC
Brainstem receptor and partly in the neurone that innervates it, in the case of
epithelial receptors. Transduction varies with the modality of the stimu-
Sensory vagal neurone lus, and usually causes depolarization of the receptor membrane (or
hyperpolarization, in the retina). In mechanoreceptors, transduction
may involve the deformation of membrane structure, which causes
Prevertebral sympathetic ganglion either strain or stretch-sensitive ion channels to open. In chemorecep-
tors, receptor action may resemble that for ACh at neuromuscular
Spinal sensory neurone Immune and tissue junctions. Visual receptors share similarities with chemoreceptors:
defence signals:
light causes changes in receptor proteins, which activate G proteins,
Spinal cord local and systemic
Intestinofugal resulting in the release of second messengers and altered membrane
neurone permeability.
Neurocrine signals: The quantitative responses of sensory endings to stimuli vary greatly
local and circulating and increase the flexibility of the functional design of sensory systems.
Although increased excitation with increasing stimulus level is a
Intrinsic common pattern (‘on’ response), some receptors respond to decreased
sensory stimulation (‘off’ response). Even unstimulated receptors show varying
neurone degrees of spontaneous background activity against which an increase
or decrease in activity occurs with changing levels of stimulus. In all
Stretch
Gut lumen
r thec ee rp
e
to isr s
a
nst u ind ii te id a,
l
w buh re sn
t
(s tt him
e
u dl ya nti ao mn icis pm ha ai sn e)ta i fn oe lld
o
wa et da bs yte a ad gy
r
ale dv ue al l,
adaptation to steady level (the static phase). Though all receptors show
Signals from lumen these two phases, one or other may predominate, providing a distinc-
e.g. nutrients, antigens,
tion between rapidly adapting endings that accurately record the rate
irritants, secretions
of stimulus onset, and slowly adapting endings that signal the constant
amplitude of a stimulus, e.g. position sense. Dynamic and static phases
are reflected in the amplitude and duration of the receptor potential
Fig. 3.26 The ways in which the nervous system, neuroendocrine system and also in the frequency of action potentials in the sensory fibres. The
and immune system are integrated, demonstrated in the intestine. stimulus strength necessary to elicit a response in a receptor, i.e. its
Neurocrine signals from enteric neuroendocrine cells and signals from threshold level, varies greatly between receptors, and provides an extra
immune defence cells (e.g. lymphocytes, macrophages and mast cells) level of information about stimulus strength.
act on other cells of those systems and on neurones with sensory For further information on sensory receptors, see Nolte (2008).
endings in the intestinal wall, either locally or at a distance. Some
neuronal soma lie within enteric ganglia in the gut wall; others have their
bodies in peripheral ganglia. Neuronal signals may act locally, be FUNCTIONAL CLASSIFICATION OF RECEPTORS
transmitted to the CNS or enter a reflex pathway via sympathetic ganglia.
Receptors have been classified in several ways. They may be classified
by the modalities to which they are sensitive, such as mechanoreceptors
contains a prominent system of neuroendocrine cells, both dispersed (which are responsive to deformation, e.g. touch, pressure, sound waves,
and aggregated (neuroepithelial bodies); the numbers of both types etc.), chemoreceptors, photoreceptors and thermoreceptors. Some re-
decline during childhood. Merkel cells (see Commentary 1.3) in the ceptors are polymodal, i.e. they respond selectively to more than one
basal epidermis of the skin store neuropeptides, which they release modality; they usually have high thresholds and respond to damaging
to associated nerve endings or other cells in a neuroendocrine role, in stimuli associated with irritation or pain (nociceptors).
response to pressure and possibly other stimuli (Lucarz and Brand Another widely used classification divides receptors on the basis of
2007). Experimental animal studies have revealed 5-HT-containing their distribution in the body into exteroceptors, proprioceptors and
intraepithelial paraneurones in the urothelial lining of the urethra; interoceptors. Exteroceptors and proprioceptors are receptors of the
these cells are thought to relay information from the luminal surface somatic afferent components of the nervous system, while interoceptors
of the urethra to underlying sensory nerves. are receptors of the visceral afferent pathways.
A number of descriptions and terms have been applied to cells of Exteroceptors respond to external stimuli and are found at, or close
this system in the older literature (see online text for details). to, body surfaces. They can be subdivided into the general or cutaneous
For further reading, see Day and Salzet (2002). sense organs and special sensory organs. General sensory receptors
include free and encapsulated terminals in skin and near hairs; none
of these has absolute specificity for a particular sensory modality.
SENSORY ENDINGS
Special sensory organs are the olfactory, visual, acoustic, vestibular and
taste receptors.
GENERAL FEATURES OF SENSORY RECEPTORS Proprioceptors respond to stimuli to deeper tissues, especially of the
locomotor system, and are concerned with detecting movement,
There are three major forms of sensory receptor: neuroepithelial, epi- mechanical stresses and position. They include Golgi tendon organs,
thelial and neuronal (Fig. 3.27). muscle spindles, Pacinian corpuscles, other endings in joints, and ves-
A neuroepithelial receptor is a neurone with a soma lying near a tibular receptors. Proprioceptors are stimulated by the contraction of
sensory surface and an axon that conveys sensory signals into the CNS muscles, movements of joints and changes in the position of the body.
to synapse on second-order neurones. This is an evolutionarily primi- They are essential for the coordination of muscles, the grading of mus-
tive arrangement, and the only examples remaining in humans are the cular contraction, and the maintenance of equilibrium.
sensory neurones of the olfactory epithelium. Interoceptors are found in the walls of the viscera, glands and vessels,
An epithelial receptor is a cell that is modified from a non-nervous where their terminations include free nerve endings, encapsulated ter-
sensory epithelium and innervated by a primary sensory neurone with minals and endings associated with specialized epithelial cells. Nerve
a soma lying near the CNS, e.g. auditory receptors and taste buds. When terminals are found in the layers of visceral walls and the adventitia of
activated, this type of receptor excites its neurone by neurotransmission blood vessels, but the detailed structure and function of many of these
across a synaptic gap. endings are not well established. Encapsulated (lamellated) endings
A neuronal receptor is a primary sensory neurone that has a soma occur in the heart, adventitia and mesenteries. Free terminal arboriza-
in a craniospinal ganglion and a peripheral axon ending in a sensory tions occur in the endocardium, the endomysium of all muscles, and
terminal. All cutaneous sensors and proprioceptors are of this type; connective tissue generally. Tension produced by excessive muscular
their sensory terminals may be encapsulated or linked to special meso- contraction or by visceral distension often causes pain, particularly in
dermal or ectodermal structures to form a part of the sensory apparatus. pathological states, which is frequently poorly localized and of a deep-
The extraneural cells are not necessarily excitable, but create an appro- seated nature. Visceral pain is often referred to the corresponding der-
priate environment for the excitation of the neuronal process. matome (see Fig. 16.10). Polymodal nociceptors (irritant receptors)
The receptor stimulus is transduced into a graded change of electrical respond to a variety of stimuli such as noxious chemicals or damaging
potential at the receptor surface (receptor potential), and this initiates mechanical stimuli. They are mainly the free endings of fine, unmyeli-
an all-or-none action potential that is transmitted to the CNS. This may nated fibres that are widely distributed in the epithelia of the alimentary
occur either in the receptor, when this is a neurone, or partly in the and respiratory tracts; they may initiate protective reflexes. | 106 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Nervous system
59.e1
3
RETPAHC
They include: clear cells (so named because of their poor staining
properties in routine preparations); argentaffin cells (reduce silver
salts); argyrophil cells (absorb silver); small intensely fluorescent cells;
peptide-producing cells (particularly of the hypothalamus, hypophysis,
pineal and parathyroid glands, and placenta); Kulchitsky cells in the
lungs; and paraneurones. Many cells of the dispersed (or diffuse) neu-
roendocrine system are derived embryologically from the neural crest.
Some – in particular, cells from the gastrointestinal system – are now
known to be endodermal in origin. | 107 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
60
1
NOITCES
Free endings:
Rapidly adapting mechanoreceptor
Thermoreceptor (hot and cold)
Type I Slowly adapting mechanoreceptor
(Merkel cell ending)
Nociceptor
Type II Slowly adapting mechanoreceptor Rapidly adapting lamellated (Pacinian) corpuscle Rapidly adapting ‘field’ mechanoreceptor
(Ruffini ending) (Meissner’s corpuscle)
Fig. 3.27 Some major types of sensory ending of general afferent fibres (omitting neuromuscular, neurotendinous and hair-related types). The traces
below each type of ending indicate (top) their response (firing rate (vertical lines) and adaption with time) to an appropriate stimulus (below) of the
duration indicated. The Pacinian corpuscle’s response to vibration (rapid sequence of on–off stimuli) is also shown.
Interoceptors include vascular chemoreceptors, e.g. the carotid body, Special types of free ending are associated with epidermal structures
and baroceptors, which are concerned with the regulation of blood flow in the skin. They include terminals associated with hair follicles (peri-
and pressure and the control of respiration. trichial receptors), which branch from myelinated fibres in the deep
dermal cutaneous plexus; the number, size and form of the endings are
related to the size and type of hair follicle innervated. These endings
FREE NERVE ENDINGS respond mainly to movement when hair is deformed and belong to the
rapidly adapting mechanoreceptor group.
Sensory endings that branch to form plexuses occur in many sites (see Merkel tactile endings (see Commentary 1.3) lie either at the base
Fig. 3.27). They occur in all connective tissues, including those of the of the epidermis or around the apical ends of some hair follicles, and
dermis, fasciae, capsules of organs, ligaments, tendons, adventitia of most are innervated by large myelinated axons. Each axon expands into
blood vessels, meninges, articular capsules, periosteum, perichon- a disc that is applied closely to the base of a Merkel cell in the basal
drium, Haversian systems in bone, parietal peritoneum, walls of viscera layer of the epidermis. The cells are believed to be derived from the
and the endomysium of all types of muscle. They also innervate the epidermis, although a neural crest origin remains possible. They contain
epithelium of the skin, cornea, buccal cavity, and the alimentary and many large (50–100 nm) dense-core vesicles, presumably containing
respiratory tracts and their associated glands. Within epithelia, free transmitters. Merkel endings are thought to be slow-adapting mech-
sensory endings lack Schwann cell ensheathment and are enveloped anoreceptors, responsive to sustained pressure and sensitive to the
instead by epithelial cells. Afferent fibres from free terminals may be edges of applied objects. Their functions are controversial, however, and
myelinated or unmyelinated but are always of small diameter and low likely to be more varied.
conduction velocity. When afferent axons are myelinated, their termi-
nal arborizations lack a myelin sheath. These terminals serve several
sensory modalities. In the dermis, they may be responsive to moderate ENCAPSULATED ENDINGS
cold or heat (thermoreceptors); light mechanical touch (mechanore-
ceptors); damaging heat, cold or deformation (unimodal nociceptors); Encapsulated endings are a major group of special endings that includes
and damaging stimuli of several kinds (polymodal nociceptors). lamellated corpuscles of various kinds (e.g. Meissner’s, Pacinian), Golgi
Similar fibres in deeper tissues may also signal extreme conditions, tendon organs, neuromuscular spindles and Ruffini endings (see Fig.
which are experienced, as with all nociceptors, as ache or pain. Free 3.27). They exhibit considerable variety in their size, shape and distribu-
endings in the cornea, dentine and periosteum may be exclusively tion but share a common feature: namely, that each axon terminal is
nociceptive. encapsulated by non-excitable cells (Proske and Gandevia 2012). | 108 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Sensory endings
61
3
RETPAHC
Meissner’s corpuscles into the capsule or core, so that it is not clearly defined in mature cor-
puscles. The core consists of approximately 60 bilateral, compacted
lamellae lying on both sides of a central nerve terminal.
Meissner’s corpuscles are found in the dermal papillae of all parts of
Each corpuscle is supplied by a myelinated axon, which initially
the hand and foot, the anterior aspect of the forearm, the lips, palpebral
loses its myelin sheath and subsequently loses its ensheathing Schwann
conjunctiva and mucous membrane of the apical part of the tongue.
cell at its junction with the core. The naked axon runs through the
They are most concentrated in thick hairless skin, especially of the finger
pads, where there may be up to 24 corpuscles per cm2 in young adults. central axis of the core and ends in a slightly expanded bulb. It is in
contact with the innermost core lamellae, is transversely oval and sends
Mature corpuscles are cylindrical in shape, approximately 80 µm long
short projections of unknown function into clefts in the lamellae. The
and 30 µm across, with their long axes perpendicular to the skin surface.
axon contains numerous large mitochondria, and minute vesicles,
Each corpuscle has a connective tissue capsule and central core com-
approximately 5 nm in diameter, which aggregate opposite the clefts.
posed of a stack of flat modified Schwann cells (Fig. 3.28). Meissner’s
The cells of the capsule and core lamellae are thought to be specialized
corpuscles are rapidly adapting mechanoreceptors, sensitive to shape
fibroblasts but some may be Schwann cells. Elastic fibrous tissue forms
and textural changes in exploratory and discriminatory touch; their
an overall external capsule to the corpuscle. Pacinian corpuscles are
acute sensitivity provides the neural basis for reading Braille text.
supplied by capillaries that accompany the axon as it enters the capsule.
Pacinian corpuscles act as very rapidly adapting mechanoreceptors.
Pacinian corpuscles
They respond only to sudden disturbances and are especially sensitive
to very-high-frequency vibration. The rapidity may be partly due to the
Pacinian corpuscles are situated subcutaneously in the palmar and
lamellated capsule acting as a high pass frequency filter, damping slow
plantar aspects of the hand and foot and their digits, the external geni-
distortions by fluid movement between lamellar cells. Groups of cor-
talia, arm, neck, nipple, periosteal and interosseous membranes, and
puscles respond to pressure changes, e.g. on grasping or releasing an
near joints and within the mesenteries (Fig. 3.29). They are oval, spheri-
object.
cal or irregularly coiled and measure up to 2 mm in length and
100–500 µm or more across; the larger ones are visible to the naked Ruffini endings
eye. Each corpuscle has a capsule, an intermediate growth zone and a
central core that contains an axon terminal. The capsule is formed by
Ruffini endings are slowly adapting mechanoreceptors. They are found
approximately 30 concentrically arranged lamellae of flat cells approxi-
in the dermis of thin, hairy skin, where they function as dermal stretch
mately 0.2 µm thick (see Fig. 3.28). Adjacent cells overlap and succes-
receptors and are responsive to maintained stresses in dermal collagen.
sive lamellae are separated by an amorphous proteoglycan matrix that
They consist of the highly branched, unmyelinated endings of myeli-
contains circularly orientated collagen fibres, closely applied to the
nated afferents. They ramify between bundles of collagen fibres within
surfaces of the lamellar cells. The amount of collagen increases with
a spindle-shaped structure, which is enclosed partly by a fibrocellular
age. The intermediate zone is cellular and its cells become incorporated
sheath derived from the perineurium of the nerve. Ruffini endings
appear electrophysiologically similar to Golgi tendon organs, which
they resemble, although they are less organized structurally. Similar
structures appear in joint capsules (see below).
Golgi tendon organs
Epidermis
Golgi tendon organs are found mainly near musculotendinous junc-
tions (Fig. 3.30), where more than 50 may occur at any one site. Each
terminal is closely related to a group of muscle fibres (up to 20) as they
insert into the tendon. Golgi tendon organs are approximately 500 µm
Tactile corpuscle
long and 100 µm in diameter, and consist of small bundles of tendon
Fig. 3.30 The structure and innervation of a
Golgi tendon organ. For clarity, the perineurium
and endoneurium have been omitted to show
the distribution of nerve fibres ramifying
between the collagen fibre bundles of the
tendon.
Fig. 3.28 A tactile Meissner’s corpuscle in a dermal papilla in the skin,
demonstrated using the modified Bielschowsky silver stain technique.
(Courtesy of Professor N Cauna, University of Pittsburgh.)
Fig. 3.29 A Pacinian corpuscle in human dermis. (Courtesy of Mr Peter
Helliwell and the late Dr Joseph Mathew, Department of Histopathology,
Royal Cornwall Hospitals Trust, UK.) | 109 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
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fibres enclosed in a delicate capsule. The collagen bundles (intrafusal
fasciculi) are less compact than elsewhere in the tendon, the collagen
fibres are smaller and the fibroblasts larger and more numerous. A
single, thickly myelinated 1b afferent nerve fibre enters the capsule and
divides. Its branches, which may lose their ensheathing Schwann cells,
terminate in leaf-like enlargements containing vesicles and mitochon-
dria, which wrap around the tendon. A basal lamina or process of
Schwann cell cytoplasm separates the nerve terminals from the collagen
bundles that constitute the tendon. Golgi tendon organs are activated External capsule
by passive stretch of the tendon but are much more sensitive to active
contraction of the muscle. They are important in providing propriocep-
tive information that complements the information coming from neu-
Internal capsule
romuscular spindles. Their responses are slowly adapting and they
signal maintained tension.
Neuromuscular spindles
Neuromuscular spindles are mechanosensors essential for propriocep-
tion (Boyd 1985). Each spindle contains a few small, specialized Nuclear bag fibre
intrafusal muscle fibres, innervated by both sensory and motor nerve
fibres (Figs 3.31–3.32). The whole is surrounded equatorially by a Nuclear chain fibre
fusiform spindle capsule of connective tissue, consisting of an outer
perineurium-like sheath of flattened fibroblasts and collagen, and an Subcapsular space
inner sheath that forms delicate tubes around individual intrafusal
fibres (Fig. 3.33). A gelatinous fluid rich in glycosaminoglycans fills the
space between the two sheaths. Primary (anulospiral)
ending of group 1a
There are usually 5–14 intrafusal fibres (the number varies between afferent fibre
muscles) and two major types of fibre, nuclear bag and nuclear chain
fibres, which are distinguished by the arrangement of nuclei in their
sarcoplasm. In nuclear bag fibres, an equatorial cluster of nuclei makes
the fibre bulge slightly, whereas the nuclei in nuclear chain fibres form
a single axial row. Nuclear bag fibres are subdivided into bag1 and bag2
fibres, are greater in diameter than chain fibres and extend beyond the
surrounding capsule to the endomysium of nearby extrafusal muscle Secondary (flower
spray) ending of
fibres. Nuclear chain fibres are attached at their poles to the capsule or
group II afferent fibre
to the sheaths of nuclear bag fibres.
The intrafusal fibres resemble typical skeletal muscle fibres, except
that the zone of myofibrils is thin around the nuclei. Dynamic bag1
fibres generally lack M lines, possess little sarcoplasmic reticulum, and
have an abundance of mitochondria and oxidative enzymes, but little
glycogen. Static bag2 fibres have distinct M lines and abundant glyco-
gen. Nuclear chain fibres have marked M lines, sarcoplasmic reticulum Trail ending of
γ-efferent fibre
and T-tubules, and abundant glycogen, but few mitochondria. Each
fibre type carries distinct myosin heavy chain isoforms. These variations
reflect the contractile properties of different intrafusal fibres.
Muscle spindles receive two types of sensory innervation via the Plate ending of
γ-efferent fibre
unmyelinated terminations of large myelinated axons. Primary (anulo-
spiral) endings are equatorially placed and form spirals around the
nucleated parts of intrafusal fibres. They are the endings of large sensory
fibres (group Ia afferents), each of which sends branches to a number
of intrafusal muscle fibres. Each terminal lies in a deep sarcolemmal
groove in the spindle plasma membrane beneath its basal lamina.
M
Secondary (flower spray) endings, which may be spray-shaped or anular,
Plate ending of
are largely confined to bag2 and nuclear chain fibres, and are the
β-efferent fibre
branched terminals of somewhat thinner myelinated (group II) affer-
ents. They are varicose and spread in a narrow band on both sides of
the primary endings. They lie close to the sarcolemma, though not in
grooves. In essence, primary endings are rapidly adapting, while second-
Fig. 3.31 A neuromuscular spindle, showing nuclear bag and nuclear
ary endings have a regular, slowly adapting response to static stretch.
chain fibres within the spindle capsule (green); these are innervated by
There are three types of motor endings in muscle spindles. Two are
the sensory anulospiral and ‘flower spray’ afferent fibre endings (blue) and
from fine, myelinated, fusimotor (γ) efferents and one is from myeli-
by the γ and β fusimotor (efferent fibre) endings (red). The β efferent fibres
nated (β) efferent collaterals of axons that supply extrafusal slow twitch are collaterals of fibres innervating extrafusal slow twitch muscle cells (M).
muscle fibres. The fusimotor efferents terminate nearer the equatorial
region, where their terminals either resemble the motor end-plates of
extrafusal fibres (plate endings) or are more diffuse (trail endings). acceleration. Moreover, they are under complex central control; efferent
Stimulation of the fusimotor and β-efferents causes contraction of the (fusimotor) nerve fibres, by regulating the strength of contraction, can
intrafusal fibres and, consequently, activation of their sensory endings. adjust the length of the intrafusal fibres and thereby the responsiveness
Muscle spindles signal the length of extrafusal muscle both at rest of spindle sensory endings. In summary, the organization of spindles
and throughout contraction and relaxation, the velocity of their con- allows them to monitor muscle conditions actively in order to compare
traction and changes in velocity. These modalities may be related to the intended and actual movements, and to provide a detailed input to
different behaviours of the three major types of intrafusal fibre and their spinal, cerebellar, extrapyramidal and cortical centres about the state of
sensory terminals. The sensory fusimotor endings of one type of nuclear the locomotor apparatus.
bag fibre (dynamic bag1) are particularly concerned with signalling
rapid changes in length that occur during movement, whilst those of
the second bag fibre type (static bag2) and of chain fibres are less JOINT RECEPTORS
responsive to movement. These elements can therefore detect complex
changes in the state of the extrafusal muscle surrounding spindles and The arrays of receptors situated in and near articular capsules provide
can signal fluctuations in length, tension, velocity of length change and information on the position, movements and stresses acting on joints. | 110 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Neuromuscular junctions
63
3
RETPAHC
Static bag2 deeper layers and other articular structures (e.g. the fat pad of the tem-
fibre poromandibular joint). They are rapidly adapting, low-threshold mech-
anoreceptors, sensitive to movement and pressure changes, and they
Dynamic bag1
fibre Long-chain respond to joint movement and transient stresses in the joint capsule.
fibre They are supplied by myelinated afferent axons but are probably not
Short-chain
fibres involved in the conscious awareness of joint sensation.
Type III endings are identical to Golgi tendon organs in structure
and function; they occur in articular ligaments but not in joint capsules.
They are high-threshold, slowly adapting receptors and may serve, at
least in part, to prevent excessive stresses at joints by reflex inhibition
of the adjacent muscles. They are innervated by large myelinated affer-
Dynamic γ-efferent
ent axons.
Type IV endings are free terminals of myelinated and unmyelinated
Static γ-efferent
axons that ramify in articular capsules and the adjacent fat pads, and
II around the blood vessels of the synovial layer. They are high-threshold,
slowly adapting receptors and are thought to respond to excessive
II
movements, providing a basis for articular pain.
Afferent fibres
Ia
NEUROMUSCULAR JUNCTIONS
Static γ-efferent
Static β-efferent SKELETAL MUSCLE
Dynamic β-efferent
The most intensively studied effector endings are those that innervate
muscle, particularly skeletal muscle. All neuromuscular (myoneural)
junctions are axon terminals of motor neurones. They are specialized
for the release of neurotransmitter on to the sarcolemma of skeletal
muscle fibres, causing a change in their electrical state that leads to
contraction. Each axon branches near its terminal to innervate from
several to hundreds of muscle fibres, the number depending on the
precision of motor control required (Shi et al 2012).
The detailed structure of a motor terminal varies with the type of
muscle innervated. Two major types of ending are recognized, innervat-
Collaterals to
extrafusal muscle ing either extrafusal muscle fibres or the intrafusal fibres of neuromus-
cular spindles. In the former type, each axonal terminal usually ends
Fig. 3.32 Nuclear bag and nuclear chain fibres in a neuromuscular midway along a muscle fibre in a discoidal motor end-plate (Fig.
spindle. Dynamic β- and γ-efferents innervate dynamic bag1 intrafusal
3.34A), and usually initiates action potentials that are rapidly con-
fibres, whereas static β- and γ-efferents innervate static bag2 and nuclear
ducted to all parts of the muscle fibre. In the latter type, the axon gives
chain intrafusal fibres.
off numerous branches that form a cluster of small expansions extend-
ing along the muscle fibre; in the absence of propagated muscle excita-
tion, these excite the fibre at several points. Both types of ending are
associated with a specialized receptive region of the muscle fibre, the
sole plate, where a number of muscle cell nuclei are grouped within the
granular sarcoplasm.
MM The sole plate contains numerous mitochondria, endoplasmic retic-
ulum and Golgi complexes. The terminal branches of the axon are
plugged into shallow grooves in the surface of the sole plate (primary
CC
clefts), from where numerous pleats extend for a short distance into the
underlying sarcoplasm (secondary clefts) (Fig. 3.34B,C). The axon ter-
minal contains mitochondria and many clear, 60 nm spherical vesicles
similar to those in presynaptic boutons, which are clustered over the
zone of membrane apposition. It is ensheathed by Schwann cells whose
cytoplasmic projections extend into the synaptic cleft. The plasma
membranes of the axon terminal and the muscle cell are separated by
IIFF
a 30–50 nm gap and an interposed basal lamina, which follows the
CC surface folding of the sole-plate membrane into the secondary clefts.
Endings of fast and slow twitch muscle fibres differ in detail: the sarco-
lemmal grooves are deeper, and the presynaptic vesicles more numer-
ous, in the fast fibres.
Fig. 3.33 A neuromuscular spindle in transverse section in a human Junctions with skeletal muscle are cholinergic: the release of ACh
extraocular muscle. The spindle capsule (C) encloses intrafusal fibres (IF)
changes the ionic permeability of the muscle fibre (Sine 2012). Cluster-
of varying diameters. Typical muscle fibres (M) in transverse section are
ing of ACh receptors at the neuromuscular junction depends in part on
shown above the spindle. Toluidine blue stained resin section.
the presence in the muscle basal lamina of agrin, which is secreted by
the motor neurone, and is important in establishing the postjunctional
Structural and functional studies have demonstrated at least four types molecular machinery. When the depolarization of the sarcolemma
of joint receptor; their proportions and distribution vary with site. Three reaches a particular threshold, it initiates an action potential in the
are encapsulated endings, the fourth a free terminal arborization. sarcolemma, which is then propagated rapidly over the whole cell
Type I endings are encapsulated corpuscles of the slowly adapting surface and also deep within the fibre via the invaginations (T-tubules)
mechanoreceptor type and resemble Ruffini endings. They lie in the of the sarcolemma, causing contraction. The amount of ACh released
superficial layers of the fibrous capsules of joints in small clusters and by the arrival of a single nerve impulse is sufficient to trigger an action
are innervated by myelinated afferent axons. Being slowly adapting, potential. However, because ACh is very rapidly hydrolysed by the
they provide awareness of joint position and movement, and respond enzyme AChE, present at the sarcolemmal surface of the sole plate, a
to patterns of stress in articular capsules. They are particularly common single nerve impulse only gives rise to one muscle action potential, i.e.
in joints where static positional sense is necessary for the control of there is a one-to-one relationship between neuronal and muscle action
posture (e.g. hip, knee). potentials. Thus the contraction of a muscle fibre is controlled by the
Type II endings are lamellated receptors and resemble small versions firing frequency of its motor neurone.
of the large Pacinian corpuscles found in general connective tissue. They Neuromuscular junctions are partially blocked by high concentra-
occur in small groups throughout joint capsules, particularly in the tions of lactic acid, as in some types of muscle fatigue. | 111 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
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A Fig. 3.34 The neuromuscular junction. A, Whole-mount preparation of teased
skeletal muscle fibres (pale, faintly striated, diagonally orientated structures).
The terminal part of the axon (silver-stained, brown) branches to form motor
end-plates on adjacent muscle fibres. The sole plate recesses in the
sarcolemma, into which the motor end-plates fit, are demonstrated by the
presence of acetylcholinesterase (shown by enzyme histochemistry, blue).
B, The axonal motor end-plate and the deeply infolded sarcolemma.
C, Electron micrograph showing the expanded motor end-plate of an axon
filled with vesicles containing synaptic transmitter (ACh) (above); the deep
infoldings of the sarcolemmal sole plate (below) form subsynaptic gutters.
(A, Courtesy of Dr Norman Gregson, Division of Neurology, GKT School of
Medicine, London. C, Courtesy of Professor DN Landon, Institute of
Neurology, University College London.)
AUTONOMIC MOTOR TERMINATIONS
Autonomic neuromuscular junctions differ in several important ways
from the skeletal neuromuscular junction and from synapses in the
Motor axon Schwann cell CNS and PNS. There is no fixed junction with well-defined pre- and
postjunctional specializations. Unmyelinated, highly branched, post-
ganglionic autonomic axons become beaded or varicose as they reach
the effector smooth muscle. These varicosities are not static but move
along axons. They are packed with mitochondria and vesicles contain-
ing neurotransmitters, which are released from the varicosities during
B conduction of an impulse along the axon. The distance (cleft) between
the varicosity and smooth muscle membrane varies considerably
depending on the tissue, from 20 nm in densely innervated structures
such as the vas deferens to 1–2 µm in large elastic arteries. Unlike skel-
etal muscle, the effector tissue is a muscle bundle rather than a single
cell. Gap junctions between individual smooth muscle cells are low-
resistance pathways that allow electronic coupling and the spread of
activity within the effector bundle; they vary in size from punctate junc-
tions to junctional areas of more than 1 µm in diameter.
Adrenergic sympathetic postganglionic terminals contain dense-
cored vesicles. Cholinergic terminals, which are typical of all parasym-
pathetic and some sympathetic endings, contain clear spherical vesicles
like those in the motor end-plates of skeletal muscle. A third category
of autonomic neurones has non-adrenergic, non-cholinergic endings
Muscle cell
Muscle nucleus that contain a wide variety of chemicals with transmitter properties.
sole plate Motor end-plate with ATP is a neurotransmitter at these terminals, which express purinergic
synaptic vesicles receptors (Burnstock et al 2011). The axons typically contain large,
Motor end-plate
80–200 nm, dense opaque vesicles, congregated in varicosities at inter-
vals along their length. These terminals are formed in many sites,
including the lungs, blood vessel walls, the urogenital tract and the
C external muscle layers and sphincters of the gastrointestinal tract. In the
intestinal wall, neuronal somata lie in the myenteric plexus, and their
axons spread caudally for a few millimetres, mainly to innervate circular
muscle. Purinergic neurones are under cholinergic control from pregan-
glionic sympathetic neurones. Their endings mainly hyperpolarize
smooth muscle cells, causing relaxation, e.g. preceding peristaltic waves,
opening sphincters and, probably, causing reflex distension in gastric
filling. Autonomic efferents innervate exocrine glands, myoepithelial
cells, adipose tissue (noradrenaline (norepinephrine) released from
postganglionic sympathetic axons binds to β-receptors on adipocytes
3
to stimulate lipolysis) and the vasculature and parenchymal fields of
lymphocytes and associated cells in several lymphoid organs, including
the thymus, spleen and lymph nodes.
CNS–PNS TRANSITION ZONE
The transition between CNS and PNS usually occurs some distance
from the point at which nerve roots emerge from the brain or the spinal
cord. The segment of root that contains components of both CNS and
PNS tissue is called the CNS–PNS transition zone (TZ). All axons in the
PNS, other than postganglionic autonomic neurones, cross such a TZ.
Macroscopically, as a nerve root is traced towards the spinal cord or the
brain, it splits into several thinner rootlets that may, in turn, subdivide
into minirootlets. The TZ is located within either rootlet or minirootlet
(Fig. 3.35). The arrangement of roots and rootlets varies according to
whether the root trunk is ventral, dorsal or cranial. Thus, in dorsal roots,
the main root trunk separates into a fan of rootlets and minirootlets
that enter the spinal cord in sequence along the dorsolateral sulcus. In
certain cranial nerves, the minirootlets come together central to the TZ
and enter the brain as a stump of white matter. | 112 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Conduction of the nervous impulse
65
3
RETPAHC
R R Nerve root
R CNS tissue
Glial fringe
Mantle zone
TZ
r1 r2 r3
R
R R R
SC BS
A B C D E F G
Fig. 3.35 The nerve root–spinal cord junction. A–G, Different CNS–PNS borderline arrangements. A, A pointed borderline. The extent of the transitional
zone (TZ) is indicated. B–G, Glial fringe omitted. B, A concave borderline (white line) and inverted TZ. C, A flat borderline situated at the level of the root
(R)–spinal cord junction. D and E, A convex, dome-shaped borderline; the CNS expansion into the rootlet is moderate in D and extensive in E. F, The
root (R) splits into rootlets (r), each with its own TZ and attaching separately to the spinal cord (SC). G, The arrangement found in several cranial nerve
roots (e.g. vestibulocochlear nerve). The PNS component of the root separates into a bundle of closely packed minirootlets, each equipped with a TZ.
The minirootlets reunite centrally. BS, brainstem. (Adapted with permission from Dyck PJ, Thomas PK, Griffin JW, et al (eds) Peripheral Neuropathy,
3rd ed. Philadelphia: Saunders, 1993.)
All-or-none action potentials
Graded potentials generated at nodes along axon
Membrane
potential
Excitation Inhibition Net effect at axon
(depolarization) (hyperpolarization) hillock is excitation
+40 mV
Time
0
-80 mV
Inhibitory
axon
Excitatory
axon
Conduction
Fig. 3.36 The types of change in electrical potential that can be recorded across the cell membrane of a motor neurone at the points indicated.
Excitatory and inhibitory synapses on the surfaces of the dendrites and soma cause local graded changes of potential that summate at the axon hillock
and may initiate a series of all-or-none action potentials, which in turn are conducted along the axon to the effector terminals.
Microscopically, the TZ is characterized by an axial CNS compart- thought to prevent cell mixing at these interfaces not only by helping
ment surrounded by a PNS compartment. The zone lies more peripher- dorsal root ganglion afferents navigate their path to targets in the spinal
ally in sensory nerves than in motor nerves, but in both, the apex of cord but also by inhibiting motoneurone cell bodies exiting to the
the TZ is described as a glial dome, whose convex surface is usually periphery. For further reading, see Zujovic et al (2011).
directed distally. The centre of the dome consists of fibres with a typical
CNS organization, surrounded by an outer mantle of astrocytes (cor-
CONDUCTION OF THE NERVOUS IMPULSE
responding to the glia limitans). From this mantle, numerous glial
processes project into the endoneurial compartment of the peripheral
nerve, where they interdigitate with its Schwann cells. The astrocytes All cells generate a steady electrical potential across their plasma mem-
form a loose reticulum through which axons pass. Peripheral myeli- brane (the membrane potential). This potential is generated by an
nated axons usually cross the zone at a node of Ranvier, which is here uneven distribution of potassium ions across the membrane (higher in
termed a PNS–CNS compound node. the intracellular compartment than in the extracellular compartment),
Boundary cap (BC) cells are neural crest derivatives that form tran- and by a selective permeability of the membrane for potassium (Fig.
sient, discrete clusters localized at the presumptive dorsal root entry 3.36). The distribution of sodium ions is opposite to that for potassium
zones and motor exit points of the embryonic spinal cord. They are ions, but at rest the sodium conductance of the membrane is low. In | 113 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
NERvOuS SySTEm
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NOITCES
neurones this membrane potential is known as the resting potential, tion of neighbouring membrane. Sodium channels within the newly
and amounts to approximately −60 mV (potential inside the cell meas- depolarized segment open and positively charged sodium ions enter,
ured relative to the outside of the cell). Non-excitable cells have an even driving the local potential inside the axon towards positive values. This
higher membrane potential. Neurones receive, conduct and transmit inward current in turn depolarizes the neighbouring, downstream, non-
information by changes in membrane conductance for sodium, potas- depolarized membrane, and the cyclic propagation of the action poten-
sium, calcium or chloride ions. Increase in the sodium or calcium tial is completed. Several milliseconds after the action potential, the
conductance causes an influx of these ions and results in a depolariza- sodium channels are inactivated, a period known as the refractory
tion of the cell, while chloride influx or potassium efflux results in period. The length of the refractory period determines the maximum
hyperpolarization. Plasma membrane permeability to these ions is frequency at which action potentials can be conducted along a nerve
altered by the opening or closing of ion-specific transmembrane chan- fibre; it varies in different neurones and affects the amount of informa-
nels, triggered by voltage changes or chemical signals such as transmit- tion that can be carried by an individual fibre.
ters (Catterall 2010). Myelinated fibres are electrically insulated by their myelin sheaths
Chemically triggered ionic fluxes may be either direct, where the along most of their lengths, except at nodes of Ranvier. The distance
chemical agent (neurotransmitter) binds to the channel itself to cause between nodes, referred to as the internodal distance, is directly related
it to open, or indirect, where the neurotransmitter is bound by a trans- to axon diameter and varies between 0.2 and 2.0 mm. Voltage-gated
membrane receptor molecule that activates a complex second messen- sodium channels are clustered at nodes, and the nodal membrane is
ger system within the cell to open separate transmembrane channels. the only place where high densities of inward sodium current can be
Electrically induced changes in membrane potential depend on the generated across the axon membrane. Conduction in myelinated axons
presence of voltage-sensitive ion channels, which, when the transmem- is self-propagating, but instead of physically adjacent regions of mem-
brane potential reaches a critical level, open to allow the influx or efflux brane acting to excite one another (as occurs along unmyelinated
of specific ions. In all cases, the channels remain open only transiently, axons), it is the depolarization occurring in the neighbouring upstream
and the numbers that open and close determine the total flux of ions node that excites a node to threshold. Reaching threshold causes the
across the membrane (Bezanilla 2008). sodium channels at the node to open and generate inward sodium
The types and concentrations of transmembrane channels and current, but instead of this acting on the adjacent membrane, the high
related proteins, and therefore the electrical activity of the membranes, resistance and low capacitance of the myelin sheath directs the current
vary in different parts of the cell. Dendrites and neuronal somata depend towards the next downstream node, exciting it to threshold and com-
mainly on neurotransmitter action and show graded potentials, whereas pleting the cycle. The action potential thus jumps from node to node,
axons have voltage-gated channels that give rise to action potentials. a process known as saltatory conduction, which greatly increases the
In graded potentials, a flow of current occurs when a synapse is conduction velocity.
activated; the influence of an individual synapse on the membrane A number of disorders of the CNS and PNS include demyelination
potential of neighbouring regions decreases with distance. Thus syn- as a characteristic feature. Perhaps most common amongst these is
apses on the distal tips of dendrites may, on their own, have relatively multiple sclerosis, which is characterized by primary demyelination at
little effect on the membrane potential of the cell body. The electrical scattered sites within the CNS (it is now recognized that axonal loss
state of a neurone therefore depends on many factors, including the also contributes to the progression of multiple sclerosis). Primary
numbers and positions of thousands of excitatory and inhibitory syn- demyelination is the loss of the myelin sheath with axonal preservation,
apses, their degree of activation, and the branching pattern of the den- and is usually segmental, i.e. it rarely extends along the entire length of
dritic tree and geometry of the cell body. The integrated activity directed an affected axon. The phenomenon is associated with conduction block
towards the neuronal cell body is converted to an output directed away because the newly exposed, previously internodal, axolemma contains
from the soma at the site where the axon leaves the cell body, at its relatively few voltage-sensitive Na+ channels. There is experimental evi-
junction with the axon hillock. Voltage-sensitive channels are concen- dence that conduction can be restored in some demyelinated axons,
trated at this trigger zone, the axon initial segment, and when this and experimental and clinical evidence that remyelinated axons can
region is sufficiently depolarized, an action potential is generated and conduct at near-normal speeds, because even though their sheaths are
is subsequently conducted along the axon. thinner than the original myelin sheaths, the safety factor (i.e. the factor
by which the outward current at a quiescent node next to an excited
node exceeds the minimum current required to evoke a response) is
ACTION POTENTIAL greater than 1. The myelin loss that occurs in the early stages of Walle-
rian degeneration in both CNS and PNS, usually distal to a site of
The action potential is a brief, self-propagating reversal of membrane trauma but also in response to a prolonged period of ischaemia or
polarity. It depends on an initial influx of sodium ions, which causes a exposure to a neuronotoxic substance, is accompanied by axonal degen-
reversal of polarity to about +20 mV, followed by a rapid return towards eration (the term secondary demyelination is sometimes used to
the resting potential as potassium ions flow out. The rapid reversal describe this form of myelin loss).
process is completed in approximately 0.5 msec, followed by a slower Axonal conduction is naturally unidirectional, from dendrites and
recovery phase of up to 5 msec, when the resting potential is even soma to axon terminals. When an action potential reaches the axonal
hyperpolarized. Once the axon hillock reaches threshold, propagation terminals, it causes depolarization of the presynaptic membrane, and
of the action potential is independent of the initiating stimulus; thus as a result, quanta of neurotransmitter (which correspond to the content
the size and duration of action potentials are always the same (described of individual vesicles) are released to change the degree of excitation of
as all-or-none) for a particular neurone, no matter how much a stimulus the next neurone, muscle fibre or glandular cell.
may exceed the threshold value.
Once initiated, an action potential spreads spontaneously and at a
relatively constant velocity, within the range of 4–120 m/s. Conduction
Bonus e-book image
velocity depends on a number of factors related to the way in which
the current spreads, e.g. axonal cross-sectional area, the numbers and
positioning of ion channels, and membrane capacitance (influenced
particularly by the presence of myelin). In axons lacking myelin, action Fig. 3.1 A section through the human cerebellum stained to show
potential conduction is analogous to a flame moving along a fuse. Just the arrangement in the brain of the central white matter and the
as each segment of fuse is ignited by its upstream neighbour, each highly folded outer grey matter.
segment of axon membrane is driven to threshold by the depolariza- | 114 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
67
3
RETPAHC
Key references
KEY REFERENCES
Finger S 2001 Origins of Neuroscience: A History of Explorations into Brain Sakmann B, Neher E 2009 Single-channel Recording. New York: Springer.
Function. New York: Oxford University Press. An introduction to the patch-clamp technique and electrophysiology.
A historic introduction to the neuroscience field.
Sanes DH, Reh TA, Harris WA 2011 Development of the Nervous System,
Kandel ER, Schwartz JH, Jessell TM et al 2012 Principles of Neural Science, 3rd ed. Oxford: Elsevier, Academic Press.
5th ed. New York: McGraw–Hill. A textbook on developmental neurobiology.
A basic but comprehensive neuroscience textbook
Shepherd GM 2003 The Synaptic Organization of the Brain. New York:
Kempermann G 2011 Adult Neurogenesis 2. New York: Oxford University Oxford University Press.
Press. A description of the circuitry of the brain.
A summary of the knowledge on adult neurogenesis.
Squire L, Kandel E 2008 Memory: From Mind to Molecules. Greenwood
Kettenmann H, Ransom BR 2012 Neuroglia. New York: Oxford University Village, CO: Roberts.
Press. A description of the mechanism of memory formation.
A comprehensive textbook on glial cells.
Squire L, Berg D, Bloom FE et al 2012 Fundamental Neuroscience, 4th ed.
Levitan IB, Kaczmarek LK 2001 The Neuron: Cell and Molecular Biology. Oxford: Elsevier, Academic Press.
New York: Oxford University Press. A basic but comprehensive neuroscience textbook.
A basic neuroscience textbook with the focus on neurones.
Nicholls JG, Martin AR, Fuchs PA et al 2011 From Neuron to Brain, 5th ed.
Sunderland, MA: Sinauer Associates.
A basic and comprehensive neuroscience textbook. | 115 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Nervous system
67.e1
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CHAPTER Blood, lymphoid tissues
4
and haemopoiesis
Blood is an opaque fluid with a viscosity greater than that of water defensive cells (white blood cells, or leukocytes). The latter include
(mean relative viscosity 4.75 at 18°C), and a specific gravity of 1.06 at neutrophil, eosinophil and basophil granulocytes, B lymphocytes and
15°C. It is bright red when oxygenated, in the systemic arteries, and dark monocytes. T lymphocytes develop in the thymus from bone marrow-
red to purple when deoxygenated, in systemic veins. Blood is a mixture derived progenitors. These cells all contribute to the immune system of
of a clear liquid, plasma and cellular elements, and consequently the the human (for an overview of the immune system, see Murphy (2011)).
hydrodynamic flow of blood in vessels behaves in a complex manner Platelets are produced in the bone marrow as cellular fragments of
that is not entirely predictable by simple Newtonian equations. megakaryocytes. Only erythrocytes and platelets are generally confined
Plasma is a clear, yellowish fluid that contains many substances in to the blood vascular system, whereas all leukocytes can leave the cir-
solution or suspension: low-molecular-weight solutes give a mean culation and enter extravascular tissues. The numbers of cells doing so
freezing-point depression of 0.54°C. Plasma contains high concentra- increases greatly during inflammation caused by local infections or
tions of sodium and chloride ions, potassium, calcium, magnesium, tissue damage.
phosphate, bicarbonate, traces of many other ions, glucose, amino acids The lymphoid tissues are the thymus, lymph nodes, spleen and the
and vitamins. It also includes high-molecular-weight plasma proteins, lymphoid follicles associated mainly with the alimentary and respira-
e.g. clotting factors, particularly prothrombin; immunoglobulins and tory tracts. Lymphocytes populate lymphoid tissues and are concerned
complement proteins involved in immunological defence; glycopro- with immune defence. Lymphoid tissue also contains supportive stro-
teins, lipoproteins, polypeptide and steroid hormones, and globulins mal cells, which are non-haemopoietic in origin (e.g. thymic epithe-
for the transport of hormones and iron. The plasma is involved in the lium); non-haemopoietic follicular dendritic cells of lymph nodes and
transport of most molecules that are released or secreted by cells in splenic follicles; haemopoietically derived dendritic cells; and macro-
response to pathological or physiological stimuli and so the routine phages of the mononuclear phagocyte system. Dendritic cells and blood
chemical analysis of plasma is of great diagnostic importance. There is monocyte-derived macrophages are found additionally in most tissues
increasing interest in using metabolomics approaches for the high- and organs, where they function as antigen-presenting cells (APCs).
throughput analysis of small molecules or metabolites in the serum, as
a potential aid to diagnosis and understanding of disease (Psychogios
CELLS OF PERIPHERAL BLOOD
et al 2011).
The precipitation of the protein fibrin from plasma to form a clot
(Fig. 4.1) is initiated by the release of specific materials from damaged ERYTHROCYTES
cells and blood platelets in the presence of calcium ions. If blood or
plasma samples are allowed to stand, they will separate into a clot and Erythrocytes (red blood cells, RBCs) account for the largest proportion
a clear yellowish fluid, the serum. Clot formation is prevented by of blood cells (99% of the total number), with normal values of
removal of calcium ions, e.g. by addition of citrate, oxalate or various 4.1–6.0 × 106/µl in adult males and 3.9–5.5 × 106/µl in adult females.
organic calcium chelators (EDTA, EGTA) to the sample. Heparin is also Polycythaemia (increased red cell mass) can occur in individuals living
widely used as an anticlotting agent because it interferes with fibrin clot at high altitude, or pathologically in conditions resulting in arterial
formation. hypoxia. Reduction in red cell mass (anaemia) has many underlying
In postnatal life, blood cells are formed in the bone marrow. Hae- causes but in rare instances can be due to structural defects in erythro-
mopoiesis produces red cells (erythrocytes) and a wide variety of cytes (see below).
Each erythrocyte is a biconcave disc (see Fig. 4.1; Fig. 4.2) with a
mean diameter in dried smear preparations of 7.1 µm; in fresh prepara-
tions the mean diameter is 7.8 µm, decreasing slightly with age. Mature
erythrocytes lack nuclei. They are pale red by transmitted light, with
Fig. 4.2 A human heart muscle biopsy specimen, showing an erythrocyte
within a capillary. The erythrocyte biconcave disc is typically electron-
Fig. 4.1 Erythrocytes enmeshed in filaments of fibrin in a clot. (Courtesy dense and almost fills the capillary lumen. (Courtesy of Dr Bart Wagner,
of Michael Crowder MD.) Histopathology Department, Sheffield Teaching Hospitals, UK.) | 118 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Cells of peripheral blood
69
4
RETPAHC
paler centres because of their biconcave shape. The properties of their exposed on the aged erythrocyte. These lead to the cells being recog-
cell coat cause them to adhere to one another by their rims to form nised and taken up by macrophages. Red cells are destroyed at the rate
loose piles of cells (rouleaux). In normal blood, a few cells assume a of 5 × 1011 cells a day (or nearly 6 million a second) and are normally
shrunken, star-like, crenated form; this shape can be reproduced by replaced from the bone marrow (see Fig. 4.12) at the same rate.
placing normal biconcave erythrocytes in a hypertonic solution, which
causes osmotic shrinkage. In hypotonic solutions erythrocytes take up Blood groups
water and become spherical; they may eventually lyse to release their
haemoglobin (haemolysis), leaving red-cell ghosts.
Over 300 red cell antigens are recognizable with specific antisera. They
Erythrocytes have a plasma membrane that encloses mainly a single
can interact with naturally occurring or induced antibodies in the
protein, haemoglobin, as a 33% solution. The plasma membrane of
plasma of recipients of an unmatched transfusion, causing agglutina-
erythrocytes is 60% lipid and glycolipid, and 40% protein and
tion and lysis of the erythrocytes. Erythrocytes of a single individual
glycoprotein.
carry several different types of antigen, each type belonging to an anti-
More than 15 classes of protein are present, including two major
genic system in which a number of alternative antigens are possible in
types. Glycophorins A and B (each with a molecular mass of approxi-
different persons. So far, 19 major groups have been identified. They
mately 50 kDa) span the membrane, and their negatively charged car-
vary in their distribution frequencies between different populations,
bohydrate chains project from the outer surface of the cell. Their sialic
and include the ABO, Rhesus, MNS, Lutheran, Kell, Lewis, Duffy, Kidd,
acid groups confer most of the fixed charge on the cell surface. A second
Diego, Cartwright, Colton, Sid, Scianna, Yt, Auberger, Ii, Xg, Indian and
transmembrane macromolecule, band 3 protein, forms an important
Dombrock systems. Clinically, the ABO and Rhesus groups are of most
anion channel, exchanging bicarbonate for chloride ions across the
importance.
membrane and allowing the release of CO in the lungs.
2 Leukocytes also bear highly polymorphic antigens encoded by allelic
The filamentous protein, spectrin, is responsible for maintaining the
gene variants. These belong to the group of major histocompatibility
shape of the erythrocyte. A dimer is formed of α1 and β1 spectrin
complex (MHC) antigens, also termed human leukocyte antigens
monomers, and two dimers then come together to form a tetramer
(HLA) in humans. HLA class I antigens are expressed by all nucleated
(Machnicka et al 2013). These are joined by junctional complexes that
cells. Class II antigens are expressed on antigen-presenting cells (APCs)
contain (among other proteins) ankyrin, short actin filaments, tropo-
of the immune system, but can also be induced on many parenchymal
myosin and protein 4.1, forming a hexagonal lattice that supports the
cell types, e.g. after exposure to interferon. HLA class I and II antigens
plasma membrane (Mankelow et al 2012). The junctional complex also
play important roles in cell–cell interactions in the immune system,
interacts with transmembrane proteins. This structure gives the mem-
particularly in the presentation of antigens to T lymphocytes by APCs.
brane great flexibility; red cells are deformable but regain their bicon-
cave shape and dimensions after passing through the smallest capillaries,
which are 4 µm in diameter (Mohandas and Gallagher 2008). Erythro- LEUKOCYTES
cyte membrane flexibility also contributes to the normally low viscosity
of blood. Molecular defects in the cytoskeleton result in abnormalities Leukocytes (white blood cells) belong to at least five different categories
of red cell shape, membrane fragility, premature destruction of eryth- (see Fig. 4.12) and are distinguishable by their size, nuclear shape and
rocytes in the spleen and haemolytic anaemia (Iolascon et al 1998). cytoplasmic inclusions. In practice, leukocytes are often divided into
Fetal erythrocytes up to the fourth month of gestation differ mark- two main groups: namely, those with prominent stainable cytoplasmic
edly from those of adults, in that they are larger, are nucleated and granules, the granulocytes, and those without.
contain a different type of haemoglobin (HbF). After this time they are
progressively replaced by the adult type of cell. Granulocytes
Haemoglobin
This group consists of eosinophil granulocytes, with granules that bind
acidic dyes such as eosin; basophil granulocytes, with granules that bind
Haemoglobin (Hb) is a globular protein with a molecular mass of basic dyes strongly; and neutrophil granulocytes, with granules that
67 kDa. It consists of globulin molecules bound to haem, an iron- stain only weakly with either type of dye. Granulocytes (Fig. 4.3) all
containing porphyrin group. The oxygen-binding power of haemo- possess irregular or multilobed nuclei and belong to the myeloid series
globin is provided by the iron atoms of the haem groups, and these are of blood cells (see Fig. 4.12).
maintained in the ferrous (Fe++) state by the presence of glutathione
Neutrophil granulocytes
within the erythrocyte. The haemoglobin molecule is a tetramer, made
up of four subunits, each a coiled polypeptide chain holding a single Neutrophil granulocytes (neutrophils) are also referred to as polymor-
haem group. phonuclear leukocytes (polymorphs) because of their irregularly
Mutations in the haemoglobin chains can result in a range of pathol-
ogies (Forget and Bunn 2013).
Lifespan
Erythrocytes last between 100 and 120 days before being destroyed. As
erythrocytes age, they become increasingly fragile, and their surface
charges decrease as their content of negatively charged membrane glyco-
proteins diminishes. The lipid content of their membranes also reduces.
Aged erythrocytes are taken up by the macrophages of the spleen N
(Mebius and Kraal 2005) and liver sinusoids, usually without prior
lysis, and are hydrolysed in phagocytic vacuoles where the haemoglobin
is split into its globulin and porphyrin moieties. Globulin is further
degraded to amino acids, which pass into the general amino-acid pool.
Iron is removed from the porphyrin ring and either transported in the
circulation bound to transferrin and used in the synthesis of new hae- B
moglobin in the bone marrow, or stored in the liver as ferritin or
haemosiderin. The remainder of the haem group is converted in the
liver to bilirubin and excreted in the bile. Haemoglobin that is released
by destruction of erythrocytes in the body binds to haptoglobin, and is
taken up via CD163 receptors expressed on the surface of macrophages
(Kristiansen et al 2001).
The recognition of effete erythrocytes by macrophages appears to
take place by a number of mechanisms (Bratosin et al 1998). These Fig. 4.3 Neutrophil (N) and basophil (B) granulocytes within a renal
include the exposure of phospholipids (such as phosphatidyl serine) glomerular capillary in a human kidney biopsy. The neutrophil nucleus is
that are normally found on the inner leaflet of the membrane bilayer, more segmented (four lobes are visible) and the granules are smaller and
alterations in the carbohydrates expressed by the cells (most notably more electron-dense than in the basophil. (Courtesy of Dr Bart Wagner,
the loss of sialic acid) and the binding of autoantibodies to antigens Histopathology Department, Sheffield Teaching Hospitals, UK.) | 119 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Blood, lymphoid tissues and haemopoiesis
69.e1
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RETPAHC
In normal blood, five types of polypeptide chain can occur: namely, antibodies in the donated blood are diluted to insignificant levels.
α, β and two β-like polypeptides, γ and δ. A third, β-like η chain is Normally, however, blood is only transfused between persons with cor-
restricted to early fetal development. Each haemoglobin molecule con- responding groups because anomalous antibodies of the ABO system
tains two α-chains and two others, so that several combinations, and are occasionally found in blood and may cause agglutination or lysis.
hence a number of different types of haemoglobin molecule, are pos- The anti-ABO agglutinins, unlike those of the Rhesus system, belong to
sible. For example, haemoglobin A (HbA), which is the major adult the immunoglobulin M (IgM) class and do not cross the placenta
class, contains 2 α- and 2 β-chains; a variant, HbA with 2 α- and 2 during pregnancy.
2
δ-chains, accounts for only 2% of adult haemoglobin. Haemoglobin F The Rhesus antigen system is determined by three sets of alleles:
(HbF), found in fetal and early postnatal life, consists of 2 α- and 2 namely, Cc, Dd and Ee. The most important clinically is Dd. Inheritance
γ-chains. Adult red cells normally contain less than 1% of HbF. of the Rh factor also obeys simple Mendelian laws; it is therefore pos-
In the genetic condition thalassaemia, only one type of chain is sible for a Rhesus-negative mother to bear a Rhesus-positive child.
expressed normally, the mutant chain being absent or present at much Under these circumstances, fetal Rh antigens can stimulate the produc-
reduced levels. Thus, a molecule may contain 4 α-chains (β-thalassaemia) tion of anti-Rh antibodies by the mother; as these belong to the IgG
or 4 β-chains (α-thalassaemia). In haemoglobin S (HbS) of sickle-cell class of antibody they are able to cross the placenta. For most of the
disease, a point mutation in the β-chain gene (valine substituted for pregnancy the stroma stops the blood group antibodies from crossing
glutamine) causes the haemoglobin to polymerize under conditions of into the fetal circulation. However, immediately prior to birth, the
low oxygen concentration, thus deforming the red blood cell. antibodies can cross this barrier and cause destruction of fetal erythro-
In the ABO system, two allelic genes are inherited in simple Mende- cytes. In the first such pregnancy little damage usually occurs because
lian fashion. Thus the genome may be homozygous and carry the AA anti-Rh antibodies have not been induced, but in subsequent Rh-positive
complement, the blood group being A, or the BB complement, which pregnancies massive destruction of fetal red cells may result, causing
gives blood group B, or it may carry neither (OO), producing blood fetal or neonatal death (haemolytic disease of the newborn). Sensitiza-
group O. In the heterozygous condition the following combinations tion of the maternal immune system can also result from abortion or
can occur: AB (blood group AB), AO (blood group A) and BO (blood miscarriage, or occasionally even from amniocentesis, which may intro-
group B). The ABO blood group antigens are all membrane glycolipids. duce fetal antigens into the maternal circulation. Treatment is by
Individuals with group AB blood lack antibodies to both A and B exchange transfusion of the neonate or, prophylactically, by giving
antigens, and so can be transfused with blood of any group; they are Rh-immune (anti-D) serum to the mother after the first Rh-positive
termed universal recipients. Conversely, those with group O, universal pregnancy, which destroys the fetal Rh antigen in her circulation before
donors, can give blood to any recipient, since anti-A and anti-B sensitization can occur. | 120 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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segmented (multilobed) nuclei. They form the largest proportion of the capacity to neutrophils, but are present only in small numbers in
white blood cells (40–75% in adults, with a normal count of 2500– normal blood (100–400/µl). The nucleus has two prominent lobes
7500/µl) and have a diameter of 12–14 µm. The cells may be spherical connected by a thin strand of chromatin. Their cytoplasmic specific
in the circulation, but they can flatten and become actively motile granules are uniformly large (0.5 µm) and give the living cell a slightly
within the extracellular matrix of connective tissues. yellowish colour. The cytoplasm is packed with granules, which are
The numerous cytoplasmic granules are heterogeneous in size, spherical or ellipsoid and membrane-bound. The core of each granule
shape and content, but all are membrane-bound and contain hydro- is composed of a lattice of major basic protein, which is responsible
lytic and other enzymes. Two major types can be distinguished accord- for its strong eosinophilic staining properties. The surrounding
ing to their developmental origin and contents. Non-specific or matrix contains several lysosomal enzymes including acid phosphatase,
primary (azurophilic) granules are formed early in neutrophil matura- ribonuclease, phospholipase and a myeloperoxidase unique to
tion. They are relatively large (0.5 µm) spheroidal lysosomes contain- eosinophils.
ing myeloperoxidase, acid phosphatase, elastase and several other Like other leukocytes, eosinophils are motile. When suitably stimu-
enzymes. Specific or secondary granules are formed later, and occur in lated, they are able to pass into the extravascular tissues from the circu-
a wide range of shapes including spheres, ellipsoids and rods. These lation. They are typical minor constituents of the dermis, and of the
contain strong bacteriocidal components including alkaline phos- connective tissue components of the bronchial tree, alimentary tract,
phatase, lactoferrin and collagenase, none of which is found in primary uterus and vagina. The total lifespan of these cells is a few days, of which
granules. Conversely, secondary granules lack peroxidase and acid some 10 hours is spent in the circulation, and the remainder in the
phosphatase. Some enzymes, e.g. lysozyme, are present in both types extravascular tissues.
of granule. Eosinophil numbers rise (eosinophilia) in worm infestations and
In mature neutrophils the nucleus is characteristically multilobed also in certain allergic disorders, and it is thought that they evolved as
with up to six (usually three or four) segments joined by narrow nuclear a primary defence against parasitic attack. They have surface receptors
strands; this is known as the segmented stage. Less mature cells have for IgE that bind to IgE-antigen complexes, triggering phagocytosis and
fewer lobes. The earliest to be released under normal conditions are release of granule contents. However, they are only weakly phagocytic
juveniles (band or stab cells), in which the nucleus is an unsegmented and their most important function is the destruction of parasites too
crescent or band. In certain clinical conditions, even earlier stages in large to phagocytose. This antiparasitic effect is mediated via toxic mol-
neutrophil formation, when cells display indented or rounded nuclei ecules released from their granules (e.g. eosinophil cationic protein and
(metamyelocytes or myelocytes) may be released from the bone marrow. major basic protein). They also release histaminase, which limits the
In mature cells the edges of the nuclear lobes are often irregular. inflammatory consequences of mast cell degranulation. High local con-
In females 3% of the nuclei of neutrophils show a conspicuous ‘drum- centrations of eosinophils, e.g. in bronchial asthma and in cutaneous
stick’ formation, which represents the sex chromatin of the inactive X contact sensitivity and allergic eczema, can cause tissue destruction as
chromosome (Barr body). Neutrophil cytoplasm contains few mito- a consequence of the release of molecules such as collagenase from their
chondria but abundant cytoskeletal elements, including actin filaments, granules.
microtubules and their associated proteins, all characteristic of highly
motile cells. Basophil granulocytes
Neutrophils are important in the defence of the body against micro- Slightly smaller than other granulocytes, basophil granulocytes are
organisms. They can phagocytose microbes and small particles in the 10–14 µm in diameter, and form only 0.5–1% of the total leukocyte
circulation and, after extravasation, they carry out similar activities in population of normal blood, with a count of 25–200/µl. Their distin-
other tissues. They function effectively in relatively anaerobic condi- guishing feature is the presence of large, conspicuous basophilic gran-
tions, relying largely on glycolytic metabolism, and they fulfil an impor- ules. The nucleus is somewhat irregular or bilobed, and is usually
tant role in the acute inflammatory phase of tissue injury, responding obscured in stained blood smears by the similar colour of the basophilic
to chemotaxins released by damaged tissue. Phagocytosis of cellular granules. The granules are membrane-bound vesicles, which display a
debris or invading microorganisms is followed by fusion of the phago- variety of crystalline, lamellar and granular inclusions: they contain
cytic vacuole with granules, which results in bacterial killing and diges- heparin, histamine and several other inflammatory agents, and closely
tion. Actively phagocytic neutrophils are able to reduce oxygen resemble those of tissue mast cells. Both basophils and mast cells have
enzymatically to form reactive oxygen species including superoxide high-affinity membrane receptors for IgE and are therefore coated with
radicals and hydrogen peroxide, which enhance bacterial destruction IgE antibody. If this binds to its antigen it triggers degranulation of the
probably by activation of some of the granule contents (Segal 2005, cells, producing vasodilation, increased vascular permeability, chemo-
Nathan 2006). Neutrophils can also produce neutrophil extracellular tactic stimuli for other granulocytes, and the symptoms of immediate
traps (NETs), which are web-like structures composed of DNA and hypersensitivity, e.g. in allergic rhinitis (hay fever). Despite these simi-
proteolytic enzymes that can trap bacteria and kill them (Kaplan and larities, basophils and mast cells develop as separate lineages in the
Radic 2012). myeloid series, from haemopoietic stem cells in the bone marrow.
Phagocytosis is greatly facilitated by circulating antibodies to mol- Evidence from experimental animal models suggests that they are
ecules such as bacterial antigens, which the body has previously closely related (see Fig. 4.12) but studies on mast cell disorders in
encountered. Antibodies coat the antigenic target and bind the plasma humans indicate that their lineages diverge from a more distant ances-
complement protein, C1, to their non-variable Fc regions. This activates tral progenitor (Kocabas et al 2005). The role of mast cells in the regula-
the complement cascade, which involves some 20 plasma proteins tion of responses to pain is of interest clinically as a therapeutic target
synthesized mainly in the liver, and completes the process of opsoniza- (Chatterjea and Martinov 2015).
tion. The complement cascade involves the sequential cleavage of the
complement proteins into a large fragment, which generally binds to
Mononuclear leukocytes
the antigenic surface, and a small bioactive fragment, which is released.
The final step is the recognition of complement by receptors on the
Monocytes
surfaces of neutrophils (and macrophages), which promotes phagocy-
tosis of the organism. Monocytes are the largest of the leukocytes (15–20 µm in diameter) but
Neutrophils are short-lived; they spend some 6–7 hours circulating they form only a small proportion of the total population (2–8% with
in the blood and a few days in connective tissues. The number of cir- a count of 100–700/µl of blood). The nucleus, which is euchromatic,
culating neutrophils varies, and often rises during episodes of acute is relatively large and irregular, often with a characteristic indentation
bacterial infection. They die after carrying out their phagocytic role; on one side. The cytoplasm is pale-staining, particulate and typically
dead neutrophils, bacteria, tissue debris (including tissue damaged by vacuolated. Near the nuclear indentation it contains a prominent Golgi
neutrophil enzymes and toxins) and interstitial fluid form the charac- complex and vesicles. Monocytes are actively phagocytic cells and
teristic, greenish-yellow pus of infected tissue. The colour is derived contain numerous lysosomes. Phagocytosis is triggered by recognition
from the natural colour of neutrophil myeloperoxidase. of opsonized material, as described for neutrophils. Monocytes are
Granules may also be released inappropriately from neutrophils. highly motile and possess a well-developed cytoskeleton.
Their enzymes are implicated in various pathological conditions, e.g. Monocytes express class II MHC antigens and share other similarities
rheumatoid arthritis, where tissue destruction and chronic inflamma- to tissue macrophages and dendritic cells. Most monocytes are thought
tion occur. to be in transit via the blood stream from the bone marrow to the
peripheral tissues, where they give rise to macrophages and dendritic
Eosinophil granulocytes cells; different monocyte subsets may target inflamed tissues. Like other
Eosinophil granulocytes (eosinophils; for a review, see Rothenberg and leukocytes, they pass into extravascular sites through the walls of capil-
Hogan (2006)) are similar in size (12–15 µm), shape and motile laries and venules. | 121 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Cells of peripheral blood
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Fig. 4.5 Tubular glands
in the appendix,
showing intraepithelial
lymphocytes (short
arrows). A lymphocyte
in anaphase is
indicated (long arrow).
Fig. 4.4 A small, resting lymphocyte in human peripheral blood. The
nuclear:cytoplasmic ratio is high and the cytoplasm contains few
organelles, indicative of its quiescent state. (Courtesy of Dr Bart Wagner,
Histopathology Department, Sheffield Teaching Hospitals, UK.)
Lymphocytes
Lymphocytes (Fig. 4.4; see Figs 4.6, 4.12) are the second most numer-
ous type of leukocyte in adulthood, forming 20–30% of the total popu-
lation (1500–2700/µl of blood). In young children they are the most
numerous blood leukocyte. Most circulating lymphocytes are small,
6–8 µm in diameter; a few are medium-sized and have an increased
cytoplasmic volume, often in response to antigenic stimulation. Occa-
sionally, cells up to 16 µm are seen in peripheral blood. Lymphocytes,
like other leukocytes, are found in extravascular tissues (including lym-
phoid tissue); however, they are the only white blood cells that return
to the circulation. The lifespan of lymphocytes ranges from a few days
(short-lived) to many years (long-lived). Long-lived lymphocytes are
necessary for the maintenance of immunological memory.
Blood lymphocytes are a heterogeneous collection mainly of B and
T cells, and consist of different subsets and different stages of activity
and maturity. About 85% of all circulating lymphocytes in normal
blood are T cells. Primary immunodeficiency diseases can result from
molecular defects in T and B lymphocytes (reviewed in Cunningham-
Rundles and Ponda (2005)). Included with the lymphocytes, but prob-
ably constituting a separate lineage subset, are the natural killer (NK)
cells. NK cells most closely resemble large T cells morphologically.
Small lymphocytes (both B and T cells) contain a rounded, densely Fig. 4.6 A mature B cell (plasma cell) in human connective tissue. The
staining nucleus that is surrounded by a very narrow rim of cytoplasm, abundant rough endoplasmic reticulum is typical of a cell actively
barely visible in the light microscope. In the electron microscope (see synthesizing secretory protein, in this case immunoglobulin. The cell to
the left is a fibroblast. (Courtesy of Dr Bart Wagner, Histopathology
Fig. 4.4), few cytoplasmic organelles can be seen apart from a small
Department, Sheffield Teaching Hospitals, UK.)
number of mitochondria, single ribosomes, sparse profiles of endoplas-
mic reticulum and occasional lysosomes; these features indicate a low
metabolic rate and a quiescent phenotype. However, these cells become germinal centres in the lymphoid tissues. Following this, some B cells
motile when they contact solid surfaces, and can pass between endothe- differentiate into large basophilic (RNA-rich) plasma cells, either within
lial cells to exit from, or re-enter, the vascular system. They migrate or outside the lymphoid tissues. Plasma cells produce antibodies in
extensively within various tissues, including epithelia (Fig. 4.5). their extensive rough endoplasmic reticulum (Fig. 4.6) and secrete
Larger lymphocytes include T and B cells that are functionally acti- them into the adjacent tissues. They have a prominent pale-staining
vated or proliferating after stimulation by antigen, and NK cells. They Golgi complex adjacent to an eccentrically placed nucleus, typically
contain a nucleus, which is, at least in part, euchromatic; a basophilic with peripheral blocks of condensed heterochromatin resembling the
cytoplasm, which may appear granular; and numerous polyribosome numerals of a clock (clock-faced nucleus) (see Fig. 4.12). Other germi-
clusters, consistent with active protein synthesis. The ultrastructural nal centre B cells develop into long-lived memory cells capable of
appearance of these cells varies according to their class and is described responding to their specific antigens not only with a more rapid and
below. higher antibody output, but also with an increased antibody affinity
compared with the primary response.
B cells Antibodies are immunoglobulins, grouped into five classes accord-
B cells and the plasma cells that develop from them synthesize and ing to their heavy polypeptide chain. Immunoglobulin G (IgG) forms
secrete antibodies that can specifically recognize and neutralize foreign the bulk of circulating antibodies. Immunoglobulin M (IgM) is nor-
(non-self) macromolecules (antigens), and can direct various non- mally synthesized early in immune responses. Immunoglobulin A (IgA)
lymphocytic cells (e.g. neutrophils, macrophages and dendritic cells) to is present in breast milk, tears, saliva and other secretions of the ali-
phagocytose pathogens. B cells differentiate from haemopoietic stem mentary tract, coupled to a secretory piece (a 70 kDa protein) that is
cells in the bone marrow. After deletion of autoreactive cells, the selected synthesized by the epithelial cells. This protects the immunoglobulin
B lymphocytes then leave the bone marrow and migrate to peripheral from proteolytic degradation and is part of the process by which the
lymphoid sites (e.g. lymph nodes). Here, following stimulation by molecule is transported across the epithelium; IgA thus contributes to
antigen, they undergo further proliferation and selection, forming mucosal immunity. IgA deficiency is relatively common, particularly in | 122 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
BlOOd, lymPHOId TISSuES ANd HAEmOPOIESIS
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NOITCES
some ethnic groups (reviewed in Woof and Kerr (2006)). Immunoglob- and enhancing the immune responses mediated by those cells. In addi-
ulin E (IgE) is an antibody which binds to receptors on the surfaces of tion to Th1 and Th2 cells, other subsets of helper T cells have been
mast cells, eosinophils and blood basophils; it is found only at low described. These include Th17 cells (which secrete the cytokine IL-17),
concentrations in the circulation. Immunoglobulin D (IgD) is found implicated in autoimmune diseases (Stockinger and Veldhoen 2007).
together with IgM as a major membrane-bound immunoglobulin on Other subsets (Th9, Th22) have been described and it is likely that many
mature, immunocompetent but naïve (prior to antigen exposure) B more subsets will be characterized in the future (Jiang and Dong 2013).
cells, acting as the cellular receptor for antigen. Helper T cells are also important in directing the destruction of
When circulating antibodies bind to antigens they form immune pathogens by recruiting accessory cells (e.g. macrophages, neutrophils,
complexes. If present in abnormal quantities, these may cause patho- eosinophils) to the site of infection and by activating their effector
logical damage to the vascular system and other tissues, either by inter- functions. This process is tightly coordinated. For example, Th1 helper
fering mechanically with the permeability of the basal lamina (e.g. T cells secrete cytokines that not only attract and activate macrophages
some types of glomerulonephritis), or by causing local activation of the but also provide help for B cells and guide their immunoglobulin pro-
complement system that generates inflammatory mediators (e.g. C5a), duction to the subclasses that fix complement. Thus these antibodies
attacks cell membranes and causes vascular disease. In pregnancy, opsonize the pathogen target, which can then be recognized, ingested
maternal IgG crosses the placenta and confers passive immunity on the and destroyed by the macrophage accessory cells that bear receptors for
fetus. Maternal milk contains secretory immunoglobulins (IgA) that complement and the Fc region of IgG. These Th1 cells are sometimes
help to combat bacterial and viral organisms in the alimentary tract of referred to as delayed-type hypersensitivity T cells. In contrast, Th2 cells
the baby during the first few weeks of postnatal life. secrete cytokines that induce the development and activation of eosi-
nophils, and also induce B cells to switch their immunoglobulins to
T cells non-complement-fixing classes (e.g. IgE). Pathogens such as parasitic
There are a number of subsets of T (thymus-derived) lymphocytes, all worms can then be coated with IgE antibody and hence recognized and
progeny of haemopoietic stem cells in the bone marrow. They develop destroyed by the effector functions of the eosinophil accessory cells,
and mature in the thymus, and subsequently populate peripheral sec- which bear receptors for the Fc region of IgE.
ondary lymphoid organs, which they constantly leave and re-enter via If helper T-cell activities are non-functional, a state of immunodefi-
the circulation. As recirculating cells, their major function is immune ciency results. This means that potentially pathogenic organisms, which
surveillance. Their activation and subsequent proliferation and func- are normally kept in check by the immune system, may proliferate and
tional maturation are under the control of antigen-presenting cells. T cause overt pathology, e.g. in acquired immune deficiency syndrome
cells undertake a wide variety of cell-mediated defensive functions that (AIDS), where a virus (human immunodeficiency virus, HIV) specifi-
are not directly dependent on antibody activity, and which constitute cally infects and kills (predominantly) helper T cells, though some
the basis of cellular immunity. T-cell responses focus on the destruction antigen-presenting cells are also killed.
of cellular targets such as virus-infected cells, certain bacterial infections,
fungi, some protozoal infections, neoplastic cells and the cells of grafts Regulatory T cells
from other individuals (allografts, when the tissue antigens of the A third population of T cells, ‘regulatory’ T or ‘Treg’ cells, are important
donor and recipient are not sufficiently similar). Targets may be killed in controlling the immune response. These CD4+, CD25+ cells have an
directly by cytotoxic T cells, or indirectly by accessory cells (e.g. macro- immunomodulatory function and can dampen the effector functions
phages) that have been recruited and activated by cytokine-secreting of both cytotoxic and helper T cells. Regulatory T cells (natural Tregs)
helper T cells. A third group, regulatory T cells, acts to regulate or limit are produced in the thymus and are an important additional mecha-
immune responses. nism for maintaining self-tolerance (Safinia et al 2013). Treg function
Functional groups of T cells are classified according to the molecules is antigen-specific and depends on direct cell–cell contact. Molecules
they express on their surfaces. The majority of cytokine-secreting helper secreted or induced by Treg cells, such as IL-10 or transforming growth
T cells express CD4, while cytotoxic T cells are characterized by CD8. factor beta (TGF-β), also play an important role in mediating Treg sup-
Regulatory T cells co-express CD4 and CD25. The CD (cluster of dif- pressive effects on the immune system. Similar induced regulatory T
ferentiation) prefix provides a standard nomenclature for all cell-surface cells can be induced in the periphery and may be important in the
molecules. At present, more than 330 different CD antigens have been induction of oral tolerance to ingested antigens, as well as tolerance to
designated; each one represents a cell surface molecule that can be tissue-specific molecules that are not expressed in the thymus (Schmitt
identified by specific antibodies. Further details of the classification are and Williams 2013).
beyond the scope of this publication and are given in Male et al (2012).
Structurally, T lymphocytes present different appearances depending Natural killer (NK) cells
on their type and state of activity. When resting, they are typically Natural killer (NK) cells have functional similarities to cytotoxic T cells
small lymphocytes and are morphologically indistinguishable from but they lack other typical lymphocyte features and do not express
B lymphocytes. When stimulated, they become large (up to 15 µm), antigen-specific receptors. They normally form only a small percentage
moderately basophilic cells, with a partially euchromatic nucleus and of all lymphocyte-like cells and are usually included in the large
numerous free ribosomes, rough and smooth endoplasmic reticulum, granular lymphocyte category. When mature, NK cells have a mildly
a Golgi complex and a few mitochondria, in their cytoplasm. Cytotoxic basophilic cytoplasm. Ultrastructurally, their cytoplasm contains ribo-
T cells contain dense lysosome-like vacuoles that function in cytotoxic somes, rough endoplasmic reticulum and dense, membrane-bound
killing. vesicles 200–500 nm in diameter with crystalline cores. These contain
the protein perforin, which is capable of inserting holes in the plasma
Cytotoxic T cells membranes of target cells, and granzymes, which trigger subsequent
Cytotoxic T lymphocytes (which express CD8) are responsible for the target cell death by apoptosis. NK cells are activated to kill target cells
direct cytotoxic killing of target cells (e.g. virus-infected cells); the by a number of factors. They can recognize and kill antibody-coated
requirement for direct cell–cell contact ensures the specificity of the target cells via a mechanism termed antibody-dependent cell-mediated
response. Recognition of antigen, presented as a peptide fragment on cytotoxicity (ADCC). They also have receptors that inhibit NK destruc-
MHC class I molecules, triggers the calcium-dependent release of lytic tive activity when they recognize MHC class I on normal cells. When
granules by the T cell. These lysosome-like granules contain perforin NK cells detect the loss or downregulation of MHC class I antigens
(cytolysin), which forms a pore in the target cell membrane. They also on certain virus-infected cells and some tumour cells, they activate
contain several different serine protease enzymes (granzymes), which apoptosis-inducing mechanisms that enable them to attack these
enter the target cell via the perforin pore and induce the programmed abnormal cells, albeit relatively non-specifically. For further reading, see
cell death (apoptosis; p. 26) of the target. Vivier et al (2008) and Chan et al (2014).
Helper T cells
Helper T cells (which express CD4) are characterized by the secretion PLATELETS
of cytokines. Two major populations have been identified according to
the range of cytokines produced. Th1 helper T cells typically secrete Blood platelets, also known as thrombocytes, are relatively small
interleukin (IL)-2, tumour necrosis factor alpha (TNF-α) and interferon (2–4 µm across) irregular or oval discs present in large numbers
gamma (IFN-γ), while Th2 cells produce cytokines such as IL-4, IL-5 (200,000–400,000/µl) in blood. In freshly harvested blood samples
and IL-13. These two CD4-expressing populations are termed ‘helper’ they readily adhere to each other and to all available surfaces, unless
T cells because one aspect of their function is to stimulate the prolifera- the blood is treated with citrate or other substances that reduce the
tion and maturation of B lymphocytes and cytotoxic T lymphocytes availability of calcium ions. Platelets are anucleate cell fragments,
(mediated via cytokines such as IL-4, IL-2 and IFN-γ), thus enabling derived from megakaryocytes in the bone marrow. They are surrounded | 123 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
lymphoid tissues
73
4
RETPAHC
by a plasma membrane with a thick glycoprotein coat, which is respon- together to initiate immune responses to foreign antigens (Malhotra
sible for their adhesive properties. A band of 10 microtubules lies et al 2013). These secondary tissues include lymph nodes, spleen, and
around the perimeter of the platelet beneath the plasma membrane; lymphoid tissue associated with epithelial surfaces (mucosa-associated
the microtubules are associated with actin filaments, myosin and other lymphoid tissue, MALT), e.g. the palatine and nasopharyngeal tonsils,
proteins related to cell contraction. The cytoplasm also contains mito- Peyer’s patches in the small intestine, lymphoid nodules in the respira-
chondria, glycogen, scant smooth endoplasmic reticulum, tubular tory and urogenital systems, the skin. The microstructure of lymph
invaginations of the plasma membrane, and three major types of nodes and of MALT in general is described below. Details of all other
membrane-bound vesicle, designated α, δ and λ granules. lymphoid tissues and organs are included in the descriptions of the
Alpha granules are the largest, and have diameters of up to 500 nm. appropriate regional anatomy.
They contain platelet-derived growth factor (PDGF), fibrinogen and Lymphocytes enter secondary lymphoid tissues from the blood,
other substances. Delta granules are smaller (up to 300 nm) and usually by migration through the walls of capillaries or venules (high
contain 5-hydroxytryptamine (5-HT, serotonin) that has been endocy- endothelial venules, HEVs (see Ch. 6)) and leave by the lymphatic
tosed from the blood plasma. Lambda granules are the smallest (up to system. In the spleen, lymphocyte entry and exit take place via the
250 nm) and contain lysosomal enzymes. marginal zone and venous drainage respectively. Antigen-presenting
Platelets play an important role in haemostasis. When a blood vessel cells (dendritic cells) enter via the lymphatics, bringing with them
is damaged, platelets become activated, evert their membrane invagina- antigen from peripheral infected sites. In all the secondary tissues there
tions to form lamellipodia and filopodia, and aggregate at the site of are specific areas where either B or T cells are concentrated. After activa-
injury, plugging the wound. They adhere to each other (agglutination) tion, functionally competent lymphocytes migrate to other sites in the
and to other tissues. Adhesion is a function of the thick platelet coat body, where they combat the original infection. Organized lymphoid
and is promoted by the release of adenosine diphosphate (ADP) and structures, termed tertiary lymphoid organs, can also develop at sites of
calcium ions from the platelets in response to vessel injury. The contents chronic inflammation (Stranford and Ruddle 2012).
of released α granules, together with factors released from the damaged
tissues, initiate a complex sequence of chemical reactions in the blood
plasma, which leads to the precipitation of insoluble fibrin filaments LYMPH NODES
in a three-dimensional meshwork, the fibrin clot (see Fig. 4.1). More
platelets attach to the clot, inserting extensions of their surfaces, filopo- Lymph nodes are encapsulated centres of antigen presentation and
dia, deep into the spaces between the fibrin filaments, to which they lymphocyte activation, differentiation and proliferation, which are
adhere strongly. The platelets then contract (clot retraction) by actin– facilitated by complex trafficking of cells and lymphatic flow through
myosin interactions within their cytoplasm, and this concentrates the the structure (Girard et al 2012). They generate mature, antigen-primed
fibrin clot and pulls the walls of the blood vessel together, which limits B and T cells, and filter particles, including microbes, from the lymph
any further leakage of blood. After repair of the vessel wall, which may by the action of numerous phagocytic macrophages. A normal young
be promoted by the mitogenic activity of PDGF, the clot is dissolved by adult body contains up to 450 lymph nodes, of which 60–70 are found
enzymes such as plasmin. Plasmin is formed by plasminogen activators in the head and neck, 100 in the thorax and as many as 250 in the
in the plasma, probably assisted by lysosomal enzymes derived from abdomen and pelvis. Lymph nodes are particularly numerous in the
the λ granules of platelets. Platelets typically circulate for 10 days before neck, mediastinum, posterior abdominal wall, abdominal mesenteries,
they are removed, mainly by splenic macrophages. pelvis and proximal regions of the limbs (axillary and inguinal lymph
nodes). By far the greatest number lie close to the viscera, especially in
the mesenteries.
LYMPHOID TISSUES
Microstructure
Lymphocytes are located in many sites in the body, most obviously at
strategic sites that are liable to infection, e.g. the oropharynx. The main
areas of lymphocyte concentration are classified as primary or second- Lymph nodes (Fig. 4.7) are small, oval or kidney-shaped bodies,
ary lymphoid organs, according to whether they are involved in de novo 0.1–2.5 cm long, lying along the course of the lymphatic vessels. Each
lymphocyte generation (primary lymphoid organs, e.g. bone marrow, usually has a slight indentation on one side: the hilum, through which
thymus) or are the site of mature lymphocyte activation and initiation blood vessels enter and leave, and the efferent lymphatic vessel leaves.
of an immune response (secondary lymphoid organs, e.g. lymph nodes, Several afferent lymphatic vessels enter the capsule around the periph-
spleen). ery. Lymph nodes have a highly cellular cortex and a medulla (Fig. 4.8),
The secondary or peripheral lymphoid organs are the specialized which contains a network of minute lymphatic channels (sinuses)
sites where B and T lymphocytes and antigen-presenting cells come through which lymph from the afferent lymphatics is filtered, to be
Fig. 4.7 The structure of a lymph node.
Trabeculae Capsule Germinal centre
of secondary
Afferent lymphatics lymphoid follicle
Subcapsular sinus
Cortex
Primary lymphoid follicle
Paracortex
Medullary sinus
Medulla
Hilum
Artery
Vein Efferent lymphatic vessel
High endothelial
venule (HEV) | 124 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Blood, lymphoid tissues and haemopoiesis
73.e1
4
RETPAHC
All lymphocytes arise from pluripotent haemopoietic stem cells in
the bone marrow. The B lymphocyte lineage develops through a series
of differentiation stages within the bone marrow. The newly formed B
cells then leave through the circulation and migrate to peripheral sites.
In contrast, T-lymphocyte development requires the thymus; the bone
marrow-derived stem cells must therefore migrate via the blood circula-
tion to the thymus. After their differentiation and maturation into
immunocompetent T cells that have survived thymic selection processes
(1–3%), they re-enter the circulation and are transported to peripheral
sites where they join the pool of naïve lymphocytes that recirculate
through the secondary lymphoid organs via blood and lymphatic cir-
culation systems. | 125 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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F
C
F
M
G
F
G V
Fig. 4.9 A germinal centre in a lymphoid follicle of the human palatine
tonsil, immunolabelled to show CD38-positive B cells in the germinal
Fig. 4.8 A lymph node (human) showing cortex (C) and medulla (M), and centre (red), IgD-positive naïve B cells (green) in the mantle zone and
lymphoid follicles (F), some with germinal centres (G). Also shown are the activated, transferrin receptor (CD71)-positive cells of various lineages
subcapsular sinus (arrow) and medullary blood vessels (V). The dark line (blue). (Courtesy of Dr Cécile Chalouni, Ludwig Institute for Cancer
(top, centre) is a small crease in the tissue section and is an artefact. Research, Yale University School of Medicine, USA.)
(Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew,
Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
packed and in the outer cortical area they form lymphoid follicles or
collected at the hilum by the efferent lymphatic. The cortex is absent at nodules (see Fig. 4.8), which are populated mainly by B cells and spe-
the hilum, where the medulla reaches the surface. cialized follicular dendritic cells (FDCs) (see Fig. 4.15). The number,
The capsule is composed mainly of collagen fibres, elastin fibres degree of isolation and staining characteristics of follicles vary according
(especially in the deeper layers) and a few fibroblasts. Trabeculae of to their state of antigenic stimulation. A primary follicle is uniformly
dense connective tissue extend radially into the interior of the node populated by small, quiescent lymphocytes, whereas a secondary fol-
from the capsule. They are continuous with a network of fine type III licle has a germinal centre (Fig. 4.9), composed mainly of antigen-
collagen (reticulin) fibrils, which branch and interconnect to form a stimulated B cells, which are larger, less deeply staining and more
very dense network in the cortex, providing attachment for various cells, rapidly dividing than those at its periphery.
mostly dendritic cells, macrophages and lymphocytes. There are fewer The role of the germinal centre is to provide a microenvironment
fibres in the germinal centres of follicles (see below). Reticulin and the that allows the affinity maturation of the B-cell response, so that as the
associated proteoglycan matrix are produced by fibroblasts associated immune response progresses, the affinity or strength with which anti-
with the fibrous network. bodies bind their antigen increases (Shlomchik and Weisel 2012,
Victora and Nussenzweig 2012). There are several zones in the germinal
Lymphatic and vascular supply
centre where this is allowed to happen. In the ‘dark zone’, the B cells
(centroblasts) undergo rapid proliferation, which is associated with
Lymph nodes are permeated by channels through which lymph perco- hypermutation of their antibody molecules. They then move into the
lates after its entry from the afferent vessels. The conduit system consists ‘light zone’ (as centrocytes), where they can interact with the FDCs,
of collagen fibres and associated fibrils surrounded by fibroblast reticu- which carry intact unprocessed antigen on their surface in the form of
lar cells, forming a sponge-like reticulum that provides not only spaces immune complexes (Rezk et al 2013). The centrocytes compete for
for the lymphocytes but also a system for the transport of antigen and binding to the antigen; those whose antibody has the highest affinity
signalling molecules (such as chemokines) that control the highly survive and the rest die. T cells are also present, helping the survival of
dynamic movement and interaction of the immune cells. Dendritic cells the B cells and inducing class switching. Macrophages in the germinal
can reach inside the conduits to sample antigen, and then present it to centre phagocytose apoptotic lymphocytes (e.g. those B cells that die as
immune cells (Roozendaal et al 2008). part of the process of affinity maturation), and consequently macro-
Afferent lymphatic vessels enter at many points on the periphery, phage cytoplasm becomes filled with engulfed lipid and nuclear debris
branch to form a dense intracapsular plexus, and then open into the forming sparkling intracellular inclusions (leading to the term tingible
subcapsular sinus, a cavity that is peripheral to the whole cortex except body macrophage).
at the hilum (see Fig. 4.7). Numerous radial cortical sinuses lead from The mantle zone (see Fig. 4.9) is produced as surrounding cells are
the subcapsular sinus to the medulla, where they coalesce as larger marginalized by the rapidly growing germinal centre. It is populated by
medullary sinuses. The latter become confluent at the hilum with the cells similar to those found in primary follicles: mainly quiescent B cells
efferent vessel that drains the node. All of these spaces are lined by a with condensed heterochromatic nuclei and little cytoplasm (hence the
continuous endothelium and traversed by fine reticular fibres. deeply basophilic staining of this region in routine preparations; Fig.
Arteries and veins serving lymph nodes pass through the hilum, 4.10), a few helper T cells, FDCs and macrophages. After numerous
giving off straight branches that traverse the medulla and send out mitotic divisions the selected B cells give rise to small lymphocytes,
minor branches as they do so. In the cortex, arteries form dense arcades some of which become memory B cells and leave the lymph node to
of arterioles and capillaries in numerous anastomosing loops, eventu- join the recirculating pool, while others leave to mature as antibody-
ally returning to highly branched venules and veins. Capillaries are secreting plasma cells either in the lymph node medulla or in peripheral
especially profuse around the follicles, which contain fewer vessels. tissues.
Postcapillary HEVs are abundant in the paracortical zones. They form The deep cortex or paracortex lies between the cortical follicles and
an important site of blood-borne lymphocyte extravasation into lym- the medulla, and is populated mainly by T cells, which are not organ-
phoid tissue, apparently by migration through labile endothelial tight ized into follicles. Both CD4 and CD8 T-cell subsets are present. The
junctions (occluding junctions, zonulae adherentes). The density of the paracortex also contains interdigitating dendritic cells. These dendritic
capillary beds increases greatly when lymphocytes multiply in response cells include Langerhans cells from the skin and other squamous epi-
to antigenic stimulation. Veins leave a node through its principal trabec- thelia, which have migrated as veiled cells via the afferent lymphatics
ulae and capsule, and drain them and the surrounding connective into the draining lymph nodes (see Fig. 4.14). Their role is to present
tissue. processed antigen to T cells. The region expands greatly in T cell-
dominated immune responses, when its cells are stimulated to prolifer-
Cells and cellular zones of lymph nodes
ate and disperse to peripheral sites.
In the medulla, lymphocytes are much less densely packed in irregu-
Although most of the cells in a lymph node are B and T lymphocytes, lar, branching medullary cords between which the reticulin network
their distribution is not homogeneous. In the cortex, cells are densely is easily seen. Other cells include macrophages, which are more numer- | 126 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Fig. 4.10 A germinal
centre in a follicle of
mucosa-associated
lymphoid tissue (MALT)
in the mucosa and
submucosa of the
appendix. The bases of
tubular glands of the
mucosal epithelium are
seen in the upper field.
H
S
S
Fig. 4.11 Haemopoietic tissue (H) in the marrow cavity of a fetal long
bone undergoing endochondral ossification (top). Islands of densely
ous in the medulla than in the cortex, plasma cells and a few packed nucleated haemopoietic cells of different lineages are separated
granulocytes. by large vascular sinusoids (S), which are filled with mature red blood
cells in the general circulation.
MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT)
tonsils they include modified stratified squamous reticulated epithelial
Large amounts of unencapsulated lymphoid tissue exist in the walls of cells (see p. 576). The main function of B lymphocytes in MALT is to
the gastrointestinal, respiratory, reproductive and urinary tracts, and in produce IgA for secretion into the lumen of the tracts that they line
the skin; they are collectively termed mucosa-associated lymphoid (Cerutti et al 2011).
tissue (MALT), most of which is found in the gut as gut-associated Many of the lymphocytes migrating between cells in the basal
lymphoid tissue (GALT) (Koboziev et al 2010). regions of epithelia (see Fig. 4.5) are effector cytotoxic and helper T cells
Throughout the body, MALT includes an extremely large population that have already been selected in lymphoid nodules and are engaged
of lymphocytes, reflecting the size of the gastrointestinal tract. Lym- in immune responses. Similar cells, and activated IgA-producing B cells
phoid cells are located in the lamina propria and in the submucosa as and plasma cells, are also scattered throughout the entire mucosal
discrete follicles or nodules. More scattered cells, derived from these lamina propria.
follicles, are found throughout the lamina propria and in the base of
the epithelium (see Figs 4.5, 4.10). MALT includes macroscopically
HAEMOPOIESIS
visible lymphoid masses, notably the peripharyngeal lymphoid ring of
tonsillar tissue (palatine, nasopharyngeal, tubal and lingual), and the
Peyer’s patches of the small intestine, all of which are described else- Postnatally, blood cells are formed primarily in the bone marrow. Other
where. Most MALT consists of microscopic aggregates of lymphoid tissues, particularly the spleen and liver, may develop haemopoietic
tissue, which lack a fibrous capsule. Lymphocyte populations are sup- activity once more, if production from the marrow is inadequate.
ported mechanically by a network of fine type III collagen (reticulin)
fibres and associated fibroblasts, as they are in lymph nodes.
BONE MARROW
In common with lymph nodes, MALT provides centres for the activa-
tion and proliferation of B and T lymphocytes in its follicles and para-
follicular zones, respectively. The function of cells in these zones, Bone marrow is a soft pulpy tissue that is found in the marrow cavities
including antigen-presenting cells (follicular dendritic cells and inter- of all bones (Fig. 4.11) and even in the larger Haversian canals of lamel-
digitating dendritic cells) and macrophages, as well as T and B cells, is lar bone. It differs in composition in different bones and at different
similar to that found in lymph nodes. The close proximity of lym- ages, and occurs in two forms: yellow and red marrow. In old age the
phocytes within MALT to an epithelial surface facilitates their access to marrow of the cranial bones undergoes degeneration and is then termed
pathogens. MALT lacks afferent lymphatic vessels. Lymphocytes migrate gelatinous marrow.
into MALT through its HEVs and leave mainly via its efferent lymphat-
Yellow marrow
ics, which drain interstitial fluid as lymph; the lymphocyte population
in MALT is not fixed. Migration from MALT follows a different route
from the major peripheral route of recirculation. After antigen activa- Yellow marrow consists of a framework of connective tissue that sup-
tion, lymphocytes travel via the regional lymph nodes to disperse ports numerous blood vessels and cells, most of which are adipocytes.
widely along mucosal surfaces to provide protective T- and B-cell A small population of typical red marrow cells persists and may be
immunity. reactivated when the demand for blood cells becomes sufficiently great.
Follicle-associated epithelium Red marrow
The epithelium covering MALT varies in type according to its location. Red marrow is found throughout the skeleton in the fetus and during
It is unusual in possessing cells that are involved in sampling antigens the first years of life. After about the fifth year the red marrow, which
and transferring them to antigen-presenting cells in the underlying represents actively haemopoietic tissue, is gradually replaced in the long
tissues; appropriate clones of T and B cells in local lymphoid tissues are bones by yellow marrow. The replacement starts earlier, and is generally
then activated and amplified prior to their exit via the lymphatics. more advanced, in the more distal bones. By 20–25 years of age, red
Specialized epithelial cells in the small and large intestine have charac- marrow persists only in the vertebrae, sternum, ribs, clavicles, scapulae,
teristic short microvilli on their luminal surfaces and are known as pelvis and cranial bones, and in the proximal ends of the femur and
microfold (M) cells (Kraehenbuhl and Neutra 2000); in the palatine humerus. | 127 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Red bone marrow consists of a network of loose connective tissue, To generate a complete set of blood cells from a single pluripotent
the stroma, which supports clusters of haemopoietic cells (haemopoi- cell may take some months. The later progenitor cells form mature cells
etic cords or islands) and a rich vascular supply in which large, thin- of their particular lineages more quickly. However, because they are not
walled sinusoids are the main feature (see Fig. 4.11). The vascular self-renewing, grafts of these later cells eventually fail because the cells
supply is derived from the nutrient artery to the bone, which ramifies they produce all ultimately die. This is of considerable importance in
in the bone marrow, and terminates in thin-walled arterioles from bone marrow replacement therapy. The presence of pluripotent stem
which the sinusoids arise. These, in turn, drain into disproportionately cells in the donor marrow is essential for success; only 5% of the normal
large veins. Lymphatic vessels are absent from bone marrow. The stroma number are needed to repopulate the marrow. Following replacement
contains a variable amount of fat, depending on age, site and the hae- therapy, T lymphocytes reconstitute more slowly than the other haemo-
matological status of the body, and small patches of lymphoid tissue poietic lineages, reflecting the progressive reduction in size of the
are also present. Marrow thus consists of vascular and extravascular thymus with age (chronic involution).
compartments, both enclosed within a bony framework from which Within the bone marrow there is also a population of mesenchy-
they are separated by a thin layer of endosteal cells. mal stem cells that can differentiate into a wide variety of non-
haemopoietic cells. These pluripotent stem cells can also be found in
Stroma
the circulation, and are being investigated for their use in repairing
Stroma is composed of a delicate network of fine type III collagen damaged organs (see Commentary 1.2).
(reticulin) fibres secreted by highly branched, specialized fibroblast-like
cells (reticular cells) derived from embryonic mesenchyme. When hae- Lymphocytes
mopoiesis stops, as occurs in most limb bones in adult life, these cells
(or closely related cells) become distended with lipid droplets and fill
Lymphocytes are a heterogeneous group of cells that may share a
the marrow with yellow fatty tissue (yellow marrow). If there is a later
common ancestral lymphoid progenitor cell, distinct from the myeloid
demand for haemopoiesis, the stellate stromal cells reappear. The
progenitor cell (see Fig. 4.12). The first identifiable progenitor cell is
stroma also contains numerous macrophages attached to extracellular
the lymphoblast, which divides several times to form prolymphocytes;
matrix fibres. These cells actively phagocytose cellular debris created by
both cells are characterized by a high nuclear:cytoplasmic ratio. B cells
haemopoietic development, especially the extruded nuclei of erythro-
undergo differentiation to their specific lineage subset entirely within
blasts, remnants of megakaryocytes and cells that have failed the
the bone marrow and migrate to peripheral or secondary lymphoid
B-lymphocyte selection process. Stromal cells play a major role in
tissues as naïve B cells, ready to respond to antigen. However, T cells
the control of haemopoietic cell differentiation, proliferation and
require the specialized thymic microenvironment for their develop-
maturation.
ment. During fetal and early postnatal life, and subsequently at lower
Marrow sinusoids are lined by a single layer of endothelial cells,
levels throughout life, progenitor cells migrate to the thymus where they
supported by reticulin on their basal surfaces. Although the endothelial
undergo a process of differentiation and selection as T cells, before
cells are interconnected by tight junctions, their cytoplasm is extremely
leaving to populate secondary lymphoid tissues.
thin in places, and the underlying basal lamina is discontinuous. The
passage of newly formed blood cells from the haemopoietic compart- B-cell development
ment into the blood stream appears to occur through an interactive
B cells start their development in the subosteal region of the bone
process with the endothelium, producing temporary apertures (large
marrow and move centripetally as differentiation progresses. Their
fenestrae) in their attenuated cytoplasm.
development entails the rearrangement of immunoglobulin genes to
Haemopoietic tissue create a unique receptor for antigen on each B cell, and the progressive
expression of cell-surface and intracellular molecules required for
Cords and islands of haematogenous cells consist of clusters of
mature B-lymphocyte function. Autoreactive cells that meet their self-
immature blood cells in various stages of development; several differ-
antigen within the bone marrow are eliminated. Overall, some 25% of
ent cell lineages are typically represented in each focal group. One or
B cells successfully complete these developmental and selection proc-
more macrophages lie at the core of each such group of cells. These
esses; those that fail die by apoptosis and are removed by macrophages.
macrophages engage in phagocytic functions, are important in trans-
Bone marrow stromal cells (fibroblasts, fat cells and macrophages)
ferring iron to developing erythroblasts for haemoglobin synthesis,
express cell-surface molecules and secreted cytokines that control
and may play a role, with other stromal cells, in regulating the rate of
B-lymphocyte development. The mature naïve B lymphocytes leave via
cell proliferation and maturation of the neighbouring haemopoietic
the central sinuses. They express antigen receptors (immunoglobulin)
cells.
of IgM and IgD classes. Class switching to IgG, IgA and IgE occurs in
the periphery following antigen activation in response to signals from
T helper cells.
CELL LINEAGES
T-cell (thymocyte) development
Haemopoietic stem cells
T cells develop within the thymus from blood-borne, bone marrow-
derived progenitors that enter the thymus via HEVs at the corticomedul-
Within the adult marrow there is a very small number (0.05% of hae- lary junction. They first migrate to the outer (subcapsular) region of the
mopoietic cells) of self-renewing, pluripotent stem cells that are capable thymic cortex and then, as in the bone marrow, move progressively
of giving rise to all blood cell types, including lymphocytes (Fig. 4.12). inwards towards the medulla as development continues. T-cell develop-
Although they cannot be identified morphologically in the marrow, ment involves gene rearrangements in the T-cell receptor (TcR) loci to
they can be recognized in aspirates by the expression of specific cell- create unique receptors for antigen on each cell, together with the pro-
surface marker proteins (e.g. CD34). It is thought that haemopoietic gressive expression of molecules required for mature T-cell function.
stem cells occupy specific environmental niches in the marrow associ- Selection of the receptor repertoire is more stringent for T cells than for
ated with the endosteum of trabecular bone or with sinusoidal endothe- B cells because of the way in which mature T cells recognize peptides
lium, and that their microenvironment is important in homeostasis, derived from protein antigens presented in conjunction with specific
the balance between self-renewal and differentiation. Stem cells can molecules of the major histocompatibility complex (MHC) expressed
also be found (at lower concentrations) in the peripheral blood, par- on the surfaces of cells. Thus mature CD8 (cytotoxic) T cells recognize
ticularly after treatment with appropriate cytokines. antigen in the form of short peptides complexed with the polymorphic
Progressively more lineage-restricted committed progenitor cells MHC class I molecules, while CD4 (helper/regulatory) T cells recognize
develop from these ancestors (see Laiosa et al (2006) for a review) to the peptides in the context of MHC class II molecules. As the TcR
produce the various cell types found in peripheral blood. The commit- recognizes both the peptide and the MHC molecule, the T cell will only
ted progenitor cells are often termed colony-forming units (CFU) of the recognize peptides bound to their own (self) type of MHC; it will not
lineage(s), e.g. CFU-GM cells give rise, after proliferation, to neutrophil ‘see’ peptides in combination with allelically different MHC molecules
granulocytes, monocytes and certain dendritic cells, whereas CFU-E (i.e. those from other individuals). This is termed MHC restriction of
produce only erythrocytes. Each cell type undergoes a period of matura- T-cell recognition. Selection of T cells in the thymus must ensure the
tion in the marrow, often accompanied by several structural changes, survival of those T cells that can respond only to foreign antigens,
before release into the general circulation. In some lineages, e.g. the bound to their own (self) class of MHC molecule. Cells that are incap-
erythroid series, the final stages of maturation take place in the circula- able of binding to self MHC molecules, or which bind to self-antigens,
tion, whereas in the monocytic lineage, they occur after the cells have are eliminated by apoptotic cell death (see p. 26); it is estimated that
left the circulation and entered peripheral tissues where they differenti- up to 95% of T-cell progenitors undergo apoptosis in this way. Cells
ate into macrophages and some dendritic cells. that express an appropriate TcR and have effective MHC-restricted | 128 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Neutrophil Megakaryocyte Platelet
CFU-GM CFU-Mk BFU-E
CFU-E
Eosinophil
CFU-GEMM
Myeloblast CFU-G
Common myeloid
progenitor
Basophil
Erythroblast
Monoblast CFU-M Haemopoietic
stem cell
Mast cell
Common lymphoid
progenitor
Monocyte Erythrocyte
NK cell T cell B cell
Osteoclast Macrophage Dendritic cell Lymphocyte Plasma cell
Fig. 4.12 The origins and lineage relationships of haemopoietically derived cells of the immune system. Mature cells and selected progenitors (all human)
are illustrated (magnifications vary). The dendritic cell was cultured from peripheral blood, immunolabelled to show HLA-DR and photographed using
Nomarski optics. The megakaryocyte and erythroblast are from a bone marrow smear, stained with May–Grünwald–Giemsa (MGG); the remaining cells
illustrated are from peripheral blood smears (Wright’s stain), sections of connective tissue (plasma cell, mast cell), bone (osteoclast) and lung alveolus
(macrophage). Platelets (one is arrowed) are subcellular fragments of bone marrow megakaryocytes. Note that circulating small lymphocytes cannot be
classified further with routine staining methods. For further explanation of cellular structure and staining properties, along with abbreviations, see the
text. (Dendritic cell image courtesy of Dr Cécile Chalouni, Ludwig Institute for Cancer Research, Yale University School of Medicine, USA. All other
images courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) | 129 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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NOITCES
binding properties survive to become mature, naïve T cells that leave colony-forming unit for granulocytes and macrophages (CFU-GM). Dif-
the thymus and populate the periphery. ferent colony-stimulating factors (CSF) act on the common progenitor
Thymic stromal cells play a crucial role in T-cell development and to direct its subsequent differentiation pathway. Monocyte progenitors
selection. Thymic epithelial cells in the cortex express both MHC class pass through a proliferative monoblast stage (14 µm) and then form
I and II molecules and are unique in their ability to select T cells that differentiating promonocytes, which are slightly smaller cells in which
recognize self MHC with a moderate affinity (positive selection). Dele- production of small lysosomes begins. After further divisions, mono-
tion of self-antigen reactive cells (negative selection) is mainly control- cytes (up to 20 µm) are released into the general circulation. Most
led by thymic dendritic cells located at the corticomedullary junction migrate into perivascular and extravascular sites, which they then popu-
and in the medulla, although the epithelium can also perform this late as macrophages, while others may give rise to certain dendritic cells,
function. Apoptotic thymocytes are removed by thymic macrophages. including Langerhans cells.
The role of the thymic epithelium in thymocyte differentiation is
complex and involves cell–cell contact as well as the secretion of soluble Platelets
mediators such as cytokines, chemokines, neuroactive peptides (e.g.
somatostatin) and thymic hormones (e.g. thymulin). Thymic fibro- Platelets arise in a unique manner by the shedding of thousands of
blasts and the extracellular matrix also play a role. cytoplasmic fragments from the tips of processes of megakaryocytes in
the bone marrow. The first detectable cell of this line is the highly
Erythrocytes basophilic megakaryoblast (15–50 µm), followed by a promegakaryo-
cyte stage (20–80 µm), in which synthesis of granules begins. Finally,
Erythrocytes and granulocytes belong to the myeloid lineage. The earli- the fully differentiated megakaryocyte, a giant cell (35–160 µm) with a
est identifiable erythroid progenitor cells are capable of rapid bursts of large, dense, polyploid, multilobed nucleus, appears. Once differentia-
cell division to form numerous daughter cells; they have thus been tion is initiated from the CFU-Meg, DNA replicates without cytoplasmic
named burst-forming units of the erythroid line (BFU-E; see Fig. 4.12). division (endoreduplication), and the chromosomes are retained
They give rise to the CFU-E, which, with their immediate progeny, are within a single polyploid nucleus that may contain up to 256n chro-
sensitive to the hormone erythropoietin. This hormone, produced in mosomes (where n is the haploid complement present in gametes).
the kidney, induces further differentiation along the erythroid line. Megakaryocyte lineage characteristics and disorders are reviewed in Sun
The first readily identifiable cell of the erythroid series is the pro- et al (2006).
erythroblast, which is a large (about 20 µm) cell with a large euchro- The cytoplasm contains fine basophilic granules and becomes par-
matic nucleus and a moderately basophilic cytoplasm. It also responds titioned into proplatelets by invaginations of the plasma membrane.
to erythropoietin. The proerythroblast contains small amounts of fer- These are seen ultrastructurally as a network of tubular profiles, which
ritin and bears some of the protein spectrin on its plasma membrane. coalesce to form cytoplasmic islands 3–4 µm in diameter. Individual
Proerythroblasts proliferate to produce smaller (12–16 µm) basophilic platelets are shed into the circulation from a long, narrow process of
erythroblasts, rich in ribosomes, in which haemoglobin-RNA synthesis megakaryocyte cytoplasm that is protruded through an aperture in the
begins. The cytoplasm becomes partially, and then uniformly, eosi- sinusoidal endothelium.
nophilic (the polychromatic erythroblast and orthochromatic erythro-
blast respectively). These cells are only 8–10 µm in diameter and
PHAGOCYTES AND ANTIGEN-PRESENTING CELLS
contain very little cytoplasmic RNA. The nucleus becomes pyknotic
(dense, deep-staining, shrunken) and is finally extruded from the cell,
leaving an anucleate reticulocyte, which enters a sinusoid. Its reticular Macrophages and neutrophils (see above) are specialized phagocytes.
staining pattern, visible using special stains, results from residual cyto- Certain dendritic cells (see Fig. 4.12), e.g. Langerhans cells of the skin
plasmic RNA, which is usually lost within 24 hours of entering the and other stratified squamous epithelia, are ‘professional’ antigen-
peripheral blood circulation. Reticulocyte numbers in peripheral blood presenting cells (APCs); they take up foreign material by endocytosis
are therefore a good indicator of the rate of red-cell production. The and macropinocytosis, and are uniquely capable of efficiently activating
whole process of erythropoiesis takes 5–9 days. naïve as well as mature T lymphocytes. Macrophages are also able to
process and present antigen to lymphocytes, but are less effective than
Granulocytes dendritic cells. In addition, they play an important role in the effector
arm of the immune response, clearing the infectious agent by phagocy-
tosis. The third major cell type involved in antigen presentation and
Granulocyte formation involves major changes in nuclear morphology
T-cell activation is the B lymphocyte, which is particularly efficient at
and cytoplasmic contents, which are best known for the neutrophil.
taking up antigen that binds to its surface immunoglobulin (see above).
Initially, myeloid progenitor cells transform into large (10–20 µm)
Follicular dendritic cells of lymph nodes, MALT and the spleen are
myeloblasts that are similar in general size and appearance to proeryth-
capable of presenting non-processed antigen to B lymphocytes, but are
roblasts. These proliferative cells have large euchromatic nuclei and lack
not classic APCs because they cannot present antigen to helper T cells.
cytoplasmic granules. They differentiate into slightly larger promyelo-
APCs endocytose antigen, digest it intracellularly, mostly to peptide
cytes, in which the first group of specific proteins is synthesized in the
fragments, and present the fragments on their surfaces, generally in
rough endoplasmic reticulum and Golgi apparatus. The proteins are
conjunction with MHC class II molecules. (Class II molecules are nor-
stored in large (0.3 µm) primary (non-specific) granules, which are
mally found only on APCs, although many other cells can express class
large lysosomes containing acid phosphatase. Smaller secondary (spe-
II molecules in inflammatory situations.) Recognition of foreign antigen
cific) granules are formed in the smaller myelocyte, which is the last
is controlled by a variety of APC cell-surface receptors: Fc and comple-
proliferative stage. The nucleus is typically flattened or slightly indented
ment receptors mediate uptake of opsonized material, while pattern
on one side in myelocytes.
recognition receptors of the innate immune system, e.g. Toll-like recep-
In the next, metamyelocyte, stage, the cell size (10–15 µm) decreases,
tors and scavenger receptors, directly recognize pathogen-derived
the nucleus becomes heterochromatic and horseshoe-shaped, and
molecules.
protein synthesis almost stops. As the neutrophil is released, the nucleus
becomes first heavily indented (the juvenile stab or band form), and
subsequently segmented into up to six lobes, characteristic of the MACROPHAGES
mature neutrophil. The whole process usually takes 7 days to complete
(3 days proliferating and 4 days maturing). Neutrophils may then be
The mononuclear phagocyte system consists of the blood monocytes,
stored in the marrow for a further 4 days, depending on demand, before
from which the other types are derived, and various tissue macrophages,
their final release into the circulation.
some of which have tissue-specific names. Certain dendritic cells are
Eosinophils and basophils pass through a similar sequence but their
sometimes included in the mononuclear phagocyte system; although
nuclei do not become as irregular as that of the neutrophil. It is thought
they share a common lineage ancestor, they appear to form a discrete
that these cells each arise from distinct colony-forming units, which are
branch of the family tree. Most monocytes and macrophages express
separate from the CFU-GM.
class II MHC molecules.
Macrophages are very variable in size (generally 15–25 µm) and are
Monocytes
found in many tissues of the body, where they constitute a heterogene-
ous family of cells (reviewed in Gordon and Taylor (2005)). They
Monocytes are formed in the bone marrow. Monocytes and neutrophils are migrant cells in all general connective tissues, in bone marrow and
appear to be closely related cells; together with some of the antigen- all lymphoid tissues, and include alveolar macrophages in the lung
presenting dendritic cells, they arise from a shared progenitor, the and Kupffer cells in liver sinusoids. Macrophages often aggregate in | 130 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Phagocytes and antigen-presenting cells
79
4
RETPAHC
subserous connective tissue of the pleura and peritoneum, where they activity is greatly increased when the target has been coated in antibody
are visible as milky spots near small lymphatic trunks. They cluster (opsonized) or complement, or both. Once phagocytosis has occurred,
around the terminations of small (penicillar) arterioles in the spleen the vacuole bearing the ingested particle fuses with endosomal vesicles,
and are distributed, more diffusely, throughout the splenic cords. which contain a wide range of lysosomal enzymes, including many
Osteoclasts in bone are closely related to macrophages; they are hydrolases, and oxidative systems capable of rapid bacteriocidal action.
syncytial cells derived from the fusion of up to 30 progenitor monocytes These activities are much enhanced when macrophages are stimulated
in bone tissue, where they differentiate further. Microglia of the central (activated macrophages) by cytokines, e.g. IFN-γ, which are secreted by
nervous system originate from an embryonic monocyte precursor and other cells of the immune system, especially T lymphocytes.
migrate into the central nervous system during its development. They Close antibody-mediated binding may initiate the release of lyso-
differ from macrophages in that normally they are quiescent cells in somal enzymes on to the surfaces of the cellular targets to which the
which MHC class II expression is downregulated, and they display little macrophages bind. This process of cytotoxicity is also used by other
phagocytic activity. cells, including neutrophils and eosinophils, particularly if the targets
Macrophages vary in structure depending on their location in the are too large to be phagocytosed (e.g. nematode worm parasites).
body. All have a moderately basophilic cytoplasm containing some
rough and smooth endoplasmic reticulum, an active Golgi complex and Secretory activities
a large, euchromatic and somewhat irregular nucleus. These features are
consistent with an active metabolism: synthesis of lysosomal enzymes
Activated macrophages can synthesize and secrete various bioactive
continues in mature cells. All macrophages have irregular surfaces with
substances, e.g. IL-1, which stimulate the proliferation and maturation
protruding filopodia and they contain varying numbers of endocytic
of other lymphocytes, greatly amplifying the reaction of the immune
vesicles, larger vacuoles and lysosomes. Some macrophages are highly
system to foreign antigens. They also synthesize TNF-α, which is able
motile, whereas others tend to remain attached and sedentary, e.g. in
to kill small numbers of neoplastic cells. TNF-α depresses the anabolic
hepatic and lymphoid sinuses. Within connective tissues, macrophages
activities of many cells in the body, and may be a major factor mediat-
may fuse to form large syncytia (giant cells) around particles that are
ing cachexia (wasting), which typically accompanies more advanced
too large to be phagocytosed, or when stimulated by the presence of
cancers. Other macrophage products include plasminogen activator,
infectious organisms, e.g. Mycobacterium tuberculosis.
which promotes clot removal; various lysosomal enzymes; several com-
When blood-borne monocytes enter the tissues through the endothe-
plement and clotting factors; and lysozyme (an antibacterial protein).
lial walls of capillaries and venules, they can undergo a limited number
In pathogenesis, these substances may be released inappropriately and
of rounds of mitosis as tissue macrophages before they die and are
damage healthy tissues, e.g. in rheumatoid arthritis and various other
replaced from the bone marrow, typically after several weeks. There is
inflammatory conditions.
some evidence that alveolar macrophages of the lung are able to
undergo many more mitoses than other macrophages.
DENDRITIC CELLS
Phagocytosis
There are two distinct groups of dendritic cell: myeloid dendritic cells
The uptake of particulate material and microorganisms is carried out (also known as classic dendritic cells) and plasmacytoid dendritic cells
by macrophages in many tissues and organs. When present in general (Liu 2001, Merad et al 2013, Gerlach et al 2013). These cells can arise
connective tissue, they ingest and kill invading microorganisms and from both common lymphoid progenitors and common myeloid pro-
remove debris that has been produced as a consequence of tissue genitors. Both groups of cells are involved in antigen presentation,
damage. They recognize, engulf and rapidly ingest apoptotic cells in all though have somewhat different functional roles in controlling both
situations; the mechanism of apoptotic cell uptake does not activate the the adaptive and innate immune systems. The myeloid dendritic cells
phagocyte for antigen presentation, and so the process is immunologi- are professional APCs, which are able to process and present antigen to
cally silent. In the lung, alveolar macrophages constantly patrol the T lymphocytes, including naïve T cells. They are present as immature
respiratory surfaces, to which they migrate from pulmonary connective dendritic cells in the epidermis of the skin (Fig. 4.14) and other
tissue (Fig. 4.13). They engulf inhaled particles, including bacteria,
surfactant and debris, and many enter the sputum (hence their alterna- Langerhans Precursor Blood
tive names, dust cells or, in cardiac disease, heart failure cells, which are cell cell vessel
full of extravasated erythrocytes). They perform similar scavenger func-
tions in the pleural and peritoneal cavities. In lymph nodes, macro- Cornified layer
phages line the walls of sinuses and remove particulate matter from
lymph as it percolates through them. In the spleen and liver, macro-
phages are involved in particle removal and in the detection and
Prickle cell layer Epidermis
destruction of aged or damaged erythrocytes. They begin the degrada-
tion of haemoglobin for recycling iron and amino acids.
Macrophages bear surface receptors for the Fc portions of antibodies
and for the fragments of the C3 component of complement. Phagocytic Basal layer
Migrating veiled cell
Afferent lymphatic Dermis
Subcapsular sinus
Capsule
Lymphoid follicle
in cortex
Interdigitating dendritic Lymph node
cell in paracortex
Fig. 4.14 Dendritic cells in the skin and lymphoid tissues. Their migratory
routes are shown: from blood-borne, marrow-derived precursors to
Fig. 4.13 Alveolar macrophages (dust cells, arrows) containing ingested immature dendritic cells (Langerhans cells) in skin, and then to migrating
carbon particles, in alveoli and interalveolar septa of the human lung. veiled cells in afferent lymphatic vessels and interdigitating dendritic cells
(Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, in lymph nodes. An example of each cell in the sequence (arrowed) is
Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) shown in red. | 131 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
BlOOd, lymPHOId TISSuES ANd HAEmOPOIESIS
80
1
NOITCES
stratified squamous epithelia, e.g. the oral mucosa (Langerhans cells),
and in the dermis and most other tissues (interstitial dendritic cells),
where they are concerned with immune surveillance. Immature den-
dritic cells have an antigen-capturing function. They respond to chemo-
tactic signals, e.g. defensins released by epithelial cells in the small
intestine, and they express pattern recognition receptors (e.g. Toll-like
receptors) on their surface. Binding of pathogen-associated molecular
pattern molecules (PAMPs) derived from bacteria (e.g. carbohydrate,
lipopolysaccharide or DNA) to these receptors stimulates the dendritic
cells to become activated and migrate via the lymphatics to nearby
secondary lymphoid tissues, where they can present antigen to T cells.
They can also be activated by recognition of damage-associated pattern
molecules (DAMPs), such as ATP, DNA, heat-shock proteins and high-
mobility group box 1 (HMGB1) released from injured or necrotic cells.
Mature dendritic cells are known as veiled cells when in the afferent
lymphatics and the subcapsular sinuses of lymph nodes, and as inter-
digitating dendritic cells once they are within the lymphoid tissue
proper. Their function within the secondary lymphoid tissue is to
present their processed antigen to T lymphocytes, and thus to initiate
Fig. 4.15 Follicular dendritic cells (brown) in a germinal centre of the
and stimulate the immune response. For a review of research on den-
human palatine tonsil (immunoperoxidase-labelled). (Courtesy of Marta
dritic cell function, see Colonna et al (2006). Perry MD, UMDS, London.)
Langerhans cells
respond to antigen presented by dendritic cells. The T cells are stimu-
Langerhans cells (see Fig. 4.14) are one of the best-studied types of lated not only by recognition of the antigen–MHC complex by the TcR,
immature dendritic cell (reviewed in Berger et al (2006), Chopin and but also by interaction with co-stimulatory molecules expressed by the
Nutt (2014)). They are present throughout the epidermis of skin, where dendritic cells, and by cytokines secreted by the cells. These cytokines
they were first described, but are most clearly identifiable in the stratum not only help activate the T cell but can also direct the nature of the
spinosum. They have an irregular nucleus and a clear cytoplasm, and T-cell response (e.g. Th1 or Th2). Appropriate T cells are thus activated
contain characteristic elongated membranous vesicles (Birbeck gran- to proliferate and are primed for carrying out their immunological
ules). Langerhans cells endocytose and process antigens, undergoing a functions. Once primed, T cells can then be stimulated by any APC,
process of maturation from antigen-capturing to antigen-presenting including macrophages and B cells.
cells that express high levels of MHC class I and II molecules,
co-stimulatory molecules and adhesion molecules. They migrate to Follicular dendritic cells
lymph nodes to activate T lymphocytes.
Follicular dendritic cells (FDCs; Fig. 4.15) are a non-migratory popula-
Interdigitating dendritic cells
tion of cells found in the follicles of secondary lymphoid tissues, where
they attract and interact with B cells. Unlike other dendritic cells, FDCs
Immature dendritic cells are found all over the body, including periph- are not haemopoietic in origin but are probably derived from the
eral blood, and function in antigen-processing and immune surveil- stromal cells of lymphoid tissues. They are unable to endocytose and
lance. Mature dendritic cells are present in T-cell-rich areas of secondary process antigen, and they lack MHC class II molecules. However, Fc
lymphoid tissue (paracortical areas of lymph nodes, interfollicular areas receptors and complement receptors CD21 and CD35 on FDCs allow
of MALT, peri-arteriolar sheaths of splenic white pulp), where they are the cells to bind immune complexes to their surface for subsequent
frequently referred to as interdigitating dendritic cells. Within the sec- presentation, as unprocessed antigen, to germinal centre B cells. Interac-
ondary lymphoid tissues, they are involved in the presentation to T tions between B cells, CD4 helper T cells and FDCs in the germinal
lymphocytes of antigens associated with either MHC class I (CD8 T centres are important in the selection of high-affinity B cells and their
cells) or MHC class II (CD4 T cells) molecules. Naïve T cells can only maturation to either plasma cells or memory B lymphocytes (Liu 2001).
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haemoglobin scavenger receptor. Nature 409:198–201. function of dendritic cells and their subsets in the steady state and the
A demonstration that CD163, which is expressed at the cell surface of inflamed setting. Annu Rev Immunol 31:563–604.
macrophages, is a scavenger receptor for haemoglobin and haptoglobin- A summary of recent data that has changed our understanding of how
bound haemoglobin. This provides insight into a molecular mechanism of dendritic cells subsets arise and function.
iron recycling by macrophages.
Murphy K 2011 Janeway’s Immunobiology, 8th ed. New York: Garland
Liu Y-J 2001 Dendritic cell subsets and lineages, and their functions in innate Science.
and adaptive immunity. Cell 106:259–62. The unifying principles of structure and function of the immune system in
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Psychogios N, Hau DD, Peng J et al 2011 The human serum metabolome.
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An explanation of the scientific principles of clinical immunology, integrated in health and disease.
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Malhotra D, Fletcher AL, Turley SJ 2013 Stromal and hematopoietic cells in 30:429–57.
secondary lymphoid organs: partners in immunity. Immunol Rev A comprehensive review of germinal centres, integrating recent findings on
251:160–76. the role of cellular dynamics in affinity maturation. | 132 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Blood, lymphoid tissues and haemopoiesis
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4
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Cerutti A, Chen K, Chorny A 2011 Immunoglobulin responses at the
mucosal interface. Annu Rev Immunol 29:273–93. Mankelow TJ, Satchwell TJ, Burton NM 2012 Refined views of multi-protein
Chan CJ, Smyth MJ, Martinet L 2015 Molecular mechanisms of natural killer complexes in the erythrocyte membrane. Blood Cells Mol Dis 49:
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Immunol 63:38–44. Mebius RE, Kraal G 2005 Structure and function of the spleen. Nat Rev
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inflamed setting. Annu Rev Immunol 31:563–604.
Colonna M, Pulendran B, Iwasaki A 2006 Dendritic cells at the host–
A summary of recent data that has changed our understanding of how
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Cunningham-Rundles C, Ponda PP 2005 Molecular defects in T- and B-cell
primary immunodeficiency diseases. Nat Rev Immunol 5:880–92. Mohandas N, Gallagher PG 2008 Red cell membrane: past, present, and
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health and disease.
Girard JP, Moussion C, Förster R 2012 HEVs, lymphatics and homeostatic
immune cell trafficking in lymph nodes. Nat Rev Immunol 12: Nathan C 2006 Neutrophils and immunity: challenges and opportunities.
762–73. Nat Rev Immunol 6:173–82.
A discussion of how the movement of immune cells into, through and out of Psychogios N, Hau DD, Peng J et al 2011 The human serum metabolome.
the lymph node is controlled. PLoS ONE 6:e16957.
An analysis of more than 4000 serum components and their concentrations
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in health and disease.
Rev Immunol 5:953–64.
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swords of innate immunity. J Immunol 189:2689–95. Rothenberg ME, Hogan SP 2006 The eosinophil. Annu Rev Immunol 24:
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macrophages, is a scavenger receptor for haemoglobin and haptoglobin- Stranford S, Ruddle NH 2012 Follicular dendritic cells, conduits, lymphatic
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A review of current research and a re-evaluation of the lineage of and 30:429–57.
functional relationships between different dendritic cell types. A comprehensive review of germinal centres, integrating recent findings on
the role of cellular dynamics in affinity maturation.
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An explanation of the scientific principles of clinical immunology, integrated
with histology, pathology and clinical examples. | 133 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
81
5
RETPAHC
Functional anatomy of the CHAPTER
5
musculoskeletal system
The musculoskeletal system consists of the specialized connective common proteoglycan molecule, aggrecan, forms huge molecular ag
tissues of the articulated bony skeleton and the skeletal muscles that gregates with other proteoglycans and with hyaluronan (see Fig. 5.1).
act across the articulations. All the specialized cells of the musculoskel
etal system (bone, cartilage, muscle, tendon) are related members of the Cartilage cells
connective tissue family and are derived from mesenchymal stem cells.
The cells of cartilage are chondroblasts and chondrocytes. Chondro
CARTILAGE blasts are actively dividing cells, often flattened and irregular in shape,
and are abundant in growing tissue where they synthesize the extracel
lular matrix (Fig. 5.2). Small projections arising from the cell mem
Cartilage is the fetal precursor tissue in the development of many bones. brane (Fig. 5.3) can form gap junctions with adjacent cells (Bruehlmann
In the adult skeleton it persists at almost all joints between bones and et al 2002), but these junctions may be lost when interstitial growth
in structures that must be deformable as well as strong, e.g. in the res causes greater cell separation. As chondroblasts mature and lose the
piratory tract. ability to divide, they develop into the larger but metabolically less
active chondrocytes. These ovalshaped cells form sparse populations
that maintain the extensive matrix of adult cartilage. The name ‘chondro
MICROSTRUCTURE OF CARTILAGE
cyte’ is commonly employed, as it is here, to denote all of the cartilage
Cartilage is a pliant, loadbearing connective tissue, covered by a fibrous
perichondrium except at its junctions with bones and over the articular
surfaces of synovial joints. It has a capacity for rapid interstitial and Proteoglycan Type II
complex collagen fibrils
appositional growth in young and growing tissues. Three types of car
tilage (hyaline cartilage, white fibrocartilage and yellow elastic cartilage)
can be distinguished on the basis of the composition and structure of
their extracellular matrices, but many features of the cells and matrix
are common to all three types, and these features will be considered
first.
Extracellular matrix
The matrix is mostly comprised of collagen and, in some cases, elastic
fibres, embedded in a highly hydrated proteoglycan gel (Fig. 5.1). Large
proteoglycan molecules have numerous side chains of glycosaminogly
cans (GAGs), carbohydrates with remarkable waterbinding properties.
A preponderance of fixed negative charges on the surface of GAGs
strongly attract polarized water molecules, causing wet cartilage to swell
until restricted by tension in the collagen network, or by external
loading. In this way, cartilage develops a compressive turgor that enables
it to distribute loading evenly on to subchondral bone, rather like a
water bed. Effectively, water is held in place by proteoglycans, which are
themselves held in place by the collagen network. Other constituents
of cartilage include dissolved salts, noncollagenous proteins, and
glycoproteins.
Collagens are described on page 38. Most fibrous tissues contain
collagen type I, which forms large fibres with a wavy ‘crimped’ structure;
however, this type of collagen is only found in cartilage in the outer
layers of the perichondrium and in white fibrocartilage. More typical of Proteoglycan
cartilage is collagen type II, which forms very thin fibrils dispersed monomer
between the proteoglycan molecules so that they do not clump together
to form larger fibres. Collagen type II fibrils are often less than 50 nm Large
proteoglycan
in diameter and are too small to be seen by light microscopy. Trans complex
mission electron microscopy reveals that they have a characteristic
crossbanding (65 nm periodicity) and are interwoven to create a three
dimensional meshwork. The collagen network varies in different types
of cartilage and with age. The length of collagen fibrils and fibres in Hyaluronan
cartilage is unknown, but even relatively short fibrils can reinforce the
matrix by interacting physically and chemically with each other, and Core protein
with other matrix constituents including proteoglycans (Hukins and Glycosaminoglycan
chain
Aspden 1985), reflecting the fact that the term collagen means ‘glue
maker’.
Collagen type II is found in the notochord, the nucleus pulposus of Fig. 5.1 The fine structural organization of hyaline cartilage matrix. Large
an intervertebral disc, the vitreous body of the eye, and the primary proteoglycan complexes and type II collagen fibres (cross-banded and of
corneal stroma. different diameters) are depicted. Proteoglycan complexes bind to the
Cartilage proteoglycans are similar to those found in general, i.e. surface of these fibres via their monomeric side chains and link them
nonspecialized, connective tissue. The most common GAG side chains together. The arrangement of glycosaminoglycans and core protein of the
in cartilage are chondroitin sulphate and keratan sulphate. The most proteoglycan monomer is illustrated in the expansion. | 134 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
FunCTionAl AnATomy oF THE musCuloskElETAl sysTEm
82
1
noiTCEs
B C
Cc
P Cb
M B
C
M
B C
A B
Fig. 5.2 Sections through hyaline cartilage. A, A low-power view of human rib, showing perichondrium (P), young chondroblasts (Cb) embedded in
pale-staining interterritorial matrix, and mature chondrocytes (Cc) embedded in the basophilic interterritorial matrix (centre and right). B, Higher
magnification of hyaline cartilage in human bronchial wall, showing isogenous groups of chondrocytes (C). Note the more deeply stained basophilic
zones (B) (rich in acidic proteoglycans) around the cell clusters, with older, paler-staining matrix (M) between clusters. (B, Courtesy of Mr Peter Helliwell
and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
Collagen is synthesized within the rough endoplasmic reticulum in
the same way as it is in fibroblasts. Polypeptide chains are assembled
into triple helices, and some carbohydrate is added. After transport to
the Golgi apparatus, where further glycosylation occurs, the resulting
procollagen molecules are secreted into the extracellular space. Termi
nal registration peptides are cleaved from their ends, forming tropocol
lagen molecules, and the final assembly into collagen fibrils takes
place. Core proteins of the proteoglycan complexes are also synthe
sized in the rough endoplasmic reticulum and addition of GAG chains
begins; the process is completed in the Golgi complex. Hyaluronan,
which lacks a protein core, is synthesized by enzymes on the surface of
the chondrocyte; it is not modified postsynthetically, and is extruded
directly into the matrix without passing through the endoplasmic
reticulum.
Matrix turnover is much slower in cartilage than in more metaboli
cally active tissues. Collagen turnover is particularly slow, leaving it
vulnerable to the slow process of nonenzymatic glycation, which
makes the tissue yellow, stiff and vulnerable to injury (DeGroot et al
2004). Proteoglycans are turned over faster than collagen, with an esti
mated turnover time of 5 years for adult humans.
Cartilage is often described as avascular. Certainly, the ability of the
matrix to deform under load makes it difficult for hollow blood vessels
to persist in the tissue beyond early childhood, but a limited vascular
Fig. 5.3 An electron micrograph of chondroblasts in rabbit femoral supply is often found on the cartilage surface, from where it can revas
condylar cartilage. The central cell has an active euchromatic nucleus cularize the tissue following injury or degeneration. Metabolite trans
with a prominent nucleolus, and its cytoplasm contains concentric
port to cartilage cells is mostly by the process of diffusion down a
cisternae of rough endoplasmic reticulum, scattered mitochondria,
concentration gradient from the cartilage surface, although fluid
lysosomes and glycogen aggregates. The plasma membrane bears
‘pumping’ as a result of changing mechanical loading can contribute
numerous short filopodia which project into the surrounding matrix. The
under certain circumstances. Metabolite transport severely limits cell
latter shows a delicate feltwork of collagen fibrils within finely granular
density and metabolic rate in the adult, and this in turn restricts carti
interfibrillary material. No pericellular lacuna is present; the matrix
lage thickness to a few millimetres (Junger et al 2009). Cartilage cells
separates the central chondroblast from the cytoplasm of two adjacent
situated further than this from a nutrient vessel do not survive, and their
chondroblasts (left, and crescentic profile). (Preparation courtesy of Susan
Smith, Department of Anatomy, GKT School of Medicine, London.) surrounding matrix typically becomes calcified. In the larger cartilages,
and during the rapid growth of some fetal cartilages, vascular cartilage
canals penetrate the tissue at intervals, providing an additional source
of nutrients. In some cases these canals are temporary structures but
cells embedded in an extensive matrix. Chondrocytes are normally in
others persist throughout life.
close contact with their dense matrix (see Fig. 5.3); however, artefacts
of tissue processing can sometimes give the illusion of an empty space
Hyaline cartilage
or ‘lacuna’ surrounding each cell or group of cells in histological sec
tions. One or more chondrocytes can form a chondron, which consists
of the cells and their pericellular matrix (see Fig. 5.2B), surrounded by Hyaline (glassy) cartilage has a homogeneous, opalescent appearance,
a protective basket of collagen (Roberts et al 1991, Youn et al 2006). sometimes appearing bluish. It is firm and smooth to the touch and
Chondrocytes synthesize and secrete all of the major components shows considerable deformability. The size, shape and arrangement of
of the cartilage matrix, and their ultrastructure is typical of cells that are cells vary at different sites and with age. Chondrocytes are flat near the
active in making and secreting proteins. The nucleus is round or oval, surface perichondrium, and rounded or angular deeper in the tissue
appears euchromatic and possesses one or more nucleoli. The cyto (see Fig. 5.2A). Groups of two or more cells frequently form a cell nest
plasm is filled with rough endoplasmic reticulum, transport vesicles and (isogenous cell group) surrounded by a basket of fine collagen fibrils
Golgi complexes, and contains many mitochondria and frequent lyso (see Fig. 5.2B). Within such a chondron, daughter cells of a common
somes, together with numerous glycogen granules, intermediate fila chondroblast often meet at a straight line. The pericellular matrix
ments (vimentin) and pigment granules. When these cells mature to closest to the cells is typically lacking in collagen fibrils, but rich in
the relatively inactive chondrocyte stage, the nucleus becomes hetero proteoglycans that can exhibit basophilic and metachromatic staining.
chromatic, the nucleolus smaller, and the protein synthetic machinery More distant and older interterritorial matrix appears paler and is
much reduced; the cells may also accumulate large lipid droplets. mostly collagen type II (75% of dry weight) and proteoglycans (22%). | 135 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Cartilage zone
Articular surface
Collagen fibrils
Superficial or
tangential
Middle or
Chondrocyte
intermediate
Deep or
radial
Tide mark
Calcified
Subchondral
bone
Fig. 5.4 Articular cartilage from the anterior region of the lateral femoral
condyle of a young adult human female. Three-dimensional digital 1mm
volumetric fluorescence imaging of serially sectioned, eosin-Y and
Fig. 5.5 Articular cartilage is not homogenous: the various zones are
acridine orange-stained tissue. Articular surface (top), articular cartilage
different in terms of cell size and shape, and the orientation of the
and subchondral bone (below). Note the changes in size and spatial
collagen fibril network.
distribution of articular chondrocytes through the thickness of the
cartilage. (Courtesy of Professor Robert L. Sah, Drs Won C. Bae, Kyle D.
Jadin, Benjamin L. Wong, Kelvin W. Li and Mrs Barbara L. Schumacher, (Properties of the articular surface are described below under ‘Synovial
Department of Bioengineering and Whitaker Institute of Biomedical joints’, p. 97.) Deeper within the tangential zone, the collagen fibrils
Engineering, University of California, San Diego.) increase in diameter and density, and gradually merge with the transi
tional (or intermediate) zone. Here, the chondrocytes are large and
After adolescence, hyaline cartilage may become calcified as part of rounded, and surrounded by collagen fibrils in a range of oblique ori
the normal process of bone development, or as an agerelated, degen entations. Deeper still, in the radial zone, the cells are often disposed
erative change. In costal cartilage, the matrix tends to fibrous striation, in vertical columns, interspersed with vertical collagen fibrils. The
especially in old age when cellularity diminishes. The xiphoid process matrix in this zone contains collagen types IX and XI, as well as collagen
and the cartilages of the nose, larynx and trachea (excepting the elastic II. An undulating band known as the tidemark indicates the start of the
cartilaginous epiglottis and corniculate cartilages) resemble costal car deepest zone, the zone of calcified cartilage, which has mechanical
tilage in microstructure. Hyaline cartilage is the prototypical form, but properties intermediate between cartilage and bone. This calcified zone
it varies more with age and location than either elastic or fibrocartilage. is keyed into the subchondral bone by fine ridges and interdigitations,
Its regenerative capacity following injury is poor. which serve to prevent shearing (gliding) movements between cartilage
Articular cartilage, which covers the articular surfaces of synovial and bone. With age, articular cartilage thins by upward advancement of
joints, is a specialized hyaline cartilage that lacks a perichondrium (Fig. the tidemark, and gradual replacement of calcified cartilage by bone.
5.4). The synovial membrane overlaps and then merges into its struc Cells of articular cartilage are capable of cell division, but mitosis is
ture circumferentially (see Fig. 5.32). The thickness of articular cartilage rarely observed in adult tissue and cartilage damage is not repaired.
varies from 1 to 7 mm (typically 2 mm) in different joints, and decreases Superficial cells are lost progressively from normal young joint surfaces,
from middle to old age. Thickness does not increase in response to to be replaced by cells from deeper layers. Agerelated reductions in cell
increased mechanical loading, at least in adults, although matrix com number and activity, and biochemical changes in the extracellular
position and stiffness can adapt somewhat (Gahunia and Pritzker matrix, particularly affect the superficial zone of articular cartilage,
2012). Central regions tend to be thickest on convex osseous surfaces, increasing the risk of mechanical failure and of osteoarthritis (Lotz and
and thinnest on concave surfaces. Loeser 2012).
Articular cartilage provides an extremely smooth, firm yet deform Articular cartilage derives nutrients by diffusion from vessels of the
able layer that increases the contact area between bones and thereby synovial membrane, synovial fluid and hypochondral vessels of an
reduces contact stress (see Fig. 5.61). Microscopic undulations on the adjacent medullary cavity, some capillaries from which penetrate and
cartilage surface help to trap synovial fluid between the articulating occasionally traverse the calcified cartilage zone. The contributions from
bones (see Fig. 5.60) and enable fluidfilm lubrication to reduce fric these sources are uncertain and may change with age. Small molecules
tion and wear. Articular cartilage is generally too thin and stiff to be a freely traverse articular cartilage, with diffusion coefficients about half
good shock absorber, although shock absorption may be significant those in aqueous solution. Larger molecules have diffusion coefficients
where there are multiple cartilagecovered surfaces, as in the carpus and inversely related to their molecular size. The permeability of cartilage
tarsus. to large molecules is greatly affected by variations in its GAG (and hence
Adult articular cartilage shows a structural zonation defined by its water) content: a threefold increase in GAGs increases the diffusion
network of fine collagen type II fibrils (Fig. 5.5). Embedded in the deep coefficient 100fold.
calcified zone, fibrils rise vertically through the radial zone towards the Cartilaginous growth plates (see below under ‘Bone’) are also com
cartilage surface, where they appear to reorientate to run parallel to the posed of hyaline cartilage, and there are similarities between active
surface in the tangential zone. These collagen arcades can be visualized growth plates and growing articular cartilage on the epiphyses of long
using phasecontrast microscopy (Thambyah and Broom 2007) but it bones. In both cases, chondrocytes undergo a sequence of cell divisions
is likely that each arcade represents numerous discrete fibrils rather than and hypertrophy (with cells forming into columns) followed by cell
a single fibre. Their threedimensional orientation can be appreciated death, and ossification by invading osteoblasts.
by repeatedly piercing the cartilage surface with a needle; this creates a
Fibrocartilage
series of permanent elongated splits in the surface, which can be stained
by Indian ink. The resulting split line pattern (Meachim et al 1974)
reveals the predominant directions of collagen bundles in the cartilage Fibrocartilage is a dense, whitish tissue with a distinct fibrous texture.
tangential zone, which may be related to internal lines of tension gener It forms the intervertebral discs of the spine and menisci of the knee,
ated during joint movement. as well as smaller structures such as the glenoid and acetabular labra,
Each zone of articular cartilage (see Fig. 5.5) has a distinct cell mor and the lining of bony grooves for tendons. It forms a versatile and
phology and matrix composition. The tangential (or superficial) zone tough material that combines considerable tensile strength with the
has relatively small, elongated cells orientated parallel to the surface. ability to resist high compressive forces and to distribute them evenly | 136 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Fig. 5.6 White fibrocartilage in a late human fetal intervertebral disc. Fig. 5.7 Elastic cartilage, stained to demonstrate elastin fibres (blue–
Chondroblasts lie between coarse collagen type I fibres (blue) derived black). Chondroblasts and larger chondrocytes are embedded in the
from the anulus fibrosus. Mallory’s triple stain. matrix, which also contains collagen type II fibres.
on to underlying bone (Adams et al 2013). Histologically, fibrocartilage sation foreshadows that of the future cartilage. They also become
is intermediate between dense fibrous connective tissues such as tendon rounded, with prominent round or oval nuclei and a low cytoplasm:
and ligaments, and hyaline cartilage. In some structures such as interver nucleus ratio. Each cell differentiates into a chondroblast as it secretes
tebral discs, matrix composition and cell types vary from one location a basophilic halo of matrix, composed of a delicate network of fine type
to another, reflecting varying mechanical properties. II collagen fibrils, type IX collagen and proteoglycan core protein. At
Regions of fibrocartilage that are loaded predominantly in tension some sites, continued secretion of matrix separates the cells, producing
consist of large crimped fibres of collagen type I embedded in a hydrated typical hyaline cartilage. Elsewhere, many cells become fibroblasts; col
proteoglycan gel. Cells are rounded in young tissue (Fig. 5.6), but lagen synthesis predominates and chondroblastic activity appears only
become elongated and fibroblastlike with age. They may be linked by in isolated groups or rows of cells that become surrounded by dense
gap junctions (Bruehlmann et al 2002). Those regions that are loaded bundles of collagen fibres to form white fibrocartilage. In yet other sites,
predominantly in compression appear more homogeneous, contain a the matrix of early cellular cartilage is permeated first by anastomosing
high proportion of fine collagen type II fibrils in an abundant proteo oxytalan fibres, and later by elastin fibres. In all cases, developing car
glycan gel, and contain rounded, chondrocytelike cells. Fibrocartilage tilage is surrounded by condensed mesenchyme, which differentiates
could therefore be regarded as a mingling of two types of tissue rather into a bilaminar perichondrium. The cells of the outer layer become
than a separate type of cartilage. However, no other tissue combines fibroblasts and secrete a dense collagenous matrix lined externally by
high proportions of proteoglycans with collagen type I, suggesting that vascular mesenchyme. The cells of the inner layer contain differentiated,
fibrocartilage should be regarded as a distinct class of connective tissue. but mainly resting, chondroblasts or prechondroblasts.
The articular surfaces of bones that ossify in mesenchymal mem Cartilage grows by interstitial and appositional mechanisms. Inter
branes (e.g. squamous temporal, mandible and clavicle) are covered by stitial growth is the result of continued mitosis of early chondroblasts
white fibrocartilage. The deep layers, adjacent to hypochondral bone, throughout the tissue mass and is obvious only in young cartilage,
resemble calcified regions of the radial zone of hyaline articular carti where plasticity of the matrix permits continued expansion. When a
lage. The superficial zone contains dense parallel bundles of thick col chondroblast divides, its descendants temporarily occupy the same
lagen fibres, interspersed with typical dense connective tissue fibroblasts chondron. They are soon separated by a thin septum of secreted matrix,
and little ground substance. Fibre bundles in adjacent layers alternate which thickens and further separates the daughter cells. Continuing
in direction, as they do in the cornea. A transitional zone of irregular division produces isogenous groups. Appositional growth is the result
bundles of coarse collagen and active fibroblasts separates the superfi of continued proliferation of the cells that form the internal, chondro
cial and deep layers. The fibroblasts are probably involved in elabora genic layer of the perichondrium. Newly formed chondroblasts secrete
tion of proteoglycans and collagen, and may also constitute a germinal matrix around themselves, creating superficial lacunae beneath the peri
zone for deeper cartilage. Fibre diameters and types may differ at dif chondrium. This continuing process adds additional surface, while the
ferent sites according to the functional load. entrapped cells participate in interstitial growth. Apposition is thought
to be most prevalent in mature cartilages, but interstitial growth must
Elastic cartilage persist for long periods in growthplate cartilage. Relatively little is
known about the factors that determine the overall shape of cartilage
structures.
Elastic cartilage occurs in the external ear, corniculate cartilages, epiglot
tis and apices of the arytenoids. Like hyaline cartilage, it contains typical
chondrocytes, either singly or in small groups, surrounded by a matrix
BONE
rich in type II collagen fibrils. However, the more distant interterritorial
matrix is pervaded by very fine yellow elastic fibres (Fig. 5.7) containing
the protein elastin, which show no periodic banding structure under Bone is a strong and rigid connective tissue that has evolved to enable
the electron microscope (as collagen fibrils do). A structure is termed fast terrestrial locomotion. Its strength provides support and protection
‘elastic’ if it returns to its original shape when loaded and then unloaded; for the body, while its rigidity enables it to create precisely shaped
elastic fibres (and cartilage) have the special property of being able to articular surfaces that do not distort under load, and ensures that force
do this even after being subjected to deformations greater than 15%, ful muscle contractions result in rapid limb movements rather than
which would damage collagen fibres. This characteristic is termed elastic bending of bones. Unlike cartilage, bone is a highly vascular tissue with
recoil. Most sites in which elastic cartilage occurs have vibrational func a high cell density; high cellularity enables it to adapt to changing
tions, such as laryngeal soundwave production, or the collection and mechanical demands, and to regenerate following injury.
transmission of sound waves in the ear. Elastic cartilage is resistant to
degeneration, and its capacity for limited regeneration following trau
matic injury can be appreciated from the distorted repair of a cauli MACROSCOPIC ANATOMY OF BONE
flower ear, as seen in participants of some contact sports.
Macroscopically, living bone is white. Its texture is either dense like
ivory (compact bone) or honeycombed by large cavities (trabecular,
DEVELOPMENT AND GROWTH OF CARTILAGE cancellous or spongy bone), where the bony element is reduced to a
latticework of bars and plates known collectively as trabeculae (Figs
Cartilage is usually formed in embryonic mesenchyme. Mesenchymal 5.8–5.9). Compact bone is usually limited to the outer shell or cortex
cells proliferate and become tightly packed; the shape of their conden of mature bones, where it is important in determining their strength | 137 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Bone
85
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and providing rigid articular surfaces. Cortical thickness and architec
ture vary between and within bones, and generally decrease with age in
CC adults. Trabecular bone provides support to the cortex while minimiz
ing weight. The presence of a large central medullary canal in long
bones also helps to reduce their weight. Spaces within bones provide
convenient and secure locations for the storage of haemopoietic tissues
and fat. Bone forms a reservoir of metabolic calcium (99% of body
calcium is in the bony skeleton) and of phosphate, which is under
hormonal and cytokine control.
The proportions of compact to cancellous bone vary between and
within bones. Generally, a thick cortex is required to provide strength
in bending, e.g. in the middiaphysis of a long bone (see Fig. 5.20).
Trabecular bone provides strength in compression and so is abundant
in the epiphyses of long bones, and in the vertebral bodies of the spine.
In flat bones such as the ribs, the interior is uniformly cancellous, and
compact bone forms the surface. Internal cavities are usually filled with
marrow, either red haemopoietic or yellow adipose, according to age
CC and site. However, in some bones of the skull, notably the mastoid
process of the temporal bone and the paranasal sinuses of the frontal,
maxilla, sphenoid and ethmoid bones, many of the internal cavities are
Fig. 5.8 A vertical section 2 cm below the anterosuperior border of the
filled with air, i.e. they are variably pneumatized.
iliac crest (female, 42 years). The cancellous bone consists of intersecting
Bones vary not only in their primary shape but also in lesser surface
curved plates and struts. Osteonal (Haversian) canals can just be seen in
details (secondary markings), which appear mainly in postnatal life.
the two cortices (C) at this magnification.
Most bones display features such as elevations and depressions (fossae),
smooth areas and rough ridges. Some articular surfaces are called fossae
Fig. 5.9 Trabecular (e.g. the glenoid fossa); lengthy depressions are grooves or sulci (e.g.
bone at different sites the humeral bicipital sulcus); a notch is an incisura; and an actual gap
in the proximal part of
is a hiatus. A large projection is termed a process or, if elongated and
the same human femur.
slender or pointed, a spine. A curved process is a hamulus or cornu (e.g.
All fields are shown
the pterygoid hamuli of the sphenoid bone and the cornua of the
at the same scale.
hyoid). A rounded projection is a tuberosity or tubercle, and occasion
A, Subcapital part of
ally a trochanter. Long elevations are crests, or lines if they are less
the neck. B, Greater
developed; crests are wider and present boundary edges or lips. An
trochanter. C, Rim of
epicondyle is a projection close to a condyle and is usually a site where
the articular surface
of the head. Note the the common tendon of a superficial muscle group or the collateral liga
wide variation in ment of the adjacent joint is attached. The terms protuberance, promi
thickness, orientation nence, eminence and torus are less often applied to certain bony
and spacing of the projections. The expanded proximal ends of many long bones are often
trabeculae. (Original termed the ‘head’ or caput (e.g. humerus, femur, radius). A hole in a
photographs from bone is a foramen and becomes a canal when lengthy. Large holes may
Whitehouse WJ, Dyson be called apertures or, if covered largely by connective tissue, fenestrae.
A ED 1974 Scanning Clefts in or between bones are fissures. A lamina is a thin plate; larger
electron microscope laminae may be called squamae (e.g. the temporal squama). Large areas
studies of trabecular on many bones are featureless and as smooth as articular surfaces, from
bone in the proximal which they differ by being pierced by visible vascular foramina.
end of the human Tendons are usually attached at roughened bone surfaces. Wherever
femur. J Anat 118:
any aggregation of collagen in a muscle reaches bone, surface irregulari
417–414, by permission
ties correspond in form and extent to the pattern of tendinous fibres.
from Blackwell
Such markings are almost always elevated above the general surface, as
Publishing.)
if ossification advanced into the collagen bundles from periosteal bone.
How such secondary markings are induced is uncertain but they may
result from the continued incorporation of new collagen fibres into the
bone, perhaps necessary for minor functional adjustment. There is evi
dence that their prominence may be related to the power of the muscles
involved, and they increase with advancing years as if the pull of
muscles and ligaments exercised a cumulative effect over a limited area.
Surface markings delineate the shape of attached connective tissue
structures, e.g. an obvious tendon, intramuscular tendon or septum,
aponeurosis, or tendinous fibres mediating what is otherwise a direct
B muscular attachment. These markings may be facets, ridges, nodules,
rough areas or complex mixtures; they afford accurate indications of
the junctions of bone with muscles, tendons, ligaments or articular
capsules.
Muscle fibres do not attach directly to periosteum or bone. Force
transmission is through the connective tissue that encapsulates (epimy
sium) and pervades (perimysium and endomysium) all muscles. These
two forms of attachment of muscles, which are at the extremes of a
range of admixtures, differ in the density of collagen fibres between
muscle and bone. Where collagen is visibly concentrated, markings
appear on the bone surface. In contrast, the multitude of microscopic
connective tissue ties of direct attachment that occur over a larger area
do not visibly mark the bone, and so it appears smooth to unaided
vision and touch.
Many bones articulate with their neighbours at synovial joints. Small
articular surfaces are termed facets or foveae; larger, knuckleshaped
surfaces are condyles; a trochlea is grooved like a pulley. Articular sur
faces are smooth and covered by articular cartilage, which means that
C they lack the vascular foramina typical of the surfaces of most other
bones. | 138 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Bone minerals
Approximately 60–70% of bone dry weight is made up of inorganic
mineral salts in the form of microcrystalline hydroxyapatite (Ca
10
(PO) (OH)). The microcrystals confer hardness and much of the
4 6 2
rigidity of bone, and are the main reason why bone is easily seen on
radiographs. (Bone must be 50% mineralized to be visible on radio
graphs produced with a standard Xray unit.) Bone mineral also has
an important carbonate content, and a lower Ca/P ratio than pure
hydroxyapatite, together with a small amount of calcium phosphate.
Bone crystals are extremely small (which gives them a high surface:volume
ratio). They take the form of thin plates or leaflike structures; the largest
are 150 nm long × 80 nm wide × 5 nm thick, although most are half that
size. Up to twothirds of the mineral content of bone is thought to be
located within collagen fibrils, where the crystals are packed closely
together, with their long axes nearly parallel to the fibrils; crystal forma
tion is probably initiated in the gaps between individual collagen mol
ecules. Narrow spaces between the crystals contain water and organic
macromolecules. The mineral substances of bone are mostly acid
soluble. If they are removed, using calcium chelators such as citrates or
Fig. 5.10 A scanning electron micrograph of collagen fibres on the
ethylene diamine tetraacetic acid (EDTA), the bone retains its shape
surface of human trabecular bone. Note the branching fibres (female,
2 months, sixth rib). but becomes highly flexible.
The major ions in bone mineral include calcium, phosphate,
hydroxyl and carbonate. Less numerous ions are citrate, magnesium,
sodium, potassium, fluoride, chloride, iron, zinc, copper, aluminium,
MICROSTRUCTURE OF BONE lead, strontium, silicon and boron, many of which are present only in
trace quantities. Fluoride ions can substitute for hydroxyl ions, and
carbonate can substitute for either hydroxyl or phosphate groups.
Bone contains a mineralized collagenous extracellular matrix surround
‘Group IIA cations’, such as radium, strontium and lead, all readily
ing a range of specialized cells including osteoblasts, osteocytes and
substitute for calcium and are therefore known as boneseeking cations.
osteoclasts. Periosteum, endosteum and marrow are closely associated
tissues. All of these components will be described first individually, and Since they can be either radioactive or chemically toxic, their presence
then their overall organization will be considered. in bone, where they may be close to haemopoietic bone marrow, may
cause illness and characteristic appearances on Xrays.
Bone organic matrix Mineralization of newly synthesized osteoid is a gradual process that
slows over time; it typically reaches 70–80% in 3 weeks. Immature
woven bone mineralizes faster and so may be distinguished from adja
Approximately 10–20% of bone mass is water. A significant proportion
cent lamellar bone by its higher degree of mineralization. In cortical
(30–40%) of the remaining dry weight is made up of the organic com
bone, lamellae mostly take the form of cylindrical osteons (see Fig.
ponent of the extracellular matrix. Approximately 30% of this organic
5.16). These structures mineralize from inside to out, so that the con
matrix is collagen; the remainder includes various noncollagenous
centration of mineral is highest in the older, more peripheral, lamellae.
proteins, glycoproteins and carbohydrates. The proportions of these
Although new osteons are less mineralized than old ones, they may
components vary with age, location and metabolic status.
show one or more highly mineralized ‘arrest lines’ within their walls.
Most of the collagen in bone is an ordered branching network of
Mineral distribution is most uniform in established, highly mineralized
type I fibres (Fig 5.10). Although type I collagen fibres are found in
osteons. Overall, mineralization increases with age, even though bone
most connective tissues, their molecular structure in bone is atypical:
mass decreases.
internal crosslinking between component fibrils is stronger and chemi
cally more inert, and transverse spacings between collagen molecules
Osteoblasts
within each fibril are larger, allowing more space for the deposition of
minerals. A small amount of type V collagen is also present, probably
to help regulate fibrillogenesis. Collagen fibres contribute greatly to the Osteoblasts are derived from osteoprogenitor (stem) cells of mesenchy
cohesive mechanical strength of bone, and also to its toughness (which mal origin present in bone marrow and other connective tissues. They
is reflected in the energy required to break a bone). proliferate and differentiate into osteoblasts prior to bone formation,
Collagen is synthesized in bone by osteoblasts. Newly secreted mol stimulated by bone morphogenetic proteins (BMPs). A layer of osteo
ecules of tropocollagen lose part of their nonhelical terminal regions, blasts covers the forming surfaces of growing or remodelling bone (Fig.
thus allowing them to polymerize in the extracellular matrix to form 5.11). In relatively quiescent adult bone, they appear to be present
fibrils, which then associate to form fibres. These structures are stabi mostly on endosteal rather than periosteal surfaces, but they also occur
lized by various crosslinks, which increase in number and strength as deep within compact bone wherever osteons are being remodelled.
the tissue matures. In primary bone, collagen fibres form a complex Osteoblasts are responsible for the synthesis, deposition and minerali
interwoven meshwork that incorporates other organic molecules; this zation of the bone matrix, which they secrete. Once embedded in the
‘osteoid’ material is then mineralized to form woven (nonlamellar) matrix, they become osteocytes.
bone. In time, primary bone is almost entirely replaced by regular Osteoblasts are basophilic, roughly cuboidal mononuclear cells
laminar arrays of nearly parallel collagen fibres, which form the basis 15–30 µm across. They contain prominent bundles of actin, myosin
of lamellar bone (Currey 2002). Partially mineralized collagen net and other cytoskeletal proteins associated with the maintenance of cell
works can be seen within osteoid on the outer and internal surfaces of shape, attachment and motility. Their plasma membranes display many
bone, and in the endosteal linings of vascular canals. Collagen fibres extensions, some of which contact neighbouring osteoblasts and
from the periosteum are incorporated in cortical bone (extrinsic fibres) embedded osteocytes at intercellular gap junctions. This arrangement
and anchor this fibrocellular layer at its surface. Terminal collagen fibres facilitates coordination of the activities of groups of cells, e.g. in the
of tendons and ligaments are incorporated deep into the matrix of corti formation of large domains of parallel collagen fibres.
cal bone. They may be interrupted by new osteons during cortical drift Ultrastructurally, osteoblasts are typical proteinsecreting cells. They
(modelling) and turnover (remodelling), and remain as islands of inter synthesize and secrete collagens and a number of glycoproteins. Osteo
stitial lamellae or even trabeculae. calcin is required for bone mineralization, binds hydroxyapatite and
Bone organic matrix includes small amounts of various macromol calcium, and is used as a marker of new bone formation. Osteonectin
ecules attached to collagen fibres and surrounding bone crystals. They is a phosphorylated glycoprotein that binds strongly to hydroxyapatite
are secreted by osteoblasts and young osteocytes, and include osteonec and collagen; it may play a role in initiating crystallization and may be
tin, osteocalcin, the bone proteoglycans biglycan and decorin, the bone a cell adhesion factor. RANKL is the cell surface ligand for RANK (recep
sialoproteins osteopontin and thrombospondin, many growth factors tor for activation of nuclear factor kappa B), an osteoclast progenitor
including transforming growth factor beta (TGFβ), proteases and pro receptor (see below). Osteoprotegerin is a soluble, highaffinity decoy
tease inhibitors, often in a latent form. The functions of some of these ligand for RANKL, which restricts osteoclast differentiation. Biglycan
molecules are described with osteoblasts (see below). and decorin are bone proteoglycans that attract water; decorin also | 139 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Fig. 5.12 Osteocyte lacunae shown at high magnification in a dry ground
section of lamellar bone. The territories of three osteocytes are shown.
Their branching dendrites contact those of neighbouring cells via the
canaliculi seen here within the bone matrix. Several other osteocyte
lacunae are present, out of the focal plane in this section, and tangential
Fig. 5.11 Bone cells actively remodelling alveolar bone to accommodate
to the osteon axis.
a developing tooth. Large multicellular osteoclasts (white arrow) are
actively resorbing bone on one surface, while a layer of osteoblasts (black
arrow) is depositing osteoid on another. Osteoblasts that have become
trapped in the matrix to form osteocytes are shown in the centre (white
arrowhead). (Image courtesy of Prof. Tim Arnett, University College
London.)
binds the growth factor TGFβ. The bone sialoproteins, osteopontin
and thrombospondin, mediate osteoclast adhesion to bone surfaces by
binding to osteoclast integrins. In addition, osteoblasts secrete latent
proteases and growth factors including BMPs and TGFβ (which is also
secreted by osteoclasts and which may be a coupling factor for stimulat
ing new bone formation at resorption sites).
Although extracellular fluid is generally supersaturated with respect
to the basic calcium phosphates, mineralization does not occur in most
tissues. In bone, osteoblasts secrete osteocalcin (binds calcium at levels
sufficient to concentrate the ion locally) and contain membranebound
vesicles full of alkaline phosphatase (cleaves phosphate ions from Fig. 5.13 Human parietal bone (male neonate) showing primary osteonal
various molecules to elevate concentrations locally) and pyrophos bone (grey) and woven bone (white) containing many connecting
phatase (degrades inhibitory pyrophosphate in the extracellular fluid). osteocyte lacunae (black). Internal resorption of the bone has produced
The vesicles bud off from the osteoblast surface into newly formed large, irregular dark spaces (trabecularization).
osteoid, where they initiate hydroxyapatite crystal formation. Some
alkaline phosphatase reaches the blood circulation, where it can be
detected in conditions of rapid bone formation or turnover. Osteocytes in woven bone are larger and more irregular in shape (Fig.
Osteoblasts also play a key role in the hormonal regulation of bone 5.13). Numerous fine branching processes containing bundles of
resorption. They express receptors for parathyroid hormone (PTH), microfilaments and some smooth endoplasmic reticulum emerge from
1,25dihydroxy vitamin D (calcitriol) and other promoters of bone each cell body. At their distal tips, these processes form gap junctions
3
resorption. When activated, osteoblasts promote osteoclast differentia with the processes of adjacent cells (osteocytes, osteoblasts and bone
tion via PTHactivated expression of cell surface RANKL, which binds lining cells) so that they are in electrical and metabolic continuity.
to RANK on immature osteoclasts, establishes cell–cell contact and Extracellular fluid fills the small, variable spaces between osteocyte
triggers contactdependent osteoclast differentiation. In the presence of cell bodies and their rigid lacunae, which may be lined by a variable
PTH, osteoblasts also downregulate secretion of osteoprotegerin, a (0.2–2 µm) layer of unmineralized organic matrix. The same fluid fills
soluble decoy ligand with higher affinity for RANKL. In conditions the narrow channels or canaliculi that surround the long processes of
favouring bone deposition, secreted osteoprotegerin blocks RANKL the osteocytes. Approximately 0.25–0.5 µm wide, the canaliculi provide
binding to RANK, restricting the number of mature osteoclasts. a route for the diffusion of nutrients, gases and waste products between
Bonelining cells are flattened epitheliallike cells that cover the free osteocytes and blood vessels. Canaliculi do not usually extend through
surfaces of adult bone not undergoing active deposition or resorption. and beyond the reversal line surrounding each osteon and so do not
Generally considered to be quiescent osteoblasts or osteoprogenitor communicate with neighbouring systems.
cells, they line the periosteal surface and the vascular canals within In wellvascularized bone, osteocytes are longlived cells that actively
osteons, and form the outer boundary of the marrow tissue on the maintain the bone matrix. The average lifespan of an osteocyte varies
endosteal surface of marrow cavities. with the metabolic activity of the bone and the likelihood that it will
be remodelled, but is measured in years. Old osteocytes may retract
Osteocytes their processes from the canaliculi; when they die, their lacunae
and canaliculi may become plugged with cell debris and minerals,
which hinders diffusion through the bone. Dead osteocytes occur com
Osteocytes are the major cell type of mature bone and are distributed
monly in interstitial bone (between osteons) and in central regions of
throughout its matrix, interconnected by numerous dendritic processes
trabecular bone that escape surface remodelling. They are particularly
to form a complex cellular network (Fig. 5.12). They are derived from
noticeable by the second and third decades. Bones that experience little
osteoblasts that have become enclosed within their rigid matrix (see
turnover, e.g. the auditory ossicles, are most likely to contain aged
Fig. 5.11) and so have lost the ability to divide or to secrete new matrix.
osteocytes and have low osteocyte viability. Osteocyte death leads to
(The rigidity of mineralized bone matrix prevents interstitial growth, so
matrix resorption by osteoclast activity. Osteocytes themselves are often
that new bone must always be deposited on preexisting surfaces.)
mineralized.
Osteocytes retain contact with each other and with cells at the surfaces
of bone (osteoblasts and bonelining cells) throughout their lifespan.
Osteoclasts
Mature, relatively inactive osteocytes have an ellipsoid cell body with
their longest axis (approximately 25 µm) parallel to the surrounding
lamellae. The rather narrow rim of cytoplasm is faintly basophilic, Osteoclasts are large (diameters of 40 µm or more) polymorphic cells
contains relatively few organelles and surrounds an oval nucleus. containing up to 20 oval, closely packed nuclei (see Fig. 5.11). They lie | 140 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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OO
OO
MM
Fig. 5.14 A scanning electron micrograph of a neonatal rabbit osteoclast
actively resorbing bone in vitro from the surface of sperm whale dentine.
(Courtesy of Professor Alan Boyde, Queen Mary University of London,
London, UK.)
in close contact with the bone surface in resorption bays (Howship’s
lacunae). Their cytoplasm contains numerous mitochondria and vacu
oles, many of which are acid phosphatasepositive lysosomes. Rough
endoplasmic reticulum is relatively sparse but the Golgi complex is Fig. 5.15 An electron micrograph of woven bone from a failed fracture of
human distal tibia. Two osteoblasts (O) lie on the free surface (top). Newly
extensive. The cytoplasm also contains numerous coated transport vesi
synthesized collagenous osteoid matrix (M) is seen in the centre field,
cles and microtubule arrays involved in vesicle transport between the
with a mineralization front (electron-dense area) below (arrows). (Courtesy
Golgi stacks and the cell’s ruffled border (the highly infolded region of
of Dr Bart Wagner, Histopathology Department, Sheffield Teaching
plasma membrane of an active osteoclast at a site of bone resorption).
Hospitals, UK.)
A welldefined zone of actin filaments and associated proteins occurs
beneath the ruffled border around the circumference of a resorption
bay, in a region termed the sealing zone.
Functionally, osteoclasts are responsible for the local removal of required to propagate cracks that are sufficiently extensive to fracture
bone during bone growth and remodelling (Fig. 5.14). They dissolve the bone.
bone minerals by proton release to create an acidic local environment, Each lamella consists of a sheet of mineralized matrix containing
and they remove organic matrix by secreting lysosomal (cathepsin K) collagen fibres of similar orientation locally, running in branching
and nonlysosomal (e.g. collagenase) enzymes. Osteoclasts are stimu bundles 2–3 µm thick and often extending the full width of a lamella.
lated to resorb bone by signals from local cells (including osteoblasts, The orientation of collagen fibres and crystals differs between 0° and
macrophages and lymphocytes) and by bloodborne factors such as 90° in adjacent lamellae, as may be demonstrated by polarized light
PTH and 1,25dihydroxy vitamin D (calcitriol). Calcitonin, produced microscopy (see Fig. 5.18). At the borders of lamellae, packing of col
3
by C cells of the thyroid follicle, reduces osteoclast activity. lagen fibres into bundles is less perfect and intermediate and random
Osteoclasts differentiate from myeloid stem cells via macrophage orientations of collagen predominate.
colonyforming units. Differentiation is primarily regulated by two
cytokines: macrophagecolony stimulating factor, secreted by osteob Cortical bone
lasts, and RANKL, expressed by osteoblasts (see above). The mononu
clear precursors fuse to form terminally differentiated multinuclear The cylindrical structural units that comprise most cortical bone are
osteoclasts (Väänänen and LaitalaLeinonen 2008). Osteoclast differen termed Haversian systems or osteons (Fig. 5.17). Osteons usually lie
tiation inhibitors are potential therapeutic agents for bone loss parallel with each other (Fig. 5.18); in long bones, they lie parallel with
associated disorders, e.g. osteoporosis, rheumatoid arthritis, Paget’s the long axis of the bone. Adjacent osteons may encroach on one
disease, periodontal disease and osteosarcoma. another because they are usually formed at different times, during suc
cessive periods of bone remodelling. Irregular gaps between osteons are
Woven and lamellar bone
filled with interstitial lamellae (see Fig. 5.17A), which are the fragmen
tary remains of older osteons and circumferential lamellae. Osteons
The mechanical properties of bone depend not only on matrix compo may be spiral or they may branch, and some end blindly. They are
sition, as described above, but also on the manner in which the matrix round or ellipsoidal in crosssection. The main direction of collagen
constituents are organized. Woven bone and lamellar bone represent fibres within osteons varies: in the shaft of long bones, fibres are more
two quite distinct types of organization. longitudinal at sites that are subjected mainly to tension, and more
In woven (or bundle) bone, the collagen fibres and bone crystals are oblique at sites subjected mostly to compression. Peripheral lamellae
irregularly arranged. The diameters of the fibres vary, so that fine and of osteons contain more transverse fibres.
coarse fibres intermingle, producing the appearance of the warp and It has been estimated that there are 21 million osteons in a typical
weft of a woven fabric. Woven bone is typical of young fetal bones, but adult skeleton. Their diameter varies from 100 to 400 µm, and they
is also seen in adults during excessively rapid bone remodelling and usually contain 5–20 lamellae. Each osteon is permeated by the canal
during fracture repair (Fig. 5.15). It is formed by highly active osteo iculi of its resident osteocytes, which form pathways for the diffusion
blasts during development, and is stimulated in the adult by fracture, of metabolites between osteocytes and blood vessels. The maximum
growth factors or prostaglandin E. diameter of an osteon ensures that no osteocyte is more than 200 µm
2
Lamellar bone, which makes up almost all of an adult skeleton, is from a blood vessel, a distance that may be a limiting factor in their
more organized and is produced more slowly. The precise arrangement survival.
of lamellae (bone layers) varies from site to site. In trabeculae and the The central Haversian canals of osteons vary in size, with a mean
outer (periosteal) and inner (endosteal) surfaces of cortical bone, a few diameter of 50 µm; those near the marrow cavity are somewhat larger.
lamellae form continuous circumferential layers that are more or less Each canal contains one or two capillaries lined by fenestrated endothe
parallel to the bony surfaces. However, in more central regions of corti lium and surrounded by a basal lamina, which also encloses typical
cal bone, the lamellae are arranged in concentric cylinders around pericytes. They usually contain a few unmyelinated and occasional
neurovascular channels called Haversian canals (Fig. 5.16). This inter myelinated axons. The bony surfaces of osteonic canals are perforated
connecting, threedimensional, laminated construction increases the by the openings of osteocyte canaliculi and are lined by collagen fibres.
toughness of lamellar bone because the interfaces between lamellae are Haversian canals communicate with each other and directly or indi
effective in stopping the growth of cracks; more energy is therefore rectly with the marrow cavity via vascular (nutrient) channels called | 141 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Outer circumferential
lamellae
Osteon
Interstitial lamellae
Inner circumferential
lamellae
Haversian canal
Periosteum
Osteocyte lacuna
Canaliculi
Volkmann’s canal
Medullary trabecular bone
Osteon
Fig. 5.16 The main features of the microstructure of mature lamellar bone. Areas of compact and trabecular (cancellous) bone are included. Note the
general construction of the osteons; distribution of the osteocyte lacunae; Haversian canals and their contents; resorption spaces; and different views of
the structural basis of bone lamellation.
Volkmann’s canals, which run obliquely or at right angles to the long bone tissue. It is absent from articular surfaces, and from the points of
axes of the osteons (see Fig. 5.18). The majority of these channels insertion of tendons and ligaments (entheses) (see Fig. 5.51). The peri
appear to branch and anastomose, but some join large vascular connec osteum is highly active during fetal development, when it generates
tions with vessels in the periosteum and the medullary cavity. osteoblasts for the appositional growth of bone. These cells form a layer,
Osteons are distinguished from their neighbours by a cement line 2–3 cells deep, between the fibrous periosteum and new woven bone
that contains little or no collagen, and is strongly basophilic because it matrix. Osteoprogenitor cells within the mature periosteum are indis
has a high content of glycoproteins and proteoglycans. Cement lines tinguishable morphologically from fibroblasts. Periosteum is important
are also known as reversal lines because they mark the limit of bone in the repair of fractures; where it is absent (e.g. within the joint capsule
erosion prior to the formation of a new osteon. Canaliculi occasionally of the femoral neck) fractures are slow to heal.
pass through cement lines, and so provide a route for exchange be Quiescent osteoblasts and osteoprogenitor cells act as the principal
tween interstitial bone lamellae and vascular channels within osteons. reservoir of new boneforming cells for remodelling or repair on the
Basophilic resting lines can occur in the absence of erosion; they indi endosteal surfaces of resting adult bone. Bone endosteum is likely to
cate where bony growth has been interrupted and then resumed. be important in calcium homeostasis because it provides a total surface
area of approximately 7.5 m2. It is formed by flattened osteoblast pre
Trabecular bone cursor cells and reticular (type III collagen) fibres, and lines all the
internal cavities of bone, including the Haversian canals. It overlies the
endosteal circumferential lamellae and encloses the medullary cavity.
The organization of trabecular bone (also known as cancellous or
spongy bone) is basically lamellar, as shown most clearly under polar
ized light (Fig. 5.19). Trabeculae take the form of branching bars and
curved plates of varying width, length and thickness (50−400 µm) (see NEUROVASCULAR SUPPLY OF BONE
Fig. 5.9). They are covered in endosteal tissue because they are adjacent
to marrow cavities. Thick trabeculae and regions close to compact bone Vascular supply
may contain small osteons, but blood vessels do not otherwise lie
within trabeculae; osteocytes therefore rely on canalicular diffusion The osseous circulation supplies bone tissue, marrow, perichondrium,
from adjacent medullary vessels. In young bone, calcified cartilage may epiphysial cartilages in young bones, and, in part, articular cartilages.
occur in the cores of trabeculae, but this is generally replaced by bone The vascular supply of a long bone depends on several points of inflow
during subsequent remodelling. that feed complex and regionally variable sinusoidal networks within
the bone. The sinusoids drain to venous channels that leave through all
Periosteum, endosteum and bone marrow
surfaces that are not covered by articular cartilage. The flow of blood
through cortical bone in the shafts of long bones is mainly centrifugal
The outer surface of bone is covered by a condensed collagenous layer, (Fig. 5.20).
the periosteum. The inner surface is lined by a thinner, more cellular One or two main diaphysial nutrient arteries enter the shaft ob
endosteum. Osteoprogenitor cells, osteoblasts, osteoclasts and other liquely through nutrient foramina, which lead into nutrient canals.
cells important in the turnover and homeostasis of bone tissue lie in Their sites of entry and angulation are almost constant and characteristi
these layers. cally directed away from the dominant growing epiphysis. Nutrient
The periosteum is tethered to underlying bone by thick collagen arteries do not branch in their canals but divide into ascending and
fibres (Sharpey’s fibres), which penetrate deep into the outer cortical descending branches in the medullary cavity; these approach the | 142 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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A
A
B
B
Fig. 5.17 A, Osteons in a dry ground transverse section of bone.
Fig. 5.19 Trabecular bone in a bone marrow sample taken from the
Concentric lamellae surround the central Haversian canal of each
human posterior iliac crest. A, Irregular trabeculae of bone, surrounded by
complete osteon; they contain the dark lacunae of osteocytes and the
bone marrow haemopoietic and adipose tissue (haematoxylin and eosin
canaliculi, which are occupied in life by their dendrites. These canaliculi
stain). B, The same field viewed under polarized light, demonstrating
interconnect with canaliculi of osteocytes in adjacent lamellae. Incomplete
lamellar, non-osteonic bone with lamellae orientated in different directions
(interstitial) lamellae (e.g. centre field) are the remnants of osteons
in different regions. Osteocytes are just visible, embedded in the solid
remodelled by osteoclast erosion. B, A high-power view of osteocytes
matrix. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew,
within lamellae; a Haversian canal is seen on the right. (B, Photograph by
Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
Sarah-Jane Smith.)
Within bone, the arteries are unusual in consisting of endothelium with
only a thin layer of supportive connective tissue. The epiphysial and
metaphysial arterial supply is richer than the diaphysial supply.
H
Medullary arteries in the shaft give off centripetal branches, which
feed a hexagonal mesh of medullary sinusoids that drain into a wide,
V thinwalled central venous sinus. They also possess cortical branches,
which pass through endosteal canals to feed fenestrated capillaries in
H Haversian systems. The central sinus drains into veins that retrace the
paths of nutrient arteries, sometimes piercing the shaft elsewhere as
independent emissary veins. Cortical capillaries follow the pattern of
Haversian canals, and are mainly longitudinal with oblique connec
V
tions via Volkmann’s canals (see Fig. 5.18). At bone surfaces, cortical
capillaries make capillary and venous connections with periosteal plex
V
uses (see Fig. 5.20) formed by arteries from neighbouring muscles that
contribute vascular arcades with longitudinal links to the fibrous peri
osteum. A capillary network permeates the deeper, osteogenic perios
H
teum from this external plexus. At muscular attachments, periosteal and
Fig. 5.18 Osteons in a dry ground longitudinal section of bone. The muscular plexuses are confluent and the cortical capillaries then drain
central Haversian canals (H; tubular structures, mainly dark) show into interfascicular venules.
transverse nutrient canals (Volkmann’s canals, V), which form bridges In addition to the centrifugal supply of cortical bone, there is an
between adjacent osteons and their blood vessels. appreciable centripetal arterial flow to outer cortical zones from perios
teal vessels. The large nutrient arteries of epiphyses form many intraos
epiphyses, dividing repeatedly into smaller helical branches close to the seous anastomoses, their branches passing towards the articular surfaces
endosteal surface. The endosteal vessels are vulnerable during surgical within the trabecular spaces of the bone. Near the articular cartilages,
operations, such as intramedullary nailing, which involve passing metal these form serial anastomotic arcades (e.g. there are three or four in the
implants into the medullary canal. Near the epiphyses, diaphysial femoral head), which give off endarterial loops. The latter often pierce
vessels are joined by terminal branches of numerous metaphysial and the thin hypochondral compact bone to enter, and sometimes traverse,
epiphysial arteries (see Fig. 5.20). The former are direct branches of the calcified zone of articular cartilage, before returning to the epiphy
neighbouring systemic vessels; the latter come from periarticular vas sial venous sinusoids.
cular arcades formed on nonarticular bone surfaces. Numerous vascu In immature long bones, the supply is similar but the epiphysis is
lar foramina penetrate bones near their ends, often at fairly specific a discrete vascular zone. Epiphysial and metaphysial arteries enter
sites; some are occupied by arteries but most contain thinwalled veins. on both sides of the growth cartilage and rarely, if ever, anastomose. | 143 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Endosteal
vessels
Epiphysis
Metaphysis
Diaphysis
Periosteal vessels
Tendon
Muscular vessels
Fig. 5.20 The main features of the blood supply of a long bone. Note the contrasting supplies of the diaphysis, metaphysis and epiphysis, and their
connections with periosteal, endosteal, muscular and peri-articular vessels. The expansion shows part of the diaphysis in more detail. The marrow cavity
contains a large central venous sinus, a dense network of medullary sinusoids, and longitudinal medullary arteries and their circumferential rami.
Longitudinally oblique transcortical capillaries emerge through minute ‘cornet-shaped’ foramina to become confluent with the periosteal capillaries and
venules. The obliquity of the cortical capillaries is emphasized for clarity. Not to scale.
Growth cartilages are probably supplied from both sources, and from unmyelinated axons accompany nutrient vessels into bone and marrow,
an anastomotic collar in the adjoining periosteum. Occasionally, carti and lie in the perivascular spaces of Haversian canals. Osteoblasts
lage canals are incorporated into a growth plate. Metaphysial bone is possess receptors for several neuropeptides found in these nerves,
nourished by terminal branches of metaphysial arteries and by primary including neuropeptide Y, calcitonin generelated peptide, vasoactive
nutrient arteries of the shaft, which form terminal blindended sprouts intestinal peptide and substance P, indicating that bone has a complex
or sinusoidal loops in the zone of advancing ossification. Young peri autonomic and sensory innervation.
osteum is more vascular; its vessels communicate more freely with those
of the shaft than their adult counterparts and give off more metaphysial
branches. DEVELOPMENT AND GROWTH OF BONE
Large, irregular bones such as the scapula and innominate not only
receive a periosteal supply but are also often supplied by large nutrient Some of the bones in the skull are laid down within a fibrocellular
arteries that penetrate directly into their cancellous bone, the two mesenchymal membrane, by a process known as intramembranous
systems anastomosing freely. Short bones receive numerous fine vessels ossification. Most bones are formed by a process of endochondral ossi
that supply their compact and cancellous bone and medullary cavities fication, in which preformed cartilage templates (models) define their
from the periosteum. Arteries enter vertebrae close to the base of their initial shapes and positions, and the cartilage is replaced by bone in an
transverse processes (see Fig. 43.20). Each vertebral medullary cavity ordered sequence.
drains to two large basivertebral veins, which converge to a foramen
on the posterior surface of the vertebral body (see Fig. 43.21). Flatter Intramembranous ossification
cranial bones are supplied by numerous periosteal or mucoperiosteal
vessels. Large, thinwalled veins run tortuously in cancellous bone.
Intramembranous ossification is the direct formation of bone (mem
Lymphatic vessels accompany periosteal plexuses but have not been
brane bone) within highly vascular sheets or ‘membranes’ of condensed
convincingly demonstrated in bone.
primitive mesenchyme. At centres of ossification, mesenchymal stem
cells differentiate into osteoprogenitor cells, which proliferate around
Innervation
the branches of a capillary network, forming incomplete layers of
osteoblasts in contact with the primitive bone matrix. The cells are
Nerves are most numerous in the articular extremities of long bones, polarized, and secrete osteoid only from the surface that faces away
vertebrae and larger flat bones, and in periosteum. Fine myelinated and from the blood vessels. The earliest crystals appear in association with | 144 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Fig. 5.21 A, A section of a human fetal hand
showing cartilaginous models of the carpal bones
and the primary ossification centres, which display
varying stages of maturity, in the metacarpals and
phalanges. Note that none of the carpal elements
shows any evidence of ossification. B, A higher-
power view of an early primary ossification centre.
The cartilage cells in the shaft have hypertrophied
and this region is surrounded by a delicate tube or
collar of subperiosteal bone (red). (Photograph by
Kevin Fitzpatrick on behalf of GKT School of
Medicine, London.)
A B
extracellular matrix vesicles produced by the osteoblasts. Crystal forma
tion subsequently extends into collagen fibrils in the surrounding G
matrix, producing an early labyrinth of woven bone, the primary spon
giosa. As layers of calcifying matrix are added to the early trabeculae,
osteoblasts become enclosed within primitive lacunae. These new
H
osteocytes retain intercellular contact by means of their fine cytoplasmic
processes (dendrites) and, as these elongate, matrix condenses around
them to form canaliculi.
As matrix secretion and calcification proceed, trabeculae thicken and
vascular spaces become narrower. Where bone remains trabecular, the O
process slows and the spaces between trabeculae become occupied by
haemopoietic tissue. Where compact bone is forming, trabeculae con
tinue to thicken and vascular spaces continue to narrow. Meanwhile,
the collagen fibres of the matrix, secreted on the walls of the narrowing
spaces between trabeculae, become organized as parallel, longitudinal
or spiral bundles, and the cells they enclose occupy concentric sequen R
tial rows. These irregular, interconnected masses of compact bone each
have a central canal and are called primary osteons (primary Haversian
systems). They are later eroded, together with the intervening woven
bone, and replaced by generations of mature (secondary) osteons.
Fig. 5.22 The sequence of cellular events in endochondral ossification.
While these changes are occurring, mesenchyme condenses on the This low-magnification micrograph shows the primary ossification centre
outer surface to form a fibrovascular periosteum. Bone is laid down in a human fetal bone. See Figure 5.24 for further details. Abbreviations;
increasingly by new osteoblasts, which differentiate from osteoprogeni G, growth zone; H, hypertrophic zone; O, ossification zone; R, remodelling
tor cells in the deeper layers of the periosteum. Modelling of the zone.
growing bone is achieved by varying rates of resorption and deposition
at different sites.
ing from chondrocytes in the proliferation zone are most evident in the
Endochondral ossification
intercolumnar regions, where they appear to initiate crystal formation.
At the same time, cells in the deep layer of perichondrium around the
The hyaline cartilage model that forms during embryogenesis is a mini centre of the cartilage model differentiate into osteoblasts and form a
ature template of the bone that will subsequently develop. It becomes peripheral layer of bone. Initially, this periosteal collar, formed by
surrounded by a condensed, vascular mesenchyme or perichondrium, intramembranous ossification within the perichondrium, is a thin
which resembles the mesenchymal ‘membrane’ in which intramembra walled tube that encloses and supports the central shaft (see Figs 5.21–
nous ossification occurs. Its deeper layers contain osteoprogenitor cells. 5.22). As it increases in diameter, it also extends towards both ends of
The first appearance of a centre of primary ossification (Fig. 5.21) the shaft.
occurs when chondroblasts deep in the centre of the primitive shaft The periosteal collar, which overlies the calcified cartilaginous walls
enlarge greatly, and their cytoplasm becomes vacuolated and accumu of degenerate chondrocyte lacunae, is invaded from the deep layers of
lates glycogen. The intervening matrix is compressed into thin, often the periosteum (formerly perichondrium) by osteogenic buds. These
perforated, septa. The cells degenerate and may die, leaving enlarged are blindended capillary sprouts that are accompanied by osteopro
and sometimes confluent lacunae (primary areolae) whose thin walls genitor cells and osteoclasts. The latter excavate newly formed bone to
become calcified during the final stages (Fig. 5.22). Type X collagen is reach adjacent calcified cartilage, where they continue to erode the walls
produced in the hypertrophic zone of cartilage. Matrix vesicles originat of primary chondrocyte lacunae (Figs 5.23–5.24). This process leads to | 145 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Fig. 5.24 Endochondral ossification in human fetal bone. Spicules of
Fig. 5.23 An Alcian-blue periodic acid–Schiff (PAS)-stained section of
cartilaginous remnants (pale blue) serve as surfaces for the deposition of
human fetal femur showing the hypertrophy and palisading of cartilage
osteoid (dark blue), shown in the upper half of the field. Mineralized,
cells as the ossifying (mineralizing) front of an early primary centre of
woven bone is stained red. Three large multinucleate osteoclasts (arrows)
ossification is approached (below). Lacunae are enlarged, and matrix
are seen centre right, further eroding cartilage and remodelling the
partitions are reduced in width and exhibit increased staining density
developing bone. Blood sinusoids and haemopoietic tissue (below) fill the
following cartilage calcification. (Courtesy of Mr Peter Helliwell and the
spaces between areas of ossification. Heidenhain’s azan trichrome
late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall
preparation.
Hospitals Trust, UK.)
A CartilageBHypertrophy C Calcification of D Invasion of E Primary bone laid down F Continued growth of cartilage of G Cessation of cartilage growth and complete
template of central cells matrix in primary primary centre on calcified cartilage epiphysial plate and epiphysis; ossification of epiphysial plate (fusion of the
ossification centre by vascular remnants; secondary centre proliferation of red bone marrow epiphysis). Replacement of red bone marrow with
and formation of osteogenic buds of ossification appears yellow, adipose marrow in most adult long bones
periosteal collar of and becomes vascularized
bone
Growth
Transformation
Ossification
Remodelling
Growth: Cell division
Interstitial and appositional growth
Cell columns (palisades)
Transformation: Cell hypertrophy
Calcification of matrix
Ossification: Chondrolysis
Vascularization
Osteogenesis
Remodelling: Erosion and deposition
Fig. 5.25 The stages of endochondral ossification in a long bone.
their fusion into larger, irregular communicating spaces, secondary of dynamic change from cartilage to bone persists until longitudinal
areolae, which fill with embryonic medullary tissue (vascular mesen growth of the bone ceases.
chyme, osteoblasts and osteoclasts, haemopoietic and marrow stromal Expansion of the cartilaginous extremity (usually an epiphysis; see
cells, etc.). Osteoblasts attach themselves to the delicate residual walls Fig 5.20) keeps pace with the growth of the rest of the bone by both
of calcified cartilage and lay down osteoid, which rapidly becomes appositional and interstitial growth. The growth zone expands in all
confluent, forming a continuous lining of bone. Further layers of bone dimensions. Lateral growth of a developing long bone is caused by
are added, enclosing young osteocytes in lacunae and narrowing the occasional transverse mitosis in its chondrocytes, and by appositional
perivascular spaces. Bone deposition on the more central calcified car growth as a result of matrix deposition by cells from the perichondrial
tilage ceases as the formation of subperiosteal bone continues. collar or ring at this level. The future growth plate therefore expands in
Osteoclastic erosion of the early bone spicules then creates a primi concert with the shaft and adjacent future epiphysis. A zone of relatively
tive medullary cavity in which only a few trabeculae, composed of bone quiescent chondrocytes (the resting zone) lies on the side of the plate
with central cores of calcified cartilage (see Fig. 5.23), remain to support closest to the epiphysis. An actively mitotic zone of cells faces towards
the developing marrow tissues. These trabeculae soon become remod the shaft of the bone; the more frequent divisions in the long axis of
elled and replaced by more mature bone or by marrow. Meanwhile, the bone soon create numerous longitudinal columns (palisades) of
new, adjacent, cartilaginous regions undergo similar changes. Since discshaped chondrocytes, each in a flattened lacuna (see Fig. 5.25).
these are most advanced centrally, and the epiphyses remain cartilagi Proliferation and column formation occur in this zone of cartilage
nous, the intermediate zones exhibit a temporospatial sequence of growth (the proliferative zone), and its continued longitudinal intersti
changes when viewed in longitudinal section (Fig. 5.25). This region tial expansion provides the basic mode of elongation of a bone. | 146 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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The columns of cells show increasing maturity towards the centre of tion of osteoprogenitor cells at sutures; periosteal bone is mainly added
the shaft, as their chondrocytes increase in size and accumulate glyco externally and eroded internally, but not at uniform rates or at all times.
gen. In the hypertrophic zone, energy metabolism is depressed at the The rate of formation increases with radial distance from the centre of
level of the mineralizing front (see Fig. 5.23). The lacunae are now ossification (in this case, the future parietal eminence). Bone formation
separated by transverse and longitudinal walls, and the latter are may also occur endocranially as well as ectocranially, so changing the
impregnated with apatite crystals in what has become the zone of calci curvature of the bone. The relative positions of the original centres of
fied cartilage (or ossification zone; see Fig. 5.22). The calcified partitions ossification change in three dimensions as the skull bones thicken and
enter the zone of bone formation and are invaded by vascular mesen grow at the sutures and as the vault of the skull expands to accommo
chyme containing osteoblasts, osteoclasts, etc. The partitions, especially date the growth of the brain. Development of the outer and inner corti
the transverse ones, are then partly eroded while osteoid deposition, cal plates is accompanied by internal development of trabeculae and
bone formation and osteocyte enclosure occur on the surfaces of the marrow spaces.
longitudinal walls. Lysis of calcified partitions is mediated by osteoclast Long bones increase in length mainly by endochondral ossification
action, aided by cells associated with the terminal buds of vascular at the epiphysial growth plates. Simultaneous increase in width occurs
sinusoids that occupy, and come into close contact with, each incom by subperiosteal deposition and endosteal erosion. Growth at different
plete columnar trabecular framework. locations can occur at different rates, or even be replaced by resorption,
Continuing cell division in the growth zone adds to the epiphysial resulting in a change in the shape of a bone. This explains how, for
ends of cell columns, and the bone grows in length as this sequence of example, the tibia changes its crosssectional shape from tubular to
changes proceeds away from the diaphysial centre. The bone also grows triangular. Similarly, the waisted contours of metaphyses are preserved
in diameter as further subperiosteal bone deposition occurs near the by differential rates of periosteal erosion and endosteal deposition, as
epiphyses, and its medullary cavity enlarges transversely and longitudi metaphysial bone becomes diaphysial in position. The junction between
nally. Internal erosion and remodelling of the newly formed bone tissue a field of resorption and one of deposition on the surface of a growing
continues. bone is called a surface reversal line. The relative position of such a line
Growth continues in this way for many months or years in different may remain stable over long periods of growth and shape change.
bones, but eventually one or more secondary centres of ossification Lamellar bone forms and is remodelled at variable rates throughout
usually appear in the cartilaginous extremities. Initially, these epiphysial adult life (see below).
centres (or the ends of bones that lack epiphyses) do not display cell Normal development and maintenance of bone requires adequate
columns. Instead, isogenous cell groups hypertrophy, with matrix cal intake and absorption of calcium, phosphorus and vitamins A, C and
cification, and are then invaded by osteogenic vascular mesenchyme, D, and a balance between growth hormone (GH, somatotropin),
sometimes from cartilage canals. Bone is formed on calcified cartilage, thyroid hormones, oestrogens and androgens. Other biological influ
as described above. As an epiphysis enlarges, its cartilaginous periphery ences include prostaglandins and glucocorticoids. Vigorous mechanical
(perichondrium) also forms a zone of proliferation in which cell loading is important for the maintenance of adequate bone mass. Pro
columns are organized radially; hypertrophy, calcification, erosion and longed deficiency in any of these factors can lead to loss of bone tissue
ossification occur at increasing depths from the surface. The early (osteopaenia); if bone loss is severe (osteoporosis), it can lead to frac
osseous epiphysis is thus surrounded by a superficial growth cartilage, ture and deformity.
and the growth plate adjacent to the metaphysis soon becomes the most Vitamin D influences intestinal transport of calcium and phosphate,
active region. and therefore affects circulatory calcium levels. In adults, prolonged
As a bone reaches maturity, epiphysial and metaphysial ossification deficiency (with or without low intake) produces bones that contain
processes gradually encroach upon the growth plate from either side; regions of deformable, uncalcified osteoid (osteomalacia). During
when they meet, bony fusion of the epiphysis occurs and longitudinal growth, vitamin D deficiency can lead to severe disturbance of growth
growth of the bone ceases. The events that take place during fusion are cartilages and ossification, such as reductions of regular columnar
broadly as follows. As growth ceases, the cartilaginous plate becomes organization in growth plates, and failure of cartilage calcification even
quiescent and gradually thins; proliferation, palisading and hypertro though chondrocytes proliferate. Growth plates also become thicker
phy of chondrocytes stop, and the cells form short, irregular, conical and irregular, as exemplified in classic rickets or juvenile osteomalacia.
masses. Patchy calcification is accompanied by resorption of calcified In rickets, the uncalcified or poorly calcified cartilaginous trabeculae are
cartilage and some of the adjacent metaphysial bone, forming resorp only partially eroded; osteoblasts secrete layers of osteoid but these fail
tion channels that are invaded by vascular mesenchyme. to ossify in the metaphysial region, and ultimately gravity deforms these
Some endothelial sprouts pierce the thin plate of cartilage, and the softened bones.
metaphysial and epiphysial vessels unite. Ossification around these Vitamin C is essential for the adequate synthesis of collagen and
vessels spreads into the intervening zones and results in fusion of epi matrix proteoglycans in connective tissues. When vitamin C is deficient,
physis and metaphysis. This bone is visible in radiographs as a radio growth plates become thin, ossification almost stops, and metaphysial
dense epiphysial line (a term that is also used to describe the level of trabeculae and cortical bone are reduced in thickness, causing fragility
the perichondrial collar or ring around the growth cartilage of imma and delayed healing of fractures.
ture bones, or the surface junction between epiphysis and metaphysis Vitamin A is necessary for normal growth and for a correct balance
in a mature bone). In smaller epiphyses, which unite earlier, there is between deposition and removal of bone. Deficiency retards growth as
usually one initial eccentric area of fusion, and thinning of the residual a result of the failure of internal erosion and remodelling, particularly
cartilaginous plate. The original sites of fusion are subsequently resorbed in the cranial base. Foramina are narrowed, sometimes causing pressure
and replaced by new bone. Medullary tissue extends into the whole atrophy of the nerves that pass through them. The cranial cavity and
cartilaginous plate until union is complete and no epiphysial ‘scar’ spinal canal may fail to expand at the same rate as the developing
persists. In larger epiphyses, which unite later, similar processes also central nervous system, impairing nervous function. Conversely, excess
involve multiple perforations in growth plates, and islands of epiphysial vitamin A stimulates vascular erosion of growth cartilages, which
bone often persist as epiphysial scars. Calcified cartilage coated by bone become thin or totally lost, and longitudinal growth ceases. Retinoic
forms the epiphysial scar, and is also found below articular cartilage. It acid, a vitamin A derivative, is involved in pattern formation in limb
has been called metaplastic bone, a term also applied to sites of attach buds and in the differentiation of osteoblasts.
ments of tendons, ligaments and other dense connective tissues to Balanced endocrine functions are also essential to normal bone
bone. maturation, and disturbances in this balance may have profound
The cartilaginous surfaces of epiphyses that form synovial joints effects. In addition to its role in calcium metabolism, excess parathyroid
remain unossified, but the typical sequence of cartilaginous zones per hormone (primary hyperparathyroidism) stimulates unchecked osteo
sists in them throughout life. A similar developmental sequence occurs clastic erosion of bone, particularly subperiosteally and later endo
at synchondroses, except that the proliferative rates of chondrocytes and steally (osteitis fibrosa cystica). Growth hormone is required for normal
the replacement of cartilage by bone are similar, although not identical, interstitial proliferation in growth cartilages, ensuring normal increase
on either side of the synchondrosis. in stature. Termination of normal growth is imperfectly understood, but
may involve a fall in hormone production or in the sensitivity of chon
Postnatal growth and maintenance of bone
droblasts to insulinlike growth factors regulated by GH. Reduction of
GH production in the young leads to quiescence and thinning of
Modelling, by which is meant changes in general shape, occurs in all growth plates and hence pituitary dwarfism. Conversely, continued
growing bones. The process has been studied mainly in cranial and long hypersecretion in the immature leads to gigantism, and in the adult
bones with expanded extremities. results in thickening of bones by subperiosteal deposition; the mandi
A bone such as the parietal thickens and expands, but decreases in ble, hands and feet are the most affected, a condition known as
curvature, during growth. Accretion continues at its edges by prolifera acromegaly. | 147 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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While continued longitudinal growth of bones depends on adequate Successive layers of bone are deposited on the surface of the previous
levels of GH, effective remodelling to achieve a mature shape also layer as cohorts of osteoblasts become embedded (as osteocytes) in the
requires the action of thyroid hormones. Moreover, growth and skeletal matrix they secrete, until the most central lamella is close to the blood
maturity are closely related to endocrine activities of the ovaries, testes vessel at the axis of the cylinder. The ‘closing cone’ (see Fig. 5.26) may
and suprarenal cortices. High oestrogen levels increase deposition of contain 4000 osteoblasts per mm2. In this way, the walls of resorption
endosteal and trabecular bone; conversely, osteoporosis in postmeno canals are lined with new lamellar matrix and the vascular channels are
pausal women reflects reduced ovarian function. In men, fluctuations progressively narrowed. A hypermineralized basophilic cement (or
in the rate of growth, and the timing of skeletal maturation, depend on growthreversal) line marks the edge of a new osteon, indicating the
circulating levels of suprarenal and testicular androgens. In hypogonad border between the resorptive activity of the cutting cone and the bony
ism, growthplate fusion is delayed and the limbs therefore elongate matrix not remodelled by this activity. Remnants of the circumferential
excessively; conversely, in hypergonadism, premature fusion of the epi lamellae of old osteons form interstitial lamellae between newer
physes results in diminished stature. osteons (see Fig. 5.17A).
The remodelling unit in cancellous bone, equivalent to the second
Bone remodelling ary osteon of compact bone, is the basic (or bony) structural unit; it
has an average thickness of 40–70 µm and an average length of 100 µm,
but may be more extensive and irregular in shape. Separate structural
Stiff materials (including bone) are vulnerable to the accumulation of
units can sometimes be visualized in microradiographs because of dif
microdamage during repeated loading. In metals this can result in crack
ferences in their age and extent of mineralization (Farlay et al 2005).
propagation and ‘fatigue failure’. Bone reduces the risk of such failure
Adult bone shape and mass are partly determined by genetic inherit
by periodically renewing itself, one small region of tissue at a time. This
ance (Sigurdsson et al 2008). However, the pattern and extent of
process is referred to as ‘remodelling’ because the volume and orienta
remodelling are largely dictated by the mechanical loading applied to
tion of newly replaced matrix are not necessarily the same as the old;
the bone. Bone resorption occurs when muscle or gravitational forces
instead, bone takes this opportunity to adapt its mass and architecture
are reduced, as occurs in bed rest, or in zero gravity conditions in space
to prevailing mechanical demands. Remodelling affects the local
(Shackelford et al 2004). Reduced activity in old age is another major
balance between resorption and deposition of bone. Its primary purpose
cause of bone loss. The rate of remodelling decreases with age, which
is to renew bone rather than increase its mass, and the process continues
means that numbers of osteons and osteon fragments can be used to
throughout life, replacing approximately 10% of bone each year in
estimate the age of skeletal material at death. Conversely, increased
adults (Brandi 2009).
sporting or occupational loading of the skeleton can cause bone hyper
Internal remodelling continuously supplies young osteons with
trophy, as exemplified by the 35% increase in cortical thickness in the
labile calcium reserves, and provides a malleable bony architecture that
racket arm of elite tennis players (Jones et al 1977). Bones appear to
is responsive to changing patterns of stress. A boneremodelling unit
respond to the maximum deformation they experience (see Fig. 5.68),
consists of an advancing cutting cone and a closing cone. Activated
rather than to cumulative load. Bone subjected to constant pressure can
osteoclasts form a cutting cone that excavates a cylindrical tunnel of
actually resorb, a response that underpins much orthodontic treatment,
bone (resorption canal) and advances ahead of a central growing blood
because teeth can be made to migrate slowly through alveolar bone by
vessel at a rate of 50 µm/day. A cutting cone is typically 2 mm long and
the application of steady lateral or medial pressure.
takes 1–3 months to form; a similar period is required to create the
new (secondary) osteon by completing the closing cone (Fig. 5.26).
Osteoblasts follow the osteoclasts, filling in the space created with Growth of individual bones
new osteoid, starting at the peripheral surface or walls of the tunnel.
Ossification centres appear over a long period during bone growth:
many in embryonic life, some in prenatal life, and others well into the
postnatal growing period. Ossification centres are initially microscopic
but soon become macroscopic, which means that their growth can then
Developing be followed by radiological and other scanning techniques.
resorption
Some bones, including carpal, tarsal, lacrimal, nasal and zygomatic
canal
Time bones, inferior nasal conchae and auditory ossicles, ossify from a single
Cutting
cone centre, which may appear between the eighth intrauterine week and the
Osteoclast tenth year: a wide interval for studying growth or estimating age. Most
bones ossify from several centres, one of which appears in the centre
of the future bone in late embryonic or early fetal life (seventh week to
Resorption
canal fourth month). Ossification progresses from the centres towards the
Reversal
ends, which are still cartilaginous at birth (Fig. 5.27). These terminal
zone
regions ossify from separate centres, which are sometimes multiple, and
which appear between birth and the late teens; they are therefore sec
Fibroblast
ondary to the earlier primary centre from which much of the bone
ossifies. This is the pattern in long bones, as well as in some shorter
bones such as the metacarpals and metatarsals, and in the ribs and
clavicles.
At birth, a bone such as the tibia is typically ossified throughout its
diaphysis from a primary centre that appears in the seventh intrauterine
week, whereas its cartilaginous epiphyses ossify from secondary centres.
Osteoblast
As the epiphyses enlarge, almost all the cartilage is replaced by bone,
Closing Forming
cone osteon except for a specialized layer of articular (hyaline) cartilage that persists
at the joint surface, and a thicker zone between the diaphysis and epi
physis. Persistence of this epiphysial growth plate, or growth cartilage,
allows increase in bone length until the usual dimensions are reached,
by which time the epiphysial plate has ossified. The bone has then
Quiescent
osteoblast reached maturity. Coalescence of the epiphysis and diaphysis is fusion,
the amalgamation of separate osseous units into one.
Completed Many long bones have epiphyses at both their proximal and their
osteon distal extremities. Metacarpals, metatarsals and phalanges have only
Blood vessel
one epiphysis. Typical ribs have epiphyses for the head and articular
tubercle and one for the nonarticular area. The costal cartilages repre
sent the unossified hyaline cartilage of the developing rib and therefore
Fig. 5.26 Bone remodelling. Longitudinal and cross-sections of a time do not display epiphyses. Epiphysial ossification is sometimes complex,
line illustrating the formation of an osteon. Osteoclasts cut a cylindrical e.g. the proximal end of the humerus is wholly cartilaginous at birth
channel through bone. Osteoblasts follow, laying down bone on the and subsequently develops three centres during childhood, which coa
surface of the channel until matrix surrounds the central blood vessel of lesce into a single mass before they fuse with the diaphysis. Only one
the newly formed osteon (closing cone of a new osteon). of these centres forms an articular surface; the others form the greater | 148 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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junctions, at which bone is bonded to bone through cartilage, through
out the active years of childhood and adolescence.
Forces at growth cartilages are largely compressive but with an
element of shear. Interference with epiphysial growth may occur as a
result of trauma but more frequently follows disease; the resulting
changes in trabecular patterns of bone are visible radiographically as
dense transverse lines of arrested growth (Harris’s growth lines). Several
such lines may appear in the limb bones of children afflicted by suc
A
cessive illnesses.
Variation in skeletal development occurs between individuals, sexes
and possibly also races. The timing rather than the sequence of events
varies, and females antedate males in all groups studied. Differences
that are perhaps insignificant before birth may be as great as 2 years in
adolescence.
JOINTS
B
Joints are the regions of the skeleton where two or more bones meet
Fig. 5.27 A, A radiograph of a neonatal arm. Ossification from primary and articulate. These junctions are supported by a variety of soft tissue
centres is well advanced in all of the limb bones except the carpals, structures, and their prime functions are either to facilitate growth or
which are still wholly cartilaginous. The gaps by which individual elements to allow movement between bones. The simplest classifications of joints
appear to be separated are filled by radiolucent hyaline cartilage, in which relate to either the range of movement possible or the nature of the
epiphysial or carpal ossification will subsequently occur. Note the flaring intervening soft tissues; there is no satisfactory single classification. Free
contours, narrow midshaft and relatively expanded metaphyses of the movement occurs at synovial joints, whereas restricted movement
long bones, and the proportions of the limb segments – in particular, the occurs at synarthroses, which can be subdivided into fibrous and carti
relatively large hand – that are characteristic of this age. B, The bones laginous joints. The general characteristics of each type of joint will be
and cartilages of a neonatal left arm. Compare the radiolucent areas in considered next. Features that are specific to individual joints are dis
the radiograph (A) with the preserved cartilaginous epiphyses and carpal cussed in the relevant topographical chapters.
elements in this specimen. (B, Prepared by Michael C.E. Hutchinson;
photographed by Kevin Fitzpatrick on behalf of GKT School of Medicine,
London.) FIBROUS JOINTS
Bones in fibrous joints are joined by fibrous connective tissue that
allows little movement. Three definable subtypes are sutures, gom
and lesser tubercles, which give muscular attachments. Similar compos phoses and syndesmoses (Fig. 5.28).
ite epiphyses occur at the distal end of the humerus and in the femur,
ribs and vertebrae. Suture
Many cranial bones ossify from multiple centres. The sphenoid,
temporal and occipital bones are almost certainly composites of
Sutures are restricted to the skull (see Ch. 27 for descriptions of indi
multiple elements in their evolutionary history. Some show evidence
vidual sutures). In a suture, the two bones are separated by a layer of
of fusion between membrane and cartilage bones that unite during
membranederived connective tissue. The sutural aspect of each bone
growth.
is covered by a layer of osteogenic cells (cambial layer) overlaid by a
If bone growth rate were uniform, ossification centres would appear
capsular lamella of fibrous tissue that is continuous with the perios
in a strict descending order of bone size. However, disparate rates of
teum on both the endo and ectocranial surfaces. The region between
ossification occur at different sites and do not appear to be related to
the capsular coverings contains loose fibrous connective tissue and
bone size. The appearance of primary centres for bones of such different
decreases with age, so that the osteogenic surfaces become apposed. On
sizes as the phalanges and femora are separated by, at most, a week of
completion of growth, many sutures synostose and are obliterated.
embryonic life. Those for carpal and tarsal bones show some correlation
Synostosis occurs normally as the skull ages; it can begin in the early
between size and order of ossification, from largest (calcaneus in the
twenties and continues into advanced age. A schindylesis is a special
fifth fetal month) to smallest (pisiform in the ninth to twelfth postnatal
ized suture in which a ridged bone fits into a groove on a neighbouring
year). In individual bones, succession of centres is related to the volume
element, e.g. where the cleft between the alae of the vomer receives the
of bone that each centre produces. The largest epiphyses, e.g. the adja
rostrum of the sphenoid (see Fig. 5.28).
cent ends of the femur and tibia, are the earliest to begin to ossify
(immediately before or after birth) and are of forensic interest. At epi Gomphosis
physial plates, the rate of growth is initially equal at both ends of those
bones that possess two epiphyses. However, experimental observations
A gomphosis is a pegandsocket junction between a tooth and its
in other species have revealed that one epiphysis usually grows faster
socket, where the two components are maintained in intimate contact
than the other after birth. Since the fastergrowing end also usually fuses
by the collagen of the periodontium connecting the dental cement to
later with the diaphysis, its contribution to length is greater. Though
the alveolar bone. Strictly speaking, a gomphosis is not an articulation
faster rate has not been measured directly in human bones, later fusion
between two skeletal structures.
has been documented radiologically. The more active end of a long
limb bone is often termed the growing end but this is a misnomer.
Syndesmosis
The rate of increase in stature, which is rapid in infancy and again
at puberty, demonstrates that rates of growth at epiphyses vary. The
spurt at puberty, or slightly before, decreases as epiphyses fuse in post A syndesmosis is a truly fibrous connection between bones. It may be
adolescent years. represented by an interosseous ligament (e.g. the interosseous mem
Growth cartilages do not grow uniformly at all points, which pre brane between the radial and ulnar shafts), a slender fibrous cord, or a
sumably accounts for changes such as the alteration in angle between denser fibrous membrane (e.g. the posterior region of the sacroiliac
the humeral shaft and its neck. The junctions between epiphysis and joint: see Fig. 5.28).
diaphysis at growth plates are not uniformly flat on either surface.
Osseous surfaces usually become reciprocally curved by differential
growth, and the epiphysis forms a shallow cup over the convex end of CARTILAGINOUS JOINTS
the shaft, with cartilage intervening: an arrangement that may resist
shearing forces at this relatively weak region. Reciprocity of bone sur Cartilaginous joints may be classified as primary (synchondrosis) or
faces is augmented by small nodules and ridges, as can be seen when secondary (symphysis), depending on the nature of the intervening
the surfaces are stripped of cartilage. These adaptations emphasize the cartilage. While the distinction between fibrous and cartilaginous
formation of many immature bones from several elements held together joints is usually clear, some degree of admixture can occur in which
by epiphysial cartilages. Most human bones exhibit these complex either a predominantly fibrous articulation contains occasional islands | 149 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Suture Syndesmoses
Uniting layer Dermal bone
Interosseous
ligaments
Cambial Middle Capsular Cambial
Sacrum
Layers of sutural ligament
Synovial joint Syndesmosis
Hip bones
Radius Ulna
Gomphosis Interosseous membrane
(dento-alveolar joint)
Schindylesis
(ridge and groove)
Sphenoidal
rostrum
Vomer
Fig. 5.28 Examples of the principal varieties of fibrous
joints, each shown in section.
of cartilage, or a predominantly cartilaginous articulation contains All symphyses occur in the midline (mandibular, manubriosternal,
aligned dense bundles of collagen. These joints tend to be less rigid pubic and intervertebral) and all except the mandibular symphysis
than the fibrous articulations and some permit restricted movement occur in the postcranial skeleton and resist synostosis. The mandibular
(Figs 5.29–5.30). symphysis (symphysis menti) is histologically different from the other
symphyses; however, the widespread use of this descriptive term ensures
Primary cartilaginous joints that it remains, perhaps inappropriately, within this category.
The concept that synchondroses are temporary and concerned with
growth, whereas symphyses are permanent and concerned with move
Primary cartilaginous joints or synchondroses occur where advancing
ment, is an oversimplification and only partly correct. Both types of
centres of ossification remain separated by an area of hyaline (but non
joint must be strong, both are sites at which growth occurs, and both
articular) cartilage. They are present in all postcranial bones that form
contribute either directly or indirectly to the total movement patterns
from more than one centre of ossification. Since hyaline cartilage
of the parts involved. Movements that occur at a symphysis often
retains the capability to ossify with age, synchondroses tend to synos
depend on more than the mechanical properties of the fibrocartilagi
tose when growth is complete. Primary cartilaginous joints are almost
nous pad or disc, e.g. movements between vertebrae depend not only
exclusively associated with growth plates (see above).
on the deformability of the intervertebral disc but also on the morphol
ogy of the apophysial joints and the properties of associated ligaments
Secondary cartilaginous joints
(Adams et al 2013).
The prominent role of synchondroses in skeletal growth is widely
Secondary cartilaginous joints, or symphyses, are largely defined by the recognized, whereas growth of symphyses has received less attention.
presence of an intervening pad or disc of fibrocartilage interposed Symphysial growth may, for convenience, be considered from two inter
between the articular (hyaline) cartilage that covers the ends of two related aspects: namely, intrinsic growth of the fibrocartilaginous disc,
articulating bones. The pad or disc varies from a few millimetres to over and growth of the hyaline cartilaginous plates into which endochondral
a centimetre in thickness, and the whole region is generally bound by ossification progresses.
strong, tightly adherent, dense connective tissues. Collagenous liga
ments extend from the periostea of the articulating bones across the
symphysis. The ligaments blend with the hyaline and fibrocartilaginous SYNOVIAL JOINTS
perichondria but do not form a complete capsule. They contain plex
uses of afferent nerve terminals, which also penetrate the periphery of These are freely moving joints in which the articulating bony surfaces
the fibrocartilage. The combined strength of the ligaments and fibrocar are covered in smooth (hyaline) articular cartilage and separated by a
tilage can exceed that of the associated bones. A symphysis is designed film of viscous synovial fluid that serves as a lubricant (Fig. 5.31). Joint
to withstand a range of stresses (compression, tension, shear, bending stability is provided by a fibrous capsule (which usually has intrinsic
and torsion) but the range of movement is generally limited, both by ligamentous thickenings), and often by internal or external accessory
the physical nature of the articulation and by adjacent bones. Tears are ligaments. Synovial fluid, which also aids metabolite transport to cells
usually the result of sudden stresses that occur when the body is in an in the articular cartilages, is synthesized by the synovial membrane that
inappropriate posture. lines the joint capsule. | 150 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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A Synchondroses
Epiphysis Primary centre
Endochondral (secondary centre) e.g. basisphenoid
bone Endochondral
ossification
Hyaline Cartilaginous
cartilage growth and
transformation
Endochondral Endochondral
bone ossification
Metaphysis Primary centre Fate of
(primary centre) e.g. basioccipital synchondrosis
Varieties: Asymmetric Symmetric Synostosis
B Symphyses Terminal growth plate Synchondrosis Anular epiphysis Synostosis of
of hyaline cartilage anular epiphysis
Fibrocartilaginous Nucleus
anulus pulposus Fibrocartilage invades nucleus Obliteration of nucleus pulposus
First decade 15–25 years Mature (presacral) symphysis
Fig. 5.29 Examples of varieties of cartilaginous joints (see also Fig. 5.30). A, A sectional view of the principal tissues involved, more detailed architecture
and main growth patterns of symmetrical and asymmetrical synchondroses. Lesser degrees of asymmetry occur in some locations. Synostosis is the
normal fate of almost all synchondroses when endochondral growth has ceased. B, Intervertebral symphyses (presacral), shown in section, displaying
age-related changes. Partial or complete synostosis is the normal fate of sacral and coccygeal symphyses.
Body of sternum Articular surfaces
Sternochondral synovial joints with fibrocartilaginous articular Articular cartilage comprises a specialized type of hyaline cartilage,
surfaces (sometimes synarthroses with fibrocartilage bond)
reflecting its origin as part of the cartilaginous ‘model’ of bone in
embryonic life. Exceptions include the sternoclavicular, acromioclavicu
lar and temporomandibular joints, where articulating surfaces are
Interchondral synovial joints
covered by dense fibrous tissue containing isolated groups of chondro
cytes with little proteoglycan in their surrounding matrix, presumably
reflecting their formation by intramembranous ossification.
The most superficial cartilage, directly adjacent to the synovial fluid,
is an acellular layer approximately 3 µm thick, which contains fine col
lagen fibrils running parallel to the surface. It functions as an elastic
and protective ‘skin’ for the underlying tissue, and can appear to recoil
under tension if the cartilage is damaged. The deformability of articular
cartilage enables opposing cartilage surfaces to flatten slightly at their
area of contact, increasing contact area and decreasing contact stress
(see Fig. 5.57). This loaddistributing property of articular cartilage
Xiphoid process depends on the congruence of opposing joint surfaces (see Fig. 5.61).
Slight undulations in the surface trap synovial fluid so that fluidfilm
lubrication is possible under most circumstances; effectively, the bones
Interchondral ligaments
‘aquaplane’ on each other (Fig. 5.60). This ensures very low friction
(interchondral
and, consequently, low wear of the cartilage.
syndesmoses)
The acellular surface layer is coated with a large glycoprotein,
lubricin, which projects from the surface so that a hydrophobic region
of the molecule lies in the joint space, where it repels its counterpart
on the opposing articular surface. In this way, lubricin acts in the
manner of a lubricant such as grease to reduce friction and wear of the
surface zone. This ‘boundary lubrication’ mechanism becomes impor
tant when the fluid film has been squeezed out, e.g. after sustained
forceful loading of the joint, and loss of lubricin can lead to cartilage
degeneration (Waller et al 2013). Transmission electron microscopy
shows this lubricant layer as an interrupted electrondense surface coat
0.03–0.1 µm thick. Synovial fluid and membranous debris, the product
Costochondral synarthroses with adherent fibrocartilaginous plate; of chondrocytic necrosis, may contribute to this surface coat, which is
periosteum and perichondrium are continuous transient in nature. The ‘lamina splendens’, a structure that appears as
a bright line at the free surface of articular cartilage when oblique sec
Fig. 5.30 Less common interchondral and osseochondral junctions: see
text for other locations. General periosteum and perichondrium omitted. tions are examined by negative phase contrast microscopy, may be a | 151 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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A Simple B Compound C Complex
Synovial membrane
Capsule
Articular cartilage
Articular cartilage Synovial membrane
Synovial cavity
Articular disc
Synovial cavity
Capsule
Fig. 5.31 Synovial joints, some main structural features and one elementary type of classification: A, simple; B, compound; C, complex joints. For
clarity, the articular surfaces are artificially separated. A and C are purely diagrammatic and not related to particular joints. B, however, is a simplified
representation of some features of an elbow joint; the complicated contours due to the olecranon, coronoid and radial fossae, and profiles of articular fat
pads have been omitted for clarity.
microscopical artefact at the border between regions of different refrac
tive index, rather than an anatomically distinct surface layer. Deeper
zones of articular cartilage are described on page 83.
With advancing age, undulations on the articular surfaces deepen
and develop minute, ragged projections, perhaps as a consequence of
wear and tear. These changes are extremely slow in healthy joints, but A
are accelerated in pathologically ‘dry’ joints and where synovial fluid
viscosity is altered. SM
C
Fibrous capsule
S
A fibrous capsule completely encloses each synovial joint except where
it is interrupted by synovial protrusions (see descriptions of individual
joints for details). It is composed of interlacing bundles of parallel fibres A
of collagen type I, and is attached continuously round the ends of the
articulating bones. In small bones this attachment is usually near the
periphery of the articular surfaces, but in long bones it varies consider
ably, and part or all of the attachment may be a significant distance
from the articular surface. The joint capsule is perforated by vessels and Fig. 5.32 A section of a synovial joint and its associated highly vascular
nerves, and may contain apertures through which synovial membrane synovial membrane in a human fetal hand. The two articular cartilage
protrudes as bursae. It is lined by a synovial membrane that also covers surfaces (A, arrows) are separated on the right by a layer of synovial fluid
all nonarticular surfaces (bones, tendons and ligaments) that lie partly (S) secreted by the synovial membrane (SM), which extends a short
or wholly within the fibrous capsule. Where a tendon is attached to distance into the joint space from the capsule (C).
bone inside a synovial joint, an extension of the synovial membrane
usually accompanies it beyond the capsule. Some extracapsular tendons
are separated from the capsule by a synovial bursa continuous with the sufficiently constant to be named, e.g. the alar folds and ligamentum
interior of the joint. These protrusions are potential routes for the mucosum of the knee. Synovial villi are more numerous near articular
spread of infection into joints. margins and on the surfaces of folds and fringes, and become promi
A fibrous capsule usually exhibits local thickenings of parallel nent in some pathological states.
bundles of collagen fibres, called capsular (intrinsic) ligaments, and Accumulations of adipose tissue (articular fat pads) occur within the
named by their attachments. Some capsules are reinforced or replaced synovial membrane in many joints. These pads, and also synovial folds
by tendons of nearby muscles, or expansions from them. Accessory liga and fringes, are deformable cushions that occupy potential spaces and
ments are distinct structures, and may be located inside or outside the irregularities in joints that are not wholly filled by synovial fluid. During
joint capsule. All ligaments, although stiff in tension, are pliant in movement they accommodate to the changing shape and volume of
bending. They can rebound elastically from being stretched by up to the irregularities, a function they share with intraarticular discs and
10–15%, and are protected from injury by reflex contraction of appro menisci. They also increase the area of synovial membrane, and may
priate muscles. They do little to resist normal movements but become help to spread synovial fluid over the articular surfaces.
taut at the end of each normal range of movement. The synovial membrane has two layers: a highly cellular intimal
layer resting on a fibrous and vascular subintimal layer (subsynovial
Synovial membrane
tissue). The subintima is often composed of loose, irregular connective
tissue, but also contains organized collagen and elastin fibres lying
Synovial membrane lines the fibrous joint capsule and exposed osseous parallel to the membrane surface, interspersed with occasional fibro
surfaces, intracapsular ligaments, bursae and tendon sheaths (Fig. blasts, macrophages, mast cells and fat cells. The elastic component
5.32). It does not cover intraarticular discs or menisci, and stops at the may prevent formation of redundant folds during joint movement.
margins of articular cartilages in a transitional zone that occupies the Subintimal adipose cells form compact lobules surrounded by highly
peripheral few millimetres of cartilage. Synovial membrane secretes and vascular fibro elastic interlobular septa that provide firmness and com
absorbs a fluid that lubricates the movement between the articulating pressive turgor.
surfaces. The intimal layer consists of pleomorphic synovial cells embedded
Pink, smooth and shining, the internal synovial surface displays a in a granular, amorphous matrix. In normal human joints, synovial cells
few small synovial villi that increase in size and number with age. Folds form an interlacing, discontinuous layer, 1–3 cells and 20–40 µm thick,
and fringes of membrane may also project into a joint cavity; some are between the subintima and the joint cavity. They are not separated from | 152 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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the subintima by a basal lamina, and are distinguished from subintimal of articular margins; facilitation of rolling movements; and spread of
cells only because they associate to form a superficial layer. In many lubricant. The temporomandibular disc has attracted particular atten
locations, but particularly over loose subintimal tissue, areas are com tion because of its exceptional, perhaps unique, design and biome
monly found that are free from synovial cells. Over fibrous subintimal chanical properties.
tissue the synovial cells may be flattened and closely packed, forming The functions of labra and fat pads, two other quite common types
endotheliumlike sheets. Human synovial cells are generally elliptical, of intraarticular structure, are also uncertain. A labrum is a fibrocarti
with numerous cytoplasmic processes. Neighbouring cells are often laginous anular lip, usually triangular in crosssection, attached to an
separated by gaps, but their processes may interdigitate where they lie articular margin such as the glenoid fossa or acetabulum. It deepens
closer together. There is considerable regional variation in cell morphol the socket and increases the area of contact between articulating sur
ogy and numbers. faces, and may act as a lubricant spreader. Like menisci, labra may
There are at least two morphologically distinct populations of syno reduce the synovial space to capillary dimensions, thus limiting drag.
vial cells or synoviocytes: type A and type B. Type A synoviocytes are Unlike menisci, labra are not compressed between articular surfaces.
macrophagelike cells characterized by surface ruffles or lamellipodia, Small fibrous labra have been described along the ventral or dorsal
plasma membrane invaginations and associated pinocytotic vesicles, a margins of the zygapophysial joints at lumbar levels, as have meniscus
prominent Golgi apparatus but little rough endoplasmic reticulum. shaped fibroadipose meniscoids at the superior or inferior poles of the
They probably synthesize and release lytic enzymes and phagocytose same joints. Fat pads are soft and change shape to fill joint recesses that
joint debris from synovial fluid. Type B synoviocytes, which predomi vary in dimension according to joint position.
nate, resemble fibroblasts and have abundant rough endoplasmic
reticulum but fewer vacuoles and vesicles, and a less ruffled plasma Vascular supply and lymphatic drainage
membrane than type A synoviocytes. They probably synthesize some of
the hyaluronan of synovial fluid, the boundary lubricant lubricin, and
Numerous branches from periarticular arterial plexuses pierce the
inhibitors of the degradative enzymes synthesized by type A cells, limit
fibrous capsules to form subsynovial vascular plexuses. Some synovial
ing their potential to damage joint tissues. Synoviocytes do not divide
vessels end near articular margins in an anastomotic fringe, the circulus
actively in normal synovial membranes, but may do so in response to
articularis vasculosus. A lymphatic plexus in the synovial subintima
trauma and haemarthrosis. Under such conditions, type B synoviocytes
drains along blood vessels to the regional deep lymph nodes.
divide in situ, while type A cells increase by immigration of bone
Articular cartilage, intraarticular menisci and cartilaginous discs are
marrowderived precursors.
all avascular, presumably because high mechanical pressures in these
deformable tissues would collapse any blood vessels inside them. Labo
Synovial fluid
ratory experiments show that proteoglycans inhibit vascular growth, so
the high concentration of proteoglycans in the cartilaginous tissues of
Synovial fluid occupies synovial joints, bursae and tendon sheaths. In joints may help to exclude blood vessels. However, injury and disease
synovial joints it is clear or pale yellow, viscous and slightly alkaline at can alter both the mechanical and chemical environment within carti
rest (the pH lowers during activity), and contains a small mixed popula lage (Adams 2013), allowing revascularization in peripheral and dis
tion of cells and metachromatic amorphous particles. Fluid volume is rupted regions. The blood supply to subchondral bone is described on
low: usually less than 0.5 ml can be aspirated from a large joint such page 89.
as the knee.
The composition of synovial fluid is consistent with it being mainly
Innervation
a transudate of blood plasma: it contains protein (approximately
0.9 mg/100 ml) derived from the blood. It also contains hyaluronan,
which is thought to be a significant determinant of the viscoelastic and A movable joint is innervated by articular branches of the nerves that
thixotropic (flow ratedependent) properties of synovial fluid. A small supply the muscles acting on the joint and that also supply the skin
proportion (approximately 2%) of synovial fluid protein differs from covering the joint (Hilton’s law). Although there is overlap between the
plasma protein and is probably produced by type B synoviocytes. An territories of different nerves, each nerve innervates a specific part of the
even smaller proportion (approximately 0.5%) of synovial fluid protein capsule. The region made taut by muscular contraction is usually inner
appears to be a specialized lubricating glycoprotein, lubricin. Synovial vated by nerves that supply the antagonists. For example, during abduc
fluid contains a few cells (approximately 60 per ml in resting human tion, stretching the portion of the capsule of the hip joint supplied by
joints), including monocytes, lymphocytes, macrophages, synovial the obturator nerve elicits reflex contraction of the adductors that is
intimal cells and polymorphonuclear leukocytes; higher counts are usually sufficient to prevent damage.
found in young individuals. The amorphous metachromatic particles Myelinated axons in articular nerves innervate Ruffini endings,
and fragments of cells and fibrous tissue found in synovial fluid are lamellated articular corpuscles, and structures resembling Golgi tendon
presumed to be the byproducts of wear and tear. organs. Ruffini endings respond to stretch and adapt slowly, whereas
lamellated corpuscles respond to rapid movement and vibration, and
adapt rapidly; both types of receptor register the speed and direction of
Intra-articular menisci, discs and fat pads
movement. Golgi tendon organs, innervated by the largest myelinated
axons (10–15 µm diameter), are slow to adapt; they mediate position
An articular disc or meniscus can occur between articular surfaces where sense and also are concerned in stereognosis, i.e. recognition of shape
congruity (conformity of opposing articular surfaces) is low. The term of held objects. Simple endings are numerous at the attachments of
meniscus should be reserved for incomplete discs, like those in the knee capsules and ligaments, and are thought to be the terminals of unmy
joint and, occasionally, in the acromioclavicular joint. Complete discs, elinated and thinly myelinated nociceptive axons (see p. 59 for an
such as those in the sternoclavicular and inferior radioulnar joints, account of sensory receptors).
extend across a synovial joint, thereby dividing it structurally into two Many unmyelinated postganglionic sympathetic axons terminate
synovial cavities; they often have small perforations. The disc in the near vascular smooth muscle, and are presumably either vasomotor or
temporomandibular joint may be complete or incomplete. vasosensory. The nerve endings in synovial membrane are believed to
The main part of a disc is relatively acellular, but the surface may be supply blood vessels exclusively, from which it is assumed that synovial
covered by an incomplete stratum of flat cells, continuous at the periph membrane is normally relatively insensitive to pain.
ery with adjacent synovial membrane. Discs are usually connected to Cartilaginous structures within joints normally have no nerve supply,
their fibrous capsule by vascularized connective tissue, so that they partly because they are avascular and partly because axonal growth is
become invaded by blood vessels and afferent and vasomotor post inhibited by a high concentration of proteoglycans. However, when
ganglionic sympathetic nerves. The union between disc and capsule fibrocartilage is injured or diseased, nerves may accompany the conse
may be closer and stronger, as occurs in the knee and temporoman quent ingrowth of blood vessels and give rise to pain (Freemont et al
dibular joints. Discs and menisci are composed of fibrocartilage con 1997). Subchondral bone is normally innervated and is a likely source
taining crimped type I collagen fibres, and are not covered by synovial of pain in the spine (Peng et al 2009).
membrane.
The functions of intraarticular fibrocartilages are uncertain. Evi
Classification
dence from structural or phylogenetic data, aided by mechanical analo
gies, suggests that functions include: improvement of fit between
articulating surfaces; deployment of weight over larger surface areas; Synovial joints can be classified according to their shape (Fig. 5.33).
shock absorption; facilitation of combined movements; limitation of While this has some practical value, it should be remembered that they
translational (gliding) movements at joints such as the knee; protection are merely variations, sometimes extreme, of basic forms. Articular | 153 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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1 Plane joint 4 Ellipsoid joint
2 Hinge joint 5 Saddle joint
3 Pivot joint 6 Ball-and-socket joint
Fig. 5.33 Types of synovial joint, with selected examples.
surfaces are never truly flat, or complete spheres, cylinders, cones or metacarpophalangeal joints. Primary movements occur around two
ellipsoids. orthogonal axes, such as flexion–extension and abduction–adduction,
and may be combined as circumduction. Rotation around the third axis
Plane joints
is largely prevented by general articular shape.
Plane joints, such as intermetatarsal and some intercarpal joints, have
Saddle joints
almost flat surfaces. Slight curvature is often disregarded, although it is
usual, and movements are considered to be pure translations or sliding Saddle joints are biaxial joints in which the articular surfaces have both
between bones. concave and convex regions. Each surface is maximally convex in one
direction and maximally concave in another, at right angles to the first.
Hinge joints The convexity of the larger surface is apposed to the concavity of the
These resemble hinges because movement takes place about a single smaller surface and vice versa. Primary movements occur in two ortho
stationary axis, and so is largely restricted to one plane. Examples are gonal planes but articular shape also causes axial rotation of the moving
interphalangeal and humeroulnar joints. However, the surfaces of bone. Such ‘coupled’ rotation is never independent, and can be func
biological hinges are not truly cylindrical, and actual motion can tionally significant in habitual positioning and limitation of move
occur in more than one plane. Hinge joints possess strong collateral ment. The most familiar saddle joint is the carpometacarpal joint of the
ligaments. thumb; other examples include the ankle and calcaneocuboid joints.
Bicondylar joints are predominantly uniaxial hinge joints, but the
Ball-and-socket joints
presence of two condyles side by side allows limited rotation about a
second axis orthogonal to the first. These joints are formed from two These multiaxial joints are formed by a globoid ‘head’ articulating with
convex condyles that articulate with concave or flat surfaces. The con an opposing cup. Prime examples are the hip and shoulder joints.
dyles may lie within a common fibrous capsule (as in the knee), or in Although their surfaces resemble parts of spheres, they are not strictly
separate capsules that necessarily cooperate in all movements as a con spherical but slightly ovoid, and consequently congruence is not perfect
dylar pair (as in the temporomandibular joints). in most positions. Indeed, it occurs in only one position, at the end of
the most common movement.
Pivot joints
These are uniaxial joints in which an osseous pivot inside an osteoliga Factors influencing movement
mentous ring allows rotation only around the axis of the pivot. Pivots
may rotate in rings (e.g. the head of the radius rotates within the anular Movements at synovial joints depend on a number of factors, including
ligament and ulnar radial notch), or rings may rotate around pivots the complexity and number of articulating surfaces, and the number
(e.g. the atlas rotates around the dens of the axis). and position of the principal axes of movement.
Ellipsoid joints Complexity of form
Ellipsoid joints are biaxial, and consist of an oval, convex surface Most synovial joints are simple articulations between two articular
apposed to an elliptical concavity. Examples are the radiocarpal and surfaces. A joint with more than two articular surfaces is called a | 154 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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A B C Fig. 5.34 The shoulder joint is multiaxial and
possesses three degrees of freedom. The three
mutually perpendicular axes are shown, around which
the principal movements of flexion–extension (A),
abduction–adduction (B) and medial and lateral
rotation (C) occur. Note that these axes are referred to
the plane of the scapula and not to the coronal and
sagittal planes of the erect body. Although an infinite
variety of additional movements may occur at such a
joint, e.g. movements involving intermediate planes or
combinations, they can always be resolved
mathematically into components related to the three
axes illustrated.
Where movement is slight, the reciprocal surfaces are of similar size;
where it is wide, the habitually more mobile bone has the larger articu
lar surface.
r4
r3 Translation
Translation is the simplest motion and involves gliding or sliding
without appreciable angulation. Although frequently combined with
other movements, it is often considered the only motion permitted in
r2 some carpal and tarsal articulations. However, cineradiography reveals
that considerable angulation occurs during movements of the small
carpal and tarsal bones.
r1 Flexion
Flexion is an example of angulation, where there is a change in angle
Fig. 5.35 A profile of a section through an ovoid surface showing that it between the topographical axes of the articulating bones. Although a
may be considered as a series of segments of circles of changing radius. widely used term, flexion is difficult to define. It often means approxi
The radius of curvature of joint surfaces often changes from one location mation of two ventral surfaces around a transverse axis. However, the
to another. thumb is almost at right angles to the fingers: its ‘dorsal’ surface faces
laterally so that flexion and extension at its joints occur around antero
compound joint, e.g. the knee and the elbow (see Fig. 5.31). In all
posterior axes. At the shoulder, flexion is referred to an oblique axis
compound joints, articulating territories remain distinct. A synovial
through the centre of the humeral head in the plane of the scapular
joint that contains an intraarticular disc or meniscus is called a complex
body, the arm moving anteromedially forwards and hence nearer to the
joint, e.g. the tibiofemoral joint of the knee, and the temporomandibu
ventral aspect of the trunk. At the hip, which has a transverse axis,
lar joints.
flexion brings the morphologically dorsal (but topographically ventral)
Degrees of freedom surface of the thigh to the ventral aspect of the trunk. Description of
flexion at the ankle joint is complicated by the fact that the foot is set
Joint motion can be described by rotation and translation about three
at a right angle to the leg. Elevation of the foot diminishes this angle
orthogonal axes. There are three possible rotations (axial, abduction–
and is usually termed flexion; however, it involves the approximation
adduction, flexion–extension) and three possible translations (proxi
of two dorsal surfaces so might equally be called extension. Flexion has
modistal, mediolateral, anteroposterior). Each is a degree of freedom.
also been defined as the fetal posture, implying that elevation of the
For most joints, translations are small and can be neglected (Fig. 5.34).
foot is flexion, a view supported by withdrawal reflexes in which eleva
A few joints have minor but pure translatory movements, but most joint
tion is always associated with flexion at the knee and hip. Definitions
motion is by rotation.
based on morphological and physiological considerations are thus con
When movement is practically limited to rotation about one axis
tradictory; to avoid confusion, dorsiflexion and plantar flexion are used
(e.g. the elbow), a joint is termed uniaxial and has one degree of
to describe ankle movements.
freedom. If independent movements can occur around two axes (e.g.
flexion–extension and axial rotation in the knee), the joint is biaxial Abduction and adduction
and has two degrees of freedom. Since there are three axes for independ
Abduction and adduction occur around anteroposterior axes except at
ent rotation, joints may have up to three degrees of freedom. This
the first carpometacarpal and shoulder joints. The terms generally imply
apparently simple classification is complicated by the complexity of
lateral or medial angulation, except in digits, where arbitrary planes are
joint structure and has consequent effects on motion. Even though a
chosen (midlines of the middle digit of the hand and second digit of
true ‘ballandsocket’ joint is multiaxial and can rotate about many
the foot), because these are least mobile in this respect. Abduction of
chosen axes, for each position there is a maximum of three orthogonal
the thumb occurs around a transverse axis and away from the palm.
planes, which means that it can have, as a maximum, three degrees of
Similarly, abduction of the humerus on the scapula occurs in the scapu
freedom.
lar plane around an oblique axis at right angles to it.
For a uniaxial hinge joint with a single degree of freedom, a single
unchanging axis of rotation would be predicted. However, because the Axial rotation
shapes of joint surfaces are complex, there is a variable radius of curva
Axial rotation is a widely, but often imprecisely, used term. Its restricted
ture (Fig. 5.35) and consequently the axis of rotation will vary as joint
sense denotes movement around some notional ‘longitudinal’ axis,
movement progresses. When the variation is minor, e.g. in the elbow,
which may even be in a separate bone, e.g. the dens of the second cervi
it is often appropriate to describe a mean position for the axis, whereas
cal vertebra, on which the atlas rotates. An axis may approximate to the
in other joints, e.g. the knee, the situation is more complex.
centre of the shaft of a long bone, as in medial and lateral humeral
Motion in one direction is often linked to motion in another.
rotation (see Fig. 5.34). Alternatively, the axis may be at an angle to the
Coupled (or conjunct) movements occur as an integral and inevitable
topographical axis of a bone, as in movement of the radius on the ulna
accompaniment of the main movement. Adjunct movements can
in pronation and supination, where the axis joins the centre of the
occur independently and may or may not accompany the principal
radial head to the base of the ulnar styloid process. In these examples,
movement.
rotations can be independent adjunct motions, constituting a degree of
freedom, or obligatory (coupled) rotations, which always accompany
Types of joint movement
some other main movement as a consequence of articular geometry.
Obligatory coupled motion is frequently combined with a degree of
Joint surfaces move by translation (gliding) and angulation (rotation), voluntary adjunct motion, the latter dictating what proportion of the
usually in combination, to produce gross movements at the joint. motion occurs above the minimum obligatory component. | 155 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Circumduction
Circumduction combines successive flexion, abduction, extension and
adduction, and occurs when the distal end of a long bone circumscribes
the base of a cone that has its apex at the joint in question. Examples
are circular movements of the hand and foot about the shoulder and
hip joints, respectively.
DEVELOPMENT OF JOINTS
The development of joints is described in the context of limb develop NN
ment on page 222.
MUSCLE
CC
Most cells possess cytoskeletal elements that are capable of lengthen
ing or shortening and so enable the cell to change its shape. This
capacity is important in a variety of cellular functions, including loco
motion, phagocytosis and mitosis. Slow movements can be effected by Fig. 5.36 Skeletal muscle fibres from human lateral rectus in longitudinal
polymerization–depolymerization mechanisms involving actin and section, showing transverse striations representing the sarcomeric
tubulin, but much faster and more forceful movements can be created organization of actin and myosin filaments. The variation in fibre diameter
by the socalled ‘motor proteins’, which use energy from the hydrolysis is typical of extraocular muscles. Capillaries (C) and nerves (N) lie
of adenosine 5′triphosphate (ATP). Of these ATPdependent systems, between the fibres, orientated mainly in parallel and so are also sectioned
longitudinally. Toluidine blue stained resin section. (Provided by courtesy
one of the most widespread is based on the interaction of the motor
of the Department of Optometry and Visual Science, City University,
protein myosin with actin.
London.)
In muscle cells the filaments of actin, myosin and other associated
proteins are so abundant that they almost fill the interior of the cell.
Moreover, they align predominantly in one direction, so that interac
tions at the molecular level are translated into linear contraction of the Individual fibres are long, cylindrical structures that tend to be consist
whole cell. The ability of these specialized cells to change shape has ent in size within a given muscle, but in different muscles may range
thus become their most important property. Assemblies of contractile from 10 to 100 µm in diameter, and from a few millimetres to many
muscle cells, the muscles, are machines for converting chemical energy centimetres in length. The cytoplasm of each fibre, the sarcoplasm, is
into mechanical work. Muscle forces move limbs and drive many of the surrounded by a plasma membrane often called the sarcolemma. The
functions of the human body, and muscle tissue constitutes 40–50% of bulk of the sarcoplasm comprises the contractile machinery, organized
body mass. into myofibrils (see Fig. 5.37) 1–2 µm in diameter, which extend the
length of the fibre. Numerous moderately euchromatic, oval nuclei
usually occupy a thin transparent rim of sarcoplasm between the myofi
CLASSIFICATION OF MUSCLE
brils and the sarcolemma, and are especially numerous in the region of
the neuromuscular junction (see Fig. 3.34). In transverse section, a
Muscle cells (fibres) are also known as myocytes (the prefixes myo and muscle fibre may reveal only one or two nuclei, but it may contain
sarco are frequently used in naming structures associated with muscle). several hundred along its entire length. Myogenic satellite cells lie
They differentiate along one of three main pathways to form skeletal, between the sarcolemma and the surrounding basal lamina (see below).
cardiac or smooth muscle. Both skeletal and cardiac muscle (Ch. 6) may
be called striated muscle, because their myosin and actin filaments are Sarcomeres
organized into regular, repeating structures (sarcomeres), which give the
cells a finely crossstriated appearance when viewed microscopically.
Although myofibrils are too tightly packed to be visible by routine light
Cardiac muscle fibres are relatively short, with branched ends, and are
microscopy, their presence can be inferred from transverse striations
joined to adjacent fibres at intercellular junctional complexes called
across the tissue. Crossstriations may be demonstrated more effectively
intercalated discs, which skeletal muscle lacks. Smooth muscle cells
using special stains (see Fig. 5.36) or under polarized light, which can
lack striations because their actin and myosin are not organized into
differentiate dark, anisotropic Abands (which are birefringent and
sarcomeres.
rotate the plane of polarized light strongly) from lighter, isotropic
Other contractile cells, including myofibroblasts and myoepithelial
Ibands (rotate the plane of polarized light to a negligible degree). In
cells, are different in character and developmental origin. They contain
transverse section, skeletal muscle fibres are usually polygonal (Fig.
smooth musclelike contractile proteins and are found singly or in
5.38) and their sarcoplasm often has a stippled appearance, because
small groups.
transversely sectioned myofibrils are resolved as dots. The packing
density of muscle fibres varies, from low (in the extrinsic muscles of the
SKELETAL MUSCLE larynx) to high (in the group of muscles that elevate the mandible).
Most detail is revealed by transmission electron microscopy (Fig.
5.39). Myofibrils, approximately 1 µm in diameter, are the dominant
Skeletal muscle (striated, voluntary) is the most common muscle tissue.
ultrastructural feature. In longitudinal sections they appear as ribbons
It consists of long, parallel multinucleate cells bundled together by col
that are interrupted at regular intervals by thin dark transverse lines,
lagenous sheaths. Its regular organization enables skeletal muscle to
which correspond to discs in the parent cylindrical structure. These are
generate powerful contractions, with a power output of approximately
the Zlines or, more properly, Zdiscs (Zwischenscheiben = interval
100 watts per kilogram of tissue. However, the price paid for this organi
discs) that divide each myofibril into a linear series of repeating con
zation is a limited contractile range: skeletal muscle can shorten by only
tractile units, the sarcomeres. A sarcomere is typically 2.2 µm long in
30%. If a larger range of movement is required, it must be achieved
resting muscle. At higher power, it can be seen to consist of two types
through the amplification provided by lever systems, as described in
of filament, thick and thin, organized into regular arrays (see Figs 5.37
Figure 5.63. Skeletal muscle is innervated by somatic motor nerves and
and 5.39). Thick filaments, which are approximately 15 nm in diame
is sometimes referred to as voluntary muscle, because its contractions
ter, are composed mainly of myosin. Thin filaments, which are 8 nm
are often initiated under conscious control. However, this is a mislead
in diameter, are composed mainly of actin. The arrays of thick and thin
ing term because skeletal muscle is involved in many movements, such
filaments form a partially overlapping structure in which electron
as breathing, blinking and swallowing, which are often initiated at an
density (as seen in the electron microscope) varies according to the
unconscious level.
amount of protein present. The Aband consists of the thick filaments,
together with lengths of thin filaments that interdigitate with, and thus
MICROSTRUCTURE OF SKELETAL MUSCLE overlap, the thick filaments at either end (see Fig. 5.39; Fig. 5.40). The
central, paler region of the Aband, which is not penetrated by the thin
Skeletal muscle fibres are enormous multinucleate cells (Figs 5.36– filaments, is called the Hzone (Helle = light). At their centres, the thick
5.37), which develop by fusion of individual myoblasts (see below). filaments are linked together transversely by material that constitutes | 156 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
Functional anatomy of the musculoskeletal system
103.e1
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Titin Nebulin Myosin Actin
B Z M Z
Fig. 5.40 B, The arrangement of titin and nebulin in a skeletal muscle sarcomere. A single titin molecule spans from the Z-disc to the M-band and
contains a spring-like ‘elastic’ region that develops force when the sarcomere is stretched. Nebulin extends from the Z disc for the full length of each
actin filament. (From Prado LG et al. Isoform Diversity of Giant Proteins in Relation to Passive and Active Contractile Properties of Rabbit Skeletal
Muscles. J Gen Physiol 2005;126:461–480.) | 157 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Thin filaments
Thick filaments
Myofilaments
Fig. 5.38 A transverse cryostat section of adult human skeletal muscle.
Note the tight packing of the fibres and the peripheral location of the
dark-stained nuclei. (Photograph by Professor Stanley Salmons, from a
specimen provided by courtesy of Tim Helliwell, Department of Pathology,
University of Liverpool.)
Sarcomere The high degree of organization of thick and thin filaments is equally
evident in transverse sections (see Fig. 5.40; Fig. 5.41). The thick myosin
Myofibril filaments form a hexagonal lattice. In the regions where they overlap
the thin filaments, each myosin filament is surrounded by six actin fila
Fibres Nerve
ments at the trigonal points of the lattice. In the Iband, the thin fila
ment pattern changes from hexagonal to square as the filaments
approach the Zdisc, where they are incorporated into a square lattice
structure.
The banded appearance of individual myofibrils is a function of the
regular alternation of the thick and thin filament arrays. The size of
Mitochondrion
myofibrils places them at the limit of resolution of light microscopy;
crossstriations are only visible at that level because of the alignment
in register of the A and Ibands in adjacent myofibrils across the width
of the whole muscle fibre. In suitably stained relaxed material, the A,
I and Hbands are quite distinct, whereas the Zdiscs, which are such
a prominent feature of electron micrographs, are thin and much less
conspicuous in the light microscope, and Mlines cannot be resolved.
Muscle proteins
Myosin, the protein of the thick filament, constitutes 60% of the total
myofibrillar protein and is the most abundant contractile protein. The
thick filaments of skeletal and cardiac muscle are 1.5 µm long. Their
composition from myosin heavy and light chain assemblies is de
scribed on page 12. The other components of myosin, the regulatory
proteins tropomyosin and troponin, play a major part in the control of
contraction.
Actin is the next most abundant contractile protein and constitutes
20% of the total myofibrillar protein. In its filamentous form, Factin,
Fasciculi
it is the principal protein of the thin filaments. A number of congenital
myopathies result from gene mutations in components of the thin fila
ment assembly (Clarkson et al 2004).
A third type of long sarcomeric filament (not shown in Fig. 5.40)
connects the thick filaments to the Zdisc, and is formed by the giant
protein, titin, which has a molecular mass in the millions (Gregorio
et al 1999). Single titin molecules span the halfsarcomere between the
Mlines and the Zdiscs, into which they are inserted. They have a teth
ered portion in the Aband, where they are attached to thick filaments
as far as the Mline, and an elastic portion in the Iband. The elastic
properties of titin endow the relaxed muscle fibre with passive resist
ance to stretching, and with elastic recoil.
A number of proteins that are neither contractile nor regulatory are
responsible for the structural integrity of the myofibrils, particularly
their regular internal arrangement. A component of the Zdisc, αactinin,
is a rodshaped molecule that anchors the plusends of actin filaments
Fig. 5.37 Levels of organization within a skeletal muscle, from whole from adjacent sarcomeres to the Zdisc. Nebulin inserts into the Zdisc,
muscle to fasciculi, single fibres, myofibrils and myofilaments. associated with the thin filaments, and regulates the lengths of actin
filaments. Desmin, an intermediate filament protein characteristic of
muscle, encircles the myofibrils at the Zdisc and, with the linking
the Mline (Mittelscheibe = middle [of] disc), which is visible in most molecule plectrin, forms a meshwork that connects myofibrils together
muscles. The Iband consists of the adjacent portions of two neighbour within the muscle fibre and to the sarcolemma. Myomesin holds
ing sarcomeres in which the thin filaments are not overlapped by thick myosin filaments in their regular lattice arrangement in the region of
filaments. The thin filaments of adjacent sarcomeres are anchored in the Mline. Dystrophin is confined to the periphery of the muscle fibre,
the Zdisc, which bisects the Iband. close to the cytoplasmic face of the sarcolemma. It binds to actin | 158 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
skeletal muscle
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Fig. 5.39 The electron microscopic appearance
M
of skeletal muscle in longitudinal section. A, A
low-power view of parts of two adjacent muscle
M
fibres, separated by endomysium (E) containing
capillaries (C) and a peripherally placed nucleus
(N) in the fibre. Mitochondria (arrows) are situated
peripherally and between myofibrils (M). Myofibrils
pack the cytoplasm, with their sarcomeres
(contractile units) in register, as seen by the
C alignment of Z-discs (dark transverse lines) across
each muscle fibre. B, A sarcomere within a
myofibril, and parts of two others. (A sarcomere is
the distance between adjacent Z-discs.) Also seen
E are the A-band, bisected by the M-line, and
I-band, which here is almost obliterated in the
contracted state (see Fig. 5.40). A triad is visible
between myofibrils, comprised of a T-tubule (long
arrow) and two terminal cisternae of sarcoplasmic
reticulum (short arrows). (A, Provided courtesy of
Professor Hans Hoppeler, Institute of Anatomy,
NN University of Bern, Switzerland.)
M
Z
A
I
One
sarcomere
A B
Pseudo
H zone
Z M I
H
A
Relaxed
1 µm Sarcomere Contracted
A
Fig. 5.40 A, Sarcomeric structures. The drawings below the electron micrograph (of two myofibrils sectioned longitudinally and with their long axes
orientated transversely) indicate the corresponding arrangements of thick and thin filaments. Relaxed and contracted states are shown to illustrate the
changes that occur during shortening. Insets at the top depict the electron micrographic appearance of transverse sections through the myofibril at the
levels shown. Note that the packing geometry of the thin filaments changes from a square array at the Z-disc to a hexagonal array where they
interdigitate with thick filaments in the A-band. (Photographs by Professor Brenda Russell, Department of Physiology and Biophysics, University of Illinois
at Chicago.) (B, continued online)
intracellularly and is also associated with a large oligomeric complex with a reduced size and/or abundance of dystrophin. Female carriers
of glycoproteins, the dystroglycan/sarcoglycan complex that spans the (heterozygous for the mutant gene) of Duchenne muscular dystrophy
membrane and links specifically with merosin, the αlaminin isoform may also have mild symptoms of muscle weakness. At about 2500 kb,
2
of the muscle basal lamina. This stabilizes the muscle fibre and trans the gene is one of the largest yet discovered, which may account for the
mits forces generated internally on contraction to the extracellular high mutation rate of Duchenne muscular dystrophy (approximately
matrix. 35% of cases are new mutations). Other muscular dystrophies may
Dystrophin is the product of the gene affected in Duchenne muscu involve deficiencies in proteins functionally associated with dystrophin,
lar dystrophy, a fatal disorder that develops when mutation of the gene such as the dystroglycan/sarcoglycan complex or αlaminin; they may
2
leads to the absence of the protein (Batchelor and Winder 2006). A also be the result of mutations in proteins of the inner nuclear mem
milder form of the disease, Becker muscular dystrophy, is associated brane (Azibani et al 2014; Koch and Holaska 2014). | 159 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Fig. 5.41 An electron micrograph of skeletal
muscle in transverse section, showing parts of two
muscle fibres. Part of a capillary (C) is seen in
transverse section in the endomysial space. The
variation in the appearance of myofibrils in
cross-section is explained in Figure 5.40.
(Photograph by Professor Brenda Russell,
Department of Physiology and Biophysics,
University of Illinois at Chicago.)
C
Other sarcoplasmic structures Mitochondria
Myofibrils
Although myofibrils are the dominant ultrastructural feature, skeletal
muscle fibres contain other organelles essential for cellular function.
Ribosomes, Golgi apparatus and mitochondria are located around the
nuclei, between myofibrils and the sarcolemma, and, to a lesser extent,
between the myofibrils. Mitochondria, lipid droplets and glycogen
provide the metabolic support needed by active muscle. The mitochon
dria are elongated and their cristae are closely packed. The number of Triad
mitochondria in an adult muscle fibre is not fixed, but can increase or
decrease quite readily in response to sustained changes in activity.
Spherical lipid droplets, approximately 0.25 µm in diameter, are dis I-band Actin
tributed uniformly throughout the sarcoplasm between myofibrils. T-tubule
They represent a rich source of energy that can be tapped only by oxida
tive metabolic pathways; they are therefore more common in fibres that
have a high mitochondrial content and good capillary blood supply. Myosin
Small clusters of glycogen granules are dispersed between myofibrils A-band Sarcoplasmic
and among the thin filaments. During brief bursts of activity, they reticulum
provide an important source of anaerobic energy that is not dependent
on blood flow to the muscle fibre.
Tubular invaginations of the sarcolemma penetrate between the Z-disc
myofibrils in a transverse plane at the limit of each Aband (see Fig. T-tubule
5.39; Fig. 5.42). The lumina of these transverse (T)tubules are thus
in continuity with the extracellular space. At the ends of the muscle
fibre, where force is transmitted to adjacent connective tissue struc
tures, the sarcolemma is folded into numerous fingerlike projec
tions that strengthen the junctional region by increasing the area of
Basal lamina
attachment.
The sarcoplasmic reticulum (SR) is a specialized form of smooth
endoplasmic reticulum and forms a plexus of anastomosing membrane
T-tubules
cisternae that fills much of the space between myofibrils (see Fig. 5.42).
The cisternae expand into larger sacs, junctional sarcoplasmic reticulum
Sarcolemma
or terminal cisternae, where they come into close contact with Ttubules,
forming structures called triads (see Figs 5.39 and 5.42). The mem
branes of the SR contain calcium–ATPase pumps that transport calcium
ions into the terminal cisternae, where the ions are bound to calseques
trin, a protein with a high affinity for calcium, in dense storage granules.
In this way, calcium can be accumulated and retained in the terminal
cisternae at a much higher concentration than elsewhere in the sarco Fig. 5.42 A three-dimensional reconstruction of a mammalian skeletal
plasm. Ca2+release channels (ryanodine receptors) are concentrated muscle fibre, showing in particular the organization of the transverse (T)
mainly in the terminal cisternae and form one half of the junctional tubules and sarcoplasmic reticulum. Mitochondria lie between the
‘feet’ or ‘pillars’ that bridge the SR and Ttubules at the triads. The other myofibrils. Note that transverse tubules are found at the level of the A/I
half of the junctional feet is the Ttubule receptor that constitutes the junctions, where they form triads with the terminal cisternae of the
voltage sensor. sarcoplasmic reticulum. | 160 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Connective tissues of muscle muscles possess a single vascular pedicle supplying the muscle belly,
e.g. tensor fasciae latae (supplied by the ascending branch of the lateral
circumflex femoral artery) and gastrocnemius (supplied by the sural
The endomysium is a delicate network of connective tissue that sur
artery). Type II muscles are served by a single dominant vascular pedicle
rounds muscle fibres and forms their immediate external environment.
and several minor pedicles, and can be supported on a minor pedicle
It is the site of metabolic exchange between muscle and blood, and
as well as the dominant pedicle, e.g. gracilis (supplied by the medial
contains capillaries and bundles of small nerve fibres. Ion fluxes associ
circumflex femoral artery in the dominant pedicle). Type III muscles are
ated with the electrical excitation of muscle fibres take place through
supplied by two separate dominant pedicles, each from different source
its proteoglycan matrix. The perimysium is a more substantial connec
arteries, e.g. rectus abdominis (supplied by the superior and inferior
tive tissue structure that is continuous with the endomysium, and
epigastric arteries) and gluteus maximus (supplied by the superior and
ensheathes groups of muscle fibres to form parallel bundles, or fas
inferior gluteal arteries). Type IV muscles have multiple small pedicles
ciculi. It carries larger blood vessels and nerves, and accommodates
that, in isolation, are not capable of supporting the whole muscle, e.g.
neuromuscular spindles. Perimysial septa are themselves the inward
sartorius and tibialis anterior; about 30% survive reduction on to a
extensions of a collagenous sheath, the epimysium, which forms part
single vascular pedicle. Type V muscles have one dominant vascular
of the fascia that invests whole muscle groups.
pedicle and multiple secondary segmental pedicles, e.g. latissimus dorsi
Epimysium consists mainly of type I collagen; perimysium contains
(supplied by the thoracodorsal artery as the primary pedicle, thoraco
type I and type III collagen; endomysium contains collagen types III
lumbar perforators from the lower six intercostal arteries and the
and IV. Collagen IV is associated particularly with the basal lamina that
lumbar arteries as the segmental supply) and pectoralis major (supplied
invests each muscle fibre. The epimysial, perimysial and endomysial
by the pectoral branch of the thoracoacromial axis as the dominant
sheaths coalesce where the muscles connect to adjacent structures at
pedicle, and anterior perforators from the internal thoracic vessels as
tendons, aponeuroses and fasciae (see below).
the segmental supply).
In crosssections of muscle, the number of capillary profiles found
NEUROVASCULAR SUPPLY OF MUSCLE adjacent to fibres usually varies from 0 to 3. Muscle fibres involved in
sustained activities, such as posture, are served by a denser capillary
Vascular supply and lymphatic drainage network than fibres that are recruited only infrequently. It is common
for muscles to receive their arterial supply via more than one route. The
accessory arteries penetrate the muscle at places other than the hilum,
In most muscles, the major source artery enters on the deep surface,
and ramify in the same way as the principal artery, forming vascular
frequently in close association with the principal vein and nerve,
territories. The boundaries of adjacent territories are spanned by anas
forming a neurovascular hilum. The vessels subsequently course and
tomotic vessels, sometimes at constant calibre, but more commonly
branch within the connective tissue framework of the muscle. Smaller
through reducedcalibre arteries or arterioles that are referred to as
arteries and arterioles ramify in the perimysial septa and give off capil
‘choke vessels’. These arterial arcades link the territories into a continu
laries that run in the endomysium. The smaller vessels lie mainly paral
ous network.
lel to the muscle fibres, but also branch and anastomose around the
Veins branch in a similar way, forming venous territories that cor
fibres, forming an elongated mesh.
respond closely to the arterial territories. In the zones where the arterial
The gross vascular anatomy of muscles has been classified into five
territories are linked by choke vessels, the venous territories are linked
types according to the number and relative dominance of vascular
by anastomosing veins: in this case, without change of calibre. On either
pedicles that enter the muscle (Mathes and Nahai 1981) (Fig. 5.43).
side of these venous bridges, the valves in the adjacent territories direct
This classification has important surgical relevance in determining
flow in opposite directions towards their respective pedicles, but the
which muscles will survive, and therefore be useful for pedicled or free
connecting veins themselves lack valves and therefore permit flow in
tissue transfer procedures in plastic and reconstructive surgery. Type I
either direction.
Because of the potential for relative movement within muscle
groups, vessels tend not to cross between muscles, but radiate to them
Type I Type II Type III Type IV
from more stable sites or cross at points of fusion. Where a muscle
underlies the skin, blood vessels bridge between the two. These may be
primarily cutaneous vessels, which supply the skin directly but contrib
ute small branches to the muscle as they pass through it, or they may
be the terminal branches of intramuscular vessels, which leave the
muscle to supplement the cutaneous blood supply. The latter are less
frequent where the muscle is mobile under the deep fascia. Correspond
ence between the vascular territories in the skin and underlying tissues
gave rise to the concept of angiosomes, which are composite blocks of
tissue supplied by named distributing arteries and drained by their
Gluteus maximus companion veins (see Taylor and Pan (1998) for further analyses of
muscle angiosomes).
Pressure exerted on valved intramuscular veins during muscle con
traction functions as a ‘muscle pump’ that promotes venous return to
the heart. In some cases this role appears to be amplified by veins that
pass through the muscle after originating elsewhere in superficial or
Sartorius deep tissues. The extent to which the muscle capillary bed is perfused
can be varied in accordance with functional demand. Arteriovenous
anastomoses, through which blood can be returned directly to the
Type V
venous system without traversing the capillaries, provide an alternative,
Tensor Gracilis
fasciae latae regulated pathway.
The lymphatic drainage of muscles begins as lymphatic capillaries
in epimysial and perimysial, but not endomysial, sheaths. These con
verge to form larger lymphatic vessels that accompany the veins and
drain to the regional lymph nodes.
Innervation
Every skeletal muscle is supplied by one or more nerves. Muscles in the
limbs, face and neck are usually innervated by a single nerve, even
though the axons it contains may be derived from neurones located in
Latissimus dorsi several spinal cord segments and their associated ganglia. Muscles such
Fig. 5.43 Classification of muscles according to their blood supply. (With as those of the abdominal wall, which originate from several embryonic
permission from Cormack GC, Lamberty BGH 1994 The Arterial Anatomy segments, are supplied by more than one nerve. In most cases, the nerve
of Skin Flaps, 2nd edn. Edinburgh: Churchill Livingstone.) travels with the principal blood vessels within a neurovascular bundle | 161 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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(see Fig. 2.9), approaches the muscle near to its least mobile attach all parts of the muscle fibre are activated rapidly and almost synchro
ment, and enters the deep surface at a position that is more or less nously. Excitation–contraction coupling is the process whereby an
constant for each muscle. action potential triggers the release of calcium from the terminal cister
Nerves supplying muscle are frequently referred to as ‘motor nerves’ nae of the sarcoplasmic reticulum into the cytosol. This activates a
but they contain both motor and sensory components. The motor calciumsensitive switch in the thin filaments and so initiates contrac
component is mainly composed of large, myelinated αefferent axons, tion. At the end of excitation, the Ttubular membrane repolarizes,
which supply the muscle fibres, supplemented by small, thinly myeli calcium release ceases, calcium ions are actively transported back to the
nated γefferents, or fusimotor fibres, which innervate the intrafusal calsequestrin stores in the sarcoplasmic reticulum by the calcium–
muscle fibres of neuromuscular spindles (see p. 60), and fine, unmyeli ATPase pumps, and the muscle relaxes.
nated autonomic efferents, which innervate vascular smooth muscle. The lengths of the thick and thin filaments do not change during
The sensory component consists of large, myelinated IA and smaller muscle contraction. The sarcomere shortens by the sliding of thick and
group II afferents from the neuromuscular spindles, large myelinated thin filaments past one another, which draws the Zdiscs towards the
IB afferents from the Golgi tendon organs (see p. 59), and fine myeli middle of each sarcomere (see Fig. 5.40). As the overlap increases,
nated and unmyelinated axons that convey pain and other sensations the I and Hbands narrow to nearextinction, while the width of the
from free terminals in the connective tissue sheaths of the muscle. Abands remains constant. Filament sliding depends on the making and
Within muscles, nerves travel through the epimysial and perimysial breaking of bonds (crossbridge cycling) between myosin head regions
septa before entering the fine endomysial tissue around muscle fibres. and actin filaments. Myosin heads ‘walk’ or ‘row’ along actin filaments
Alphamotor axons branch repeatedly before they lose their myelinated using a series of short power strokes, each resulting in a relative move
sheaths to terminate in a narrow zone towards the centre of the muscle ment of 5–10 nm. Actin filament binding sites for myosin are revealed
belly, known as the motor point. Clinically, this is the place on a muscle only by the presence of calcium, which is released into the sarcoplasm
from which it is easiest to elicit a contraction with stimulating elec from the sarcoplasmic reticulum, causing a repositioning of the
trodes. Long muscles generally have two or more terminal (endplate) troponin–tropomyosin complex on actin: this is the calciumsensitive
bands because many muscle fibres do not run the full length of an switch. Myosin head binding and release are both energydependent
anatomical muscle. The terminal branch of an αmotor axon contacts and require ATP. In the absence of ATP (as occurs post mortem) the
a muscle fibre at a specialized synapse, the neuromuscular junction (see bound state is maintained, and is responsible for the muscle stiffness
Fig. 3.34). It gives off several short, tortuous branches, each ending in known as rigor mortis.
an elliptical area, the motor endplate. The underlying discoidal patch The summation of myosin power strokes leads to an average sarco
of sarcolemma, the sole plate or subneural apparatus, is thrown into mere shortening of up to 1 µm; an anatomical muscle shortens by a
deep synaptic folds. This discrete type of neuromuscular junction (en centimetre or more, depending on the muscle, because each muscle has
plaque ending) is found on muscle fibres that are capable of propagating thousands of sarcomeres in series along its length.
action potentials. A different type of ending is found on slow tonic
muscle fibres that do not have this capability, e.g. in the extrinsic ocular
Slow-twitch versus fast-twitch fibres
muscles, where slow tonic fibres form a minor component of the ana
tomical muscle. In this case the propagation of excitation is taken over
by the nerve terminals, which branch over an extended distance to form The passage of a single action potential through a motor unit elicits a
a number of small neuromuscular junctions (en grappe endings). Some twitch contraction where peak force is reached within 25–100 ms,
muscle fibres of this type receive the terminal branches of more than depending on the motor unit type involved. However, the motor
one motor neurone. The terminals of the γefferents that innervate the neurone can deliver a second nervous impulse in less time than it takes
intrafusal muscle fibres of the neuromuscular spindle also take a variety for the muscle fibres to relax. When this happens, the muscle fibres
of different forms. contract again, building the tension to a higher level. Because of this
The terminal branches of αmotor axons are normally in a ‘oneto mechanical summation, a sequence of impulses can evoke a larger force
one’ relationship with their muscle fibres: a muscle fibre receives only than a single impulse and, within certain limits, the higher the impulse
one branch, and any one branch innervates only one muscle fibre. frequency, the more force is produced (‘rate recruitment’). An alterna
When a motor neurone is excited, an action potential is propagated tive strategy is to recruit more motor units. In practice, the two mecha
along the axon and all of its branches to all of the muscle fibres that it nisms appear to operate in parallel, but their relative importance may
supplies. The motor neurone and the muscle fibres that it innervates depend on the size and/or function of the muscle; in large muscles with
can therefore be regarded as a functional unit: the ‘motor unit’. This many motor units, motor unit recruitment is probably the more impor
arrangement accounts for the more or less simultaneous contraction of tant mechanism.
a number of fibres within the muscle. The size of a motor unit varies With the exception of rare tonic fibres, skeletal muscles are com
considerably. In muscles used for precision tasks, such as the extraocular posed entirely of fibres of the twitch type. These fibres can all conduct
and intrinsic laryngeal muscles, each motor neurone innervates perhaps action potentials but they differ in other respects. Some fibres obtain
ten muscle fibres. In a large limb muscle, a motor neurone may inner their energy very efficiently by aerobic oxidation of substrates, particu
vate several hundred muscle fibres. Within a muscle, fibres belonging larly of fats and fatty acids. They have large numbers of mitochondria;
to one motor unit are distributed over a wide territory, without regard contain myoglobin, an oxygentransport pigment related to haemo
to fascicular boundaries, and they intermingle with the fibres of other globin; and are supported by a welldeveloped network of capillaries
motor units. Motor units become larger in cases of nerve damage that maintains a steady nutrient supply of oxygen and substrates. Such
because denervation induces collateral or terminal sprouting of the fibres are well suited to functions such as postural maintenance, in
remaining axons. Each new branch can reinnervate a fibre, thus increas which moderate forces need to be sustained for prolonged periods. At
ing the territory of its parent motor neurone. the other end of the spectrum, some fibres have few mitochondria, little
myoglobin and a sparse capillary network, and store energy as cytoplas
mic glycogen granules. Their immediate energy requirements are met
MUSCLE CONTRACTION largely through anaerobic glycolysis, a route that provides prompt
access to energy but that is less sustainable than oxidative metabolism.
The arrival of an action potential at the motor endplate of a neuromus They are capable of brief bursts of intense activity that must be sepa
cular junction causes acetylcholine (ACh) to be released from storage rated by extended quiescent periods during which intracellular pH and
vesicles into the highly infolded 30–50 nm synaptic cleft that separates phosphate concentrations are restored to normal values, and glycogen
the nerve ending from the sarcolemma (see Fig. 3.34). ACh is rapidly and other reserves are replenished.
bound by receptor molecules located in the junctional folds, triggering In some animals, different types of muscle fibre tend to be segregated
an almost instantaneous increase in the permeability, and hence con into different muscles. This causes some muscles to have a conspicu
ductance, of the postsynaptic membrane. This generates a local depo ously red appearance, reflecting their rich blood supply and high
larization (the endplate potential), which initiates an action potential myoglobin content associated with a predominantly aerobic metabo
in the surrounding sarcolemma. The activity of the neurotransmitter is lism, whereas other muscles have a much paler appearance, reflecting
rapidly terminated by the enzyme acetylcholinesterase (AChE), which a more anaerobic character. These variations in colour led to the early
is bound to the basal lamina in the sarcolemmal junctional folds. The classification of muscle into red and white types. This classification has
sarcolemma is an excitable membrane, and action potentials generated now been largely superseded by myosinbased typing and the presence
at the neuromuscular junction propagate rapidly over the entire surface of specific diseaserelated enzymes.
of the muscle fibre. In humans, all muscles are mixed, with fibres specialized for aerobic
Action potentials are conducted radially into the interior of the fibre working conditions intermingling with fibres of a more anaerobic or
via the Ttubules, which are extensions of the sarcolemma, ensuring that intermediate metabolic character. Different types of fibre are not readily | 162 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Table 5.1 Physiological, structural and biochemical characteristics of the major The initial phase of slowing can be explained by less rapid cycling
histochemical fibre types of calcium, resulting from reduced sarcoplasmic reticulum and changes
in the amount and molecular type of proteins involved in calcium
Characteristic Fibre types
transport and binding. Chronic stimulation also triggers the synthesis
TYPE I TYPE IIA TYPE IIX of myosin heavy and light chain isoforms of the slow muscle type; the
Physiological associated changes in crossbridge kinetics result in a lower intrinsic
speed of shortening. The muscle becomes more resistant to fatigue
Function Sustained forces, Powerful, fast movements
as in posture through changes in the metabolic pathways responsible for the genera
Motor neurone firing threshold Low Intermediate High tion of ATP and a reduced dependence on anaerobic glycolysis. There
is a switch to oxidative pathways, particularly those involved in the
Motor unit size Small Large Large
breakdown of fat and fatty acids, and an associated increase in capillary
Firing pattern Tonic, Phasic, high-frequency
low-frequency density and in the fraction of the intracellular volume occupied by
mitochondria. If stimulation is discontinued, the sequence of events is
Maximum shortening velocity Slow Fast Fast
reversed and the muscle regains, over a period of weeks, all of its origi
Rate of relaxation Slow Fast Fast
nal characteristics. The reversibility of transformation is one of several
Resistance to fatigue Fatigue-resistant Fatigue-resistant Fatigue-susceptible
lines of evidence that the changes take place within existing fibres, and
Power output Low Intermediate High
not by a process of degeneration and regeneration.
Structural Many of the changes in the protein profile of a muscle that are
Capillary density High Low induced by stimulation are now known to be the result of transcrip
Mitochondrial volume High Intermediate Low tional regulation. For example, analysis of the messenger RNA species
Z-disc Broad Narrow Narrow encoding myosin heavy chain isoforms shows that expression of the
fast myosin heavy chain mRNA is downregulated within a few days of
T-tubule and sarcoplasmic Sparse Extensive
reticulum systems the onset of chronic stimulation, while the slow myosin heavy chain
mRNA is upregulated. Although myosin isoform expression is respon
Biochemical
sive to the increase in use induced by chronic stimulation, it tends to
Myosin ATPase activity Low High
be stable under physiological conditions unless these involve a sus
Oxidative metabolism High Intermediate Low
tained departure from normal postural or locomotor behaviour.
Anaerobic glycolysis Low Intermediate High
Calcium transport ATPase Low High
DEVELOPMENT AND GROWTH
OF SKELETAL MUSCLE
distinguished in routine histological preparations but are clear when Most information about the early development of the skeletal muscu
specialized enzyme histochemical techniques are used. On the basis of lature in humans has been derived from other vertebrate species.
metabolic differences, individual fibres can be classified as oxidative However, where direct comparisons with the developing human embryo
slowtwitch (red) fibres or glycolytic fasttwitch (white) fibres. Muscles have been made, the patterns and mechanisms of muscle formation
composed mainly of oxidative slowtwitch fibres correspond to the red have been found to be the same.
muscles of classical descriptions. Muscles that are predominantly oxida The majority of the skeletal muscle in the body develops from parax
tive in their metabolism contract and relax more slowly than muscles ial mesenchyme and its segmental derivatives, the somites. A small
relying on glycolytic metabolism. This difference in contractile speed is portion forming the extraocular muscles is derived from prechordal
due in part to the activation mechanism (volume density of the sarco mesenchyme, which joins with the most rostral paraxial mesenchyme
tubular system and proteins of the calcium ‘switch’ mechanism), and and which has been demonstrated to have a myogenic fate. Skeletal
in part to molecular differences between the myosin heavy chains of muscle precursor myoblasts are derived from dermomyotomes, the
these types of muscle. These differences affect the ATPase activity of the lateral portion of the somites (see Fig. 44.3).
myosin head, which in turn alters the kinetics of its interaction with
actin, and hence the rate of crossbridge cycling. Differences between
Myogenic determination factors
myosin isoforms can be detected histochemically, and ATPase histo
chemistry continues to play a significant role in diagnostic typing (Table
5.1). Two main categories have been described: type I fibres, which are Myogenic determination factors, which can be detected in somites prior
slowcontracting, and type II, which are fastcontracting. Molecular to morphogenetic changes, are a family of nuclear phosphoproteins
analyses have revealed that type II fibres can be further subdivided that includes Myf5, myogenin, MyoD and Myf6 (herculin). They have
according to their content of myosin heavychain isoforms into types in common a 70aminoacid, basic helixloophelix (bHLH) domain
IIA and IIX. Muscle fibres may contain only one (i.e. a pure fibre) or a that is essential for protein–protein interactions and DNA binding.
combination (i.e. a hybrid fibre) of these isoforms; the five most preva Outside the bHLH domain there are sequence differences between the
lent muscle fibre types in humans are I, I/IIA, IIA, IIA/IIX, IIX. (For factors that probably confer some functional specificity. The myogenic
further reading, see Galpin et al (2012), Holland and Ohlendieck bHLH factors play a crucial role in myogenesis. Forced expression of
(2013).) There is a correlation between categories and fatigue resistance, any of them diverts nonmuscle cells to the myogenic lineage. They
such that type I fibres are generally oxidative (slow oxidative) and resist activate transcription of a wide variety of musclespecific genes by
ant to fatigue; type IIA are moderately oxidative, glycolytic (fast oxida binding directly to conserved DNA sequence motifs (–CANNTG–
tive glycolytic) and fatigueresistant; and type IIX largely rely on known as Eboxes) that occur in the regulatory regions (promoters and
glycolytic metabolism (fast glycolytic) and so are easily fatigued. enhancers) of these genes. Their effect may be achieved cooperatively
and can be repressed, e.g. by some protooncogene products. Some of
Fibre type transformation the bHLH proteins can activate their own expression. Accessory regula
Fibre type proportions in a named muscle may vary between individu tory factors, whose expression is induced by the bHLH factors, provide
als of different age or athletic ability. Fibre type grouping, where fibres an additional tier of control.
with similar metabolic and contractile properties aggregate, increases Myogenic factors do not all appear at the same stage of myogenesis
after nerve damage and with age. Grouping occurs as a result of rein (Buckingham et al 2003). In the somites, Myf-5 is expressed early,
nervation episodes, where denervated fibres are ‘taken over’ by a sprout before myotome formation, and is followed by expression of myogenin.
ing motor neurone and adopt its type properties. If the nerves to fast MyoD is expressed relatively late, together with the contractile protein
white and slow red muscles are cut and crossanastomosed in experi genes. Myf-6 is expressed transiently in the myotome and becomes the
mental animals, so that each muscle is reinnervated by the other’s nerve, major transcript postnatally. Whether this specific timing is important
the fast muscle becomes slowercontracting, and the slow muscle faster for muscle development is not yet clear. The creation of mutant (‘knock
contracting. There is evidence that such fibre type transformation may out’) mice deficient in the bHLH proteins has shown that myogenin
be a response to the patterns of impulse traffic in the nerves innervating is crucial for the development of functional skeletal muscle, and
the muscles (Minetto et al 2013). If fast muscles are stimulated continu that while neither Myf-5 nor MyoD is essential to myogenic differen
ously for several weeks at 10 Hz, a pattern similar to that normally tiation on its own, lack of both results in a failure to form skeletal
experienced by slow muscles, they develop slow contractile characteris muscle. In the limb bud the pattern of expression of the bHLH genes
tics and acquire a red appearance and a resistance to fatigue even greater is generally later than in the somite: Myf-5 is expressed first but tran
than that of slow muscles. siently, followed by myogenin and MyoD, and eventually Myf-6. These | 163 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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differences provide evidence at the molecular level for the existence of The initiation of fusion does not depend on the presence of nerve fibres,
distinct muscle cell populations in the limb and somites. It may be that since these do not penetrate muscle primordia until after the formation
the myogenic cells that migrate to the limb buds differ at the outset of primary myotubes.
from those that form the myotome, or their properties may diverge Although synthesis of the contractile machinery is not dependent on
subsequently under the influence of local epigenetic factors. fusion of myoblasts, it proceeds much more rapidly after fusion. Sar
comere formation begins at the Zdisc, which binds actin filaments
Formation of muscle fibres constituting the Iband to form I–Z–I complexes. The myosin filaments
assemble on the I–Z–I complexes to form Abands. Nebulin and titin
are among the first myofibrillar proteins to be incorporated into the
In both myotomes and limb buds, myogenesis proceeds in the follow
sarcomere, and may well determine the length and position of
ing way. Myoblasts become spindleshaped and begin to express
the contractile filaments. Desmin intermediate filaments connect the
musclespecific proteins. The mononucleate myoblasts aggregate and
Zdiscs to the sarcolemma at an early stage, and these connections are
fuse to form multinucleate cylindrical syncytia, or myotubes, in which
retained.
the nuclei are aligned in a central chain (Fig. 5.44). These primary
Myogenic cells continue to migrate and to divide, and during weeks
myotubes attach at each end to the tendons and developing skeleton.
7–9 there is extensive de novo myotube formation. Myoblasts aggregate
near the midpoint of the primary myotubes and fuse with each other
to form secondary myotubes, a process that may be related to early
Immigration neural contact. Several of these smallerdiameter myotubes may be
of myoblasts aligned in parallel with each of the primary myotubes. Each develops
a separate basal lamina and makes independent contact with the
tendon. Initially, the primary myotube provides a scaffold for the lon
gitudinal growth of the secondary myotubes but eventually they sepa
rate. At the time of their formation, the secondary myotubes express an
Proliferation ‘embryonic’ isoform of the myosin heavy chains, whereas the primary
of myoblasts myotubes express a ‘slow’ muscle isoform apparently identical to that
found in adult slow muscle fibres. In both primary and secondary
myotubes, sarcomere assembly begins at the periphery of the myotube
and progresses inwards towards its centre. Myofibrils are added con
Fusion of
stantly and lengthen by adding sarcomeres to their ends. Ttubules are
myoblasts
formed and grow initially in a longitudinal direction; since they contain
specific proteins not found in plasma membranes, they are probably
assembled via a different pathway from that which supports the growth
of the sarcolemma. The sarcoplasmic reticulum wraps around the
Primary myotube formation myofibrils at the level of the Ibands.
By 9 weeks, the primordia of most muscle groups are well defined,
contractile proteins have been synthesized and the primitive beginnings
of neuromuscular junctions can be observed, confined initially to the
primary myotubes. Although some secondary fibre formation can take
place in the absence of a nerve, most is initiated at sites of innervation
of the primary myotubes. The pioneering axons branch and establish
contact with the secondary myotubes. By 10 weeks these nerve–muscle
Secondary myotube formation contacts have become functional neuromuscular junctions and the
Secondary muscle fibres contract in response to impulse activity in the motor
myoblasts nerves. Under this new influence, the secondary fibres express fetal
(sometimes referred to as neonatal) isoforms of the myosin heavy
chains. At this stage, several crucial events take place, which may be
Primary dependent on, or facilitated by, contractile activity. As the myofibrils
muscle encroach on the centre of the myotube, the nuclei move to the periphery
fibre and the characteristic morphology of the adult skeletal muscle myofibre
is established. The myofibrils become aligned laterally, and A and
Ibands in register across the myotube produce crossstriations that are
Secondary visible at the light microscopic level. Ttubules change from a longitu
tubules dinal to a transverse orientation and adopt their adult positions; they
may be guided in this process by the sarcoplasmic reticulum, which is
Axon more strongly bound to the myofibrils.
Neuromuscular The myotubes and myofibres are grouped into fascicles by growing
junction connective tissue sheaths, and fascicles are assembled to build up entire
muscles. As development proceeds, the increase in intramuscular
volume is accommodated by remodelling of the connective tissue
matrix.
Maturing
muscle At 14–15 weeks, primary myotubes are still in the majority, but by
fibre 20 weeks the secondary myotubes predominate. During weeks 16–17,
tertiary myotubes appear; they are small and adhere to the secondary
myotubes, with which they share a basal lamina. They become inde
pendent by 18–23 weeks, their central nuclei move to the periphery,
Satellite cell
and they contribute a further generation of myofibres. The secondary
Fig. 5.44 Stages in formation of skeletal muscle. Mononucleate and tertiary myofibres are always smaller and more numerous than the
myoblasts fuse to form multinucleate primary myotubes, characterized
primary myofibres. In some large muscles, higherorder generations of
initially by central nuclei. Subsequently, other myoblasts align along the
myotubes may be formed.
primary myotubes and begin to fuse with one another, forming secondary
Late in fetal life, a final population of myoblasts appears, which will
myotubes. In large animals, such as humans, further generations of new
become the satellite cells of adult muscle. These normally quiescent
muscle fibres are similarly formed. As the contractile apparatus is
cells lie outside the sarcolemma beneath the basal lamina (see Fig. 5.44;
assembled, the nuclei move to the periphery, cross-striations become
Fig. 5.45). Mcadherin, a cell adhesion protein of possible regulatory
visible and primitive features of the neuromuscular junction emerge. Later,
small adult-type myoblasts – satellite cells – can be seen lying between significance, occurs at the site of contact between a satellite cell and its
the basal lamina and the sarcolemma of the mature muscle fibre. These muscle fibre. In a young individual, there is one satellite cell for every
too appear to be derived from cells that originated in the somites during 5–10 muscle fibre nuclei. The latter are incapable of DNA synthesis and
early development. (Redrawn from a figure provided by Terry Partridge, mitosis, and satellite cells are therefore important as the sole source of
Department of Genetic Medicine, Children’s National Medical Center, additional muscle fibre nuclei during postnatal growth of muscle (to
Washington DC.) maintain the ratio of cytoplasmic volume per nucleus as fibres increase | 164 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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in mass). After satellite cells divide, one of the daughter cells fuses with In humans, unlike many smaller mammals, muscles are histologi
the growing fibre, the other remaining as a satellite cell capable of cally mature at birth, but fibre type differentiation is far from complete.
further rounds of division. In adult skeletal muscle, satellite cells In postural muscles, the expression of type I (‘slow’) myosin increases
provide a reservoir of cells that enable exerciseinduced hypertrophy, significantly over the first few years of life. During this same period, the
and regeneration of muscle after damage (see below). proportions of fibre types in other muscles become more divergent. The
presence in adult muscles of a small proportion of fibres with an appar
Development of fibre types
ently transitional combination of protein isoforms reinforces the view
Developing myotubes express an embryonic isoform of myosin that is that changes in fibre type continue to some extent in all muscles and
subsequently replaced by fetal and adult myosin isoforms. The major throughout adult life. Fibre type transitions also occur in relation to
isoform of sarcomeric actin in fetal skeletal muscle is cardiac αactin; damage or neuromuscular disease; under these conditions, the devel
only later is this replaced by skeletal αactin. The significance of these opmental sequence of myosins may be recapitulated in regenerating
developmental sequences is not known. fibres.
The pattern of expression is fibrespecific and changes over time. In
Growth and regulation of fibre length
primary myotubes, embryonic myosin is replaced by adult slow myosin
from about 9 weeks onwards. In secondary and higherorder myotubes, Muscle fibres grow in length by addition of sarcomeres to the ends of
the embryonic myosin isoform is superseded first by fetal and then by myofibrils. In order for the mean sarcomere length, and hence filament
adult fast myosin, and a proportion go on to express adult slow myosin. overlap, to be optimized for maximum force, the number of sarcomeres
Other fibrespecific, tissuespecific and speciesspecific patterns of must be regulated throughout life. This is achieved by the addition or
myosin expression have been described in mammalian limb muscles removal of sarcomeres in response to any prolonged change of length.
and jaw muscles. For example, if a limb is immobilized in a plaster cast, the fibres of
The origin of this diversity in the temporal patterns of expression of muscles that have been fixed in a shortened position lose sarcomeres,
different fibres, even within the same muscle, is far from clear. It has while those that have been fixed in a lengthened position add sarcom
been suggested that intrinsically different lineages of myoblast emerge eres; the reverse process occurs after the cast has been removed.
at different stages of myogenesis or in response to different extracellular
cues. If this is the case, their internal programmes may be retained or Satellite cells and muscle repair
overridden when they fuse with other myoblasts or with fibres that have
already formed. The fibres that emerge from this process go on to
Until the mid20th century, the mechanisms responsible for mainte
acquire a phenotype that will depend on the further influence of hor
nance and repair of skeletal muscle were unclear. These issues were
mones and neural activity.
largely resolved by the discoveries that multinucleated muscle fibres
were formed by the fusion of mononucleated precursors, myoblasts,
and that a population of satellite cells, so called because of their posi
tion on the edge of the fibre, exist between the basal lamina of the
mature muscle fibre and its sarcolemma, where they constitute 2–5%
of the nuclei enclosed by the basal lamina.
Studies in mouse models, where genetic analysis is possible, have
shown that the functional properties of postnatal satellite cells depend
on the expression of the Pax7 gene, whereas the prenatal development
of muscle is not similarly dependent. This implies that satellite cells are
not simply the relics of prenatal myogenic cells, even though they
appear to be derived from the same embryonic source in the somites.
Moreover, satellite cells are not a homogeneous population: no two
differentiation markers concur completely. This is also the situation
in human tissue (Fig. 5.46). It has yet to be determined whether this
variation reflects a difference in position in the lineage, functional status
or adjacent environment.
The satellite cell has been established rigorously in mice as being
both necessary and sufficient for effective regeneration of damaged
skeletal muscle (Relaix and Zammit 2012). These cells proliferate to
replace their resident region of muscle in 3–4 days and to replenish the
quiescent satellite cell population. In humans, there is histological
Fig. 5.45 An electron micrograph of a satellite cell. Note the two plasma
evidence of the rapid accumulation of myoblasts, presumably derived
membranes that separate the cytoplasm of the satellite cell from that of
the muscle fibre, and the basal lamina (arrows) of the transversely from local satellite cells, at sites of muscle damage. The presumed
sectioned muscle fibre, which continues over the satellite cell (see also central role of satellite cells in muscle growth and adaptation has,
Fig. 5.39a). Compare this appearance with the normal muscle nucleus, however, been questioned by some recent research. Satellite cells are
which is seen in the adjacent fibre at the top of the micrograph. undoubtedly important during early postnatal development and
(Photograph by Dr Michael Cullen, School of Neurosciences, University of growth, and in muscle regeneration following acute injury or eccentric
Newcastle upon Tyne.) damage. In other situations, however, regulation of protein synthesis
Fig. 5.46 Two adjacent sections, fluorescence-
immunolabelled, of a regenerating muscle fibre in
a power lifter’s trapezius. A, Anti-laminin antibody
(red) shows basal lamina. Anti-CD56 (green) is a
marker of myogenic cells and of newly formed
myotubes. B, Basal lamina (red) and myogenin-
positive nuclei (green). Basal laminae outline
transversely sectioned muscle fibres, including the
original outline of the regenerating fibre (centre
field). Numerous small blood vessels, also outlined
by basal laminae, are present and probably reflect
local inflammation. Within the CD56-positive zone,
several nuclei (one arrowed) are positive for
myogenin, indicating their terminally differentiated
status. Numerous other nuclei (Hoechst dye, blue)
within the basal lamina surrounding the area of
regeneration probably include proliferating
myogenic cells and inflammatory cells. (Courtesy
of Ms Mona Lindström and Professor Lars-Eric
A B Thornell, Department of Anatomy, Umeå
University, Sweden.) | 165 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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and degradation may be more important determinants of muscle mass fied, and terms denoting action may emphasize only one of a number
(Schiaffino et al 2013). of usual actions. A given muscle may play different roles in different
A detail of wide pathological interest is the demonstration that the movements and these roles may change if the movements are assisted
failing regenerative potency of satellite cells in ageing muscle seems in or opposed by gravity.
large part to be attributable to agerelated changes in the systemic envi
ronment rather than a decline in the intrinsic capabilities of the satellite Fibre architecture
cells themselves (Conboy et al 2005).
Muscles can be classified according to their general shape and the pre
Regulation of muscle mass
dominant orientation of their fibres relative to the direction of pull (Fig.
5.47). Muscles with fibres (cells) that are largely parallel to the line of
Muscles respond to resistance exercise in training, or rehabilitation fol pull vary in form from flat, short and quadrilateral (e.g. thyrohyoid)
lowing illness or injury, by increasing in mass. This process is termed to long and straplike (e.g. sternohyoid, sartorius). In such muscles,
hypertrophy, particularly when applied to the increased muscle bulk individual fibres may run for the entire length of the muscle, or over
that occurs in response to intense physical activity. Individual muscle
fibres increase in size by the synthesis of new myofibril proteins,
increased protein turnover rates and the recruitment of satellite cells to Table 5.2 Terms used in naming muscles
provide new nuclei for existing fibres or to form new myotubes. In
inactivity, as seen in those confined to bed or wheelchair, in immobi Shape Depth Position
lized limbs, and in patients with disorders of voluntary movement, Deltoid (triangular) Superficialis (superficial) Anterior, posterior, medial,
muscles decrease in mass. This is termed atrophy, or disuse atrophy, in Quadratus (square) Profundus (deep) lateral, superior, inferior,
Rhomboid Externus/externi (external) supra-, infra-
contrast to the pathological wasting of skeletal muscle associated with
(diamond-shaped) Internus/interni (internal) Interosseus (between
some disease states, including cancer cachexia, heart failure, diabetes Teres (round) bones)
and obesity. It is also recognized that loss of skeletal muscle mass and Gracilis (slender) Attachment Dorsi (of the back)
function may be a consequence of normal healthy ageing, when it is Rectus (straight) Sternocleidomastoid (from Abdominis (of the abdomen)
Lumbrical (worm-like) sternum and clavicle to Pectoralis (of the chest)
termed sarcopenia. There is experimental evidence that this process may
mastoid process) Brachii (of the arm)
be associated with apoptosis of satellite cells and capillary endothelial Size Coracobrachialis (from the Femoris (of the thigh)
cells (Wang et al 2014). Major, minor, longus (long) coracoid process to the Oris (of the mouth)
Brevis (short) arm) Oculi (of the eye)
Latissimus (broadest)
FORM AND FUNCTION OF SKELETAL MUSCLE Longissimus (longest) Action
Extensor, flexor
Number of heads or Abductor, adductor
The names given to individual muscles are usually descriptive and are bellies Levator, depressor
based on their shape, size, number of heads or bellies, position, depth, Biceps (two heads) Supinator, pronator
attachments or actions. The meanings of some of the terms used are Triceps (three heads) Constrictor, dilator
Quadriceps (four heads)
summarized in Table 5.2. The functional roles implied by the names
Digastric (two bellies)
should be interpreted with caution because they are often oversimpli
Strap with tendinous
Quadrilateral Strap intersections Fusiform Digastric Tricipital Triangular Cruciate
Unipennate Bipennate Radial Multipennate Spiral
B
M
B— Bone
M— Muscle
T
T— Tendon
Fig. 5.47 Morphological ‘types’ of muscle based on their general form and fascicular architecture. | 166 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Fig. 5.48 The ‘detorsion’ or Vector along tendon Fig. 5.49 Force vectors in
untwisting that results from the an idealized pennate
contraction of a spirally muscle. The increase in
arranged muscle. effective cross-sectional
area made possible by
Force of muscle this architecture outweighs
contraction
the small reduction in the
component of force acting
in the direction of the
tendon.
Vector at 90° to
line of tendon
Relaxed
Contracted
shorter segments when there are transverse, tendinous intersections at If these principles are applied to a long, straplike muscle in which
intervals (e.g. rectus abdominis). In a fusiform muscle, the fibres may the fibres are predominantly parallel to the line of pull (see Fig. 5.47),
be close to parallel in the ‘belly’, but converge to a tendon at one or it will be evident that the whole muscle will be able to contract by 30%
both ends. Where fibres are oblique to the line of pull, muscles may be of its length (the same as each muscle fibre). However, such a straplike
triangular (e.g. temporalis, adductor longus) or pennate (featherlike) muscle contains relatively few muscle fibres, so the maximum tension
in construction. The latter vary in complexity from unipennate (e.g. it can develop will not be great. Compare this to the bipennate muscle
flexor pollicis longus) and bipennate (e.g. rectus femoris, dorsal interos in Figure 5.49, which contains perhaps three times as many muscle
sei) to multipennate (e.g. deltoid). Fibres may pass obliquely between fibres, all set at an angle (typically 30°) to the axis of the tendon. Each
deep and superficial aponeuroses, in a type of ‘unipennate’ form (e.g. short fibre will not be able to contract very far, and the contraction of
soleus), or they may start from the walls of osteofascial compartments the tendon will be even less, because the muscle fibres are pulling on
and converge obliquely on a central tendon in circumpennate fashion it obliquely. So, the bipennate muscle has a poor contraction distance.
(e.g. tibialis anterior). Muscles may exhibit a spiral or twisted arrange However, the total force its fibres can generate will be approximately
ment (e.g. sternocostal fibres of pectoralis major or latissimus dorsi, three times as great as the tension in the straplike muscle. Even after
which undergo a 180°twist between their medial and lateral attach this force is reduced to allow for its obliquity (in this case by cos 30°,
ments). Muscles may spiral around a bone (e.g. supinator, which winds which equals 0.87), the overall tension in the direction of the tendon
obliquely around the proximal radial shaft), or contain two or more will exceed that in the straplike muscle by a factor of 2.6 (3 × 0.87).
planes of fibres arranged in differing directions, a type of spiral some So, the bipennate muscle sacrifices contraction distance for greater
times referred to as cruciate (sternocleidomastoid, masseter and adduc maximum force. This effect would be much greater in the multipennate
tor magnus are all partially spiral and cruciate). Many muscles display muscle shown in Figure 5.47.
more than one of these major types of arrangement, and show regional
variations that correspond to contrasting, and in some cases independ
Force, strength and power
ent, actions.
Direction of force In descriptions of muscle performance, ‘force’, ‘strength’ and ‘power’ are
often used interchangeably but these terms are not synonymous. When
considering human performance, it is possible for strength to increase
Although muscles differ in their internal architecture, the resultant force
without a concomitant increase in the true forcegenerating capacities
must be directed along the line of the tendon, so forces transverse to
of the muscles involved. Strength is usually measured under circum
this direction must be in balance (see Fig. 5.47; Fig. 5.48). In straplike
stances that require the participation of several muscles, and so depends
muscles, the transverse component is negligible. In fusiform, bipennate
on skilful coordination of these muscles as well as the forces they gener
and multipennate muscles, symmetry in the arrangement of the fibres
ate. This disparity can be marked during the early stages of physical
produces a balanced opposition between transverse components,
training.
whereas in asymmetrical muscles (e.g. unipennate muscles), the fibres
Power is the rate at which a muscle can perform external work, and
generate an unopposed lateral component of force that is balanced by
is equal to force multiplied by contraction velocity. Since force depends
intramuscular pressure.
on the total crosssectional area of muscle fibres, and velocity (the rate
Muscles that incorporate a twist in their geometry unwind it as they
of muscle shortening) depends on muscle fibre length, powerful
contract, so that they tend not only to approximate their attachments
muscles tend to be long as well as fat. A prime example is the quadri
but also to bring them into the same plane. Muscles that spiral around
ceps, which is the prime mover when someone stands up from a seated
a bone tend to reduce the spiral on contraction, causing rotation.
position. A lack of power in this and other muscles is the critical factor
that limits the ability of many elderly people to live independently
Force versus range of contraction
(Reid and Fielding 2012).
Muscle fibre architecture varies because some muscles are required to
Actions of muscles
develop a large force on their tendinous insertion, whereas other
muscles are required to move their insertion through a considerable
distance. These demands are largely incompatible and require different Historically, the actions of specific muscles were estimated from simple
muscle architecture. observation. Muscle attachments were identified by dissection, and
The force developed by an active muscle depends on the tension their probable action deduced from the line of pull. With the use of
developed in each muscle fibre. If all of the muscle fibres are parallel localized electrical stimulation it became possible to study the actions
(as in the straplike muscle in Figure 5.47), then the muscle force is of selected muscles systematically in the living subject. This approach
equal to the sum of the tension in each fibre, and so will be propor was pioneered by Duchenne de Boulogne in the mid19th century.
tional to the total crosssectional area of those fibres. The range of However, the study of isolated muscles cannot reveal the manner in
contraction generated by an active muscle depends on the relative which they interact during voluntary movements. Duchenne appreci
motion that can take place between the overlapping proteins in the ated this, and supplemented electrical stimulation with observations
sarcomere, and this sets a natural limit (approximately 30%) to the of patients with partial paralysis to make more accurate deductions
amount of fibre shortening that can take place. Hence, the movement about the way in which muscles cooperate. Manual palpation can
of the tendinous insertion is proportional to the length of the muscle be used to detect muscle contraction, but only in superficial muscles
fibres. under quasistatic conditions. Modern knowledge of muscle action has | 167 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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been acquired almost entirely by recording the electrical activity that
accompanies mechanical contraction, a technique known as electromy
ography (EMG). This technique can be used to study activation of deep
as well as superficial muscles, under static and dynamic conditions.
Multiple channels of EMG can reveal coordination between different
muscles that participate in a movement. These data can be further sup
plemented by monitoring joint angle and ground reaction force, and
by recording the movement on camera or with a threedimensional
motion analysis system.
Conventionally, the action of a muscle is defined as the movement
that takes place when it contracts. However, this is an operational defi
nition: equating ‘contraction’ with shortening, and ‘relaxation’ with
lengthening is too simple in the context of whole muscles and real
movements. Whether a muscle approximates its attachments on con
traction depends on the degree to which it is activated, and the forces
against which it has to act.
Movements that involve shortening of an active muscle are termed
concentric, e.g. contraction of biceps/brachialis while raising a weight
and flexing the elbow. Movements in which the active muscle undergoes Fig. 5.50 The attachment of a tendon (pink) to skeletal muscle (orange).
lengthening are termed eccentric, e.g. in lowering the weight previously The regular dense connective tissue of the tendon consists of parallel
bundles of type I collagen fibres, which are orientated in the long axis of
mentioned, biceps/brachialis ‘pays out’ length as the elbow extends.
the tendon and the muscle to which it is attached. A few elongated
Eccentric contractions stretch the collagenous tissue sheaths within
fibroblast nuclei are visible in the tendon. (Trichrome stain.)
muscle (see below), which increases the risk of tears in muscles such as
the hamstrings, and of a more general delayedonset muscle soreness
(Proske and Morgan 2001). Muscle contraction that does not involve
TENDONS
change in muscle length is isometric.
Natural movements are accomplished by groups of muscles. Each
Gross structure and function
muscle may be classified, according to its role in the movement, as a
prime mover, antagonist, fixator or synergist. It is usually possible to
identify one or more muscles that are consistently active in initiating Tendons take the form of whitishlooking cords or straps, with a round
and maintaining a movement: these are its prime movers. Muscles that or oval crosssection. They are composed of dense, regular connective
wholly oppose the movement, or initiate and maintain the opposite tissue; 60% of their dry weight consists of large crimped fibres of col
movement, are antagonists. For example, brachialis is the prime mover lagen type I (Fig. 5.50). Other components of their matrix include
in elbow flexion, and triceps is the antagonist. To initiate a movement, collagen types II and V, elastin, glycoproteins and proteoglycans (Wang
a prime mover must overcome passive and active resistance and impart 2006). Fascicles (bundles) of collagen fibres are orientated mainly par
an angular acceleration to a limb segment until the required angular allel to the long axis of the tendon but are to some extent interwoven;
velocity is reached; it must then maintain a level of activity sufficient they may be conspicuous enough to give tendons a longitudinally stri
to complete the movement. ated appearance to the unaided eye. Tendons generally have smooth
When prime movers and antagonists contract together they behave surfaces, although large tendons may be ridged longitudinally by coarse
as fixators, stabilizing the corresponding joint by increased transarticu fasciculi (as in the osseous aspect of the angulated tendon of obturator
lar compression, and creating an immobile base on which other prime internus). Loose connective tissue between fascicles provides a conduit
movers may act. For example, flexors and extensors of the wrist for small vessels and nerves; it condenses on the surface as a sheath or
cocontract to stabilize the wrist when an object is grasped tightly in epitendineum, which may contain elastin and irregularly arranged col
the fingers. lagen fibres. The loose attachments between this sheath and the sur
Acting across a uniaxial joint, a prime mover produces a simple rounding tissue present little resistance to movements of the tendon.
movement. Acting at multiaxial joints, or across more than one joint, In situations where greater freedom of movement is required, a tendon
prime movers may produce more complex movements that contain is separated from adjacent structures by a synovial sheath.
elements that have to be eliminated by contraction of other muscles. Tendons are slightly elastic and can be stretched by 6–15% of their
The latter assist in accomplishing the movement and are considered to length without damage (Wang 2006). Some of this extensibility is
be synergists, although they may act as fixators, or even as partial attributable to the reorientation of collagen type I fibres, some to the
antagonists of the prime mover. For example, flexion of the fingers at straightening of the crimped (wavelike) structure of these fibres, and
the interphalangeal and metacarpophalangeal joints is brought about some to sliding between adjacent collagen fibrils and fibres (Screen et al
primarily by the long flexors, superficial and deep. However, these also 2004). Sliding is possible because discrete collagen fibres appear to
cross intercarpal and radiocarpal joints, and if movement at these joints reinforce connective tissue in the manner of a ‘chopped fibrecomposite’
were unrestrained, finger flexion would be less efficient. Synergistic material such as fibre glass (Hukins and Aspden 1985), rather than by
contraction of the carpal extensors eliminates this movement, and even forming a fixed scaffold (which would make growth difficult). It takes
produces some carpal extension, which increases the efficiency of the a great deal of energy to stretch a long and strong tendon, and most of
desired movement at the fingers. this elastic ‘strain energy’ can be recovered when the tension is released.
In the context of different movements, a given muscle may act as a During locomotion, the rhythmic storing and releasing of strain energy
prime mover, antagonist, fixator or synergist. Even the same movement in stretched tendons helps to smooth the movement, so that tendons
may involve a muscle in different ways if it is assisted or opposed by (rather than cartilage) act as the body’s natural shock absorbers. This
gravity. For example, in thrusting out the hand, triceps is the prime energy storage and release also reduces the metabolic cost of locomo
mover responsible for extending the forearm at the elbow, and the flexor tion. Tendons are sufficiently flexible that they can be diverted around
antagonists are largely inactive. However, when the hand lowers a heavy osseous surfaces or deflected under retinacula to redirect the angle of
object, the extensor action of the triceps is replaced by gravity, and the pull.
movement is controlled by active lengthening (eccentric ‘contraction’) The vascular supply of tendon is sparse but not negligible. Small
of the flexors. It is important to remember that all movements take arterioles from adjacent muscle tissue pass longitudinally between the
place against the background of gravity and its influence must not be fascicles, branching and anastomosing freely, and are accompanied by
overlooked. venae comitantes and lymphatic vessels. This longitudinal plexus is
augmented by small vessels from adjacent loose connective tissue or
synovial sheaths. Vessels rarely pass between bone and tendon at
osseous attachments, and the junctional surfaces are usually devoid of
TENDONS AND LIGAMENTS
foramina. A notable exception is the calcaneal (Achilles) tendon, which
does receive a blood supply across its osseotendinous junction. During
Forces developed by skeletal muscles are transferred to bone by postnatal development, tendons enlarge by interstitial growth, particu
tendons, aponeuroses and fasciae, whereas ligaments prevent excessive larly at myotendinous junctions, where there are high concentrations
separation of adjacent bones. All of these structures comprise dense of fibroblasts. Growth decreases along a tendon from the muscle to the
fibrous connective tissues containing a high proportion of type I osseous attachments. The thickness finally attained by a tendon depends
collagen. on the size and strength of the associated muscle, but also appears to | 168 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Fig. 5.51 The microstructure of bone at entheses.
A, B, The cortical shell of bone (short arrows) is
very thin at fibrocartilaginous attachment sites. In
these examples showing the attachment of the
tendons of triceps brachii (TB) and of fibularis
longus (FL), the cortical shell is approximately the
same thickness as the underlying trabeculae (T).
T
Note that in A, the superficial trabeculae (long
T
arrows) are aligned along the direction of pull of
the tendon of triceps. C, In marked contrast, the
layer of cortical bone (CB) at the fibrous
attachment site of pronator teres (PT) to the
mid-shaft of the radius, is much thicker.
D, Higher-power view of the cortical calcified shell
of tissue at a fibrocartilaginous attachment site
TB (the calcaneal or Achilles tendon), which consists
of bone (B) and calcified fibrocartilage (CF). In this
specimen, there are two tidemarks, TM1 and TM2,
associated with the cortical shell of calcified
FL
tissue. TM1 is adjacent to the zone of uncalcified
fibrocartilage (UF), and marks the mechanical
boundary between hard and soft tissues. TM2 lies
nearer the bone and indicates an earlier phase of
A B
calcification. Note the relative straightness of the
tidemarks but the highly irregular interface
between calcified fibrocartilage and bone (arrows),
PT CB UF which is important in anchoring the tendon to the
TM1 bone. Sections of human cadaveric bone stained
TM2 with Masson’s trichrome. (Photographs courtesy
of Professor Michael Benjamin, Cardiff University,
from sections cut and stained by S. Redman.)
CF
B
C D
be influenced by additional factors such as the degree of pennation of tilaginous or fibrous (Benjamin et al 2006). In fibrocartilaginous
the muscle. The cellularity, and hence the metabolic rate, of large adult entheses, four zones of tissue can be distinguished: pure dense fibrous
tendons is very low, but increases during infection or injury. Repair connective tissue (continuous with and indistinguishable from the
involves an initial proliferation of fibroblasts followed by interstitial tendon), uncalcified fibrocartilage, calcified fibrocartilage, and bone
deposition of new collagen fibres (Wang 2006). Complete remodelling (continuous with and indistinguishable from the rest of the bone).
(replacement) of the tissue, as seen in bone, does not occur in adult There are no sharp boundaries between zones, and the proportions of
tendons, so healing tendons do not quite recover their original strength. each component vary between entheses. A fibrocartilaginous enthesis is
Tendons can adapt their stiffness and strength to match prevailing usually found where a tendon approaches the bone at a high angle, e.g.
mechanical demands, but the process is slow and may be incomplete triceps brachii (Fig. 5.51A,B,D). At fibrous entheses, which are charac
(Rumian et al 2009). teristic of the shafts of long bones, the tendon approaches the bone at
The nerve supply to tendons is largely sensory and there is no evi an acute angle and merges with the periosteum before attaching to bone
dence of any capacity for vasomotor control. Golgi tendon organs, by dense fibrous connective tissue, e.g. pronator teres (Fig. 5.51C).
specialized endings that are sensitive to force, are found near myotendi Fibrous entheses generally attach to a greater area of bone compared to
nous junctions; their large myelinated afferent axons run within fibrocartilaginous entheses, enabling them to reduce stress.
branches of muscular nerves or in small rami of adjacent peripheral
nerves. They play an important role in ‘tendon reflexes’, which serve to
protect the musculoskeletal system from injury. LIGAMENTS
The microstructure and biology of ligaments is broadly similar to that
Tendon attachments
of tendons (Rumian et al 2007). Ligaments consist mostly of large
crimped fibres of collagen type I, and their cells are predominantly
Muscles connect to bones by means of tendons, aponeuroses and elongated fibroblasts. However, there are two major differences between
fasciae. The epimysial, perimysial and endomysial sheaths within tendons and ligaments: one relating to gross structure, the other to
muscle coalesce at these attachments, and interdigitate with adjacent composition. Structurally, ligaments tend to have fibres orientated in a
collagenous structures to form strong connections in which force trans range of directions because they must resist the separation of bones in
mission is aided by shear stress transfer. more than one direction, whereas collagen fibres in a tendon must align
At the myotendinous junction, muscle fibres separate into fingerlike with tension in the adjacent muscle. More diverse mechanical roles of
processes separated by insertions of tendinous collagen fibres. Although ligaments are also reflected in their composition. For example, the liga
there are no desmosomal attachments at these junctions, other speciali mentum flavum, which joins adjacent vertebrae in the spine, has a very
zations assist in the transmission of force from the interior of the fibre high elastin content which enables it to be stretched more than 80%
to the extracellular matrix. Actin filaments from the adjacent sarcom when the spine is flexed, and yet remain under tension in all postures.
eres, which would normally insert into a Zdisc at this point, instead Maintaining tension is important because this ligament lies adjacent to
penetrate a dense, subsarcolemmal filamentous matrix that provides the spinal cord, and could impinge on it if it became slack (and buckled)
attachment to the plasma membrane. This matrix is similar in character when the spine was moved into extension.
to the cytoplasmic face of an adherens junction. The structure as a
whole is homologous to the intercalated discs of cardiac muscle.
BIOMECHANICS
Integrins at the extracellular surface of the junctional sarcolemma
provide contact with the basal lamina, which adheres closely to colla
gen and reticular fibres (type III collagen) of the adjacent tendon or The purpose of this section is to explain, in a nonmathematical way,
other connective tissue structure. how mechanical principles shape the human musculoskeletal system.
Tendinous attachments to bone (also known as entheses or osteo Mechanical considerations explain why bones are stiff and tendons are
tendinous junctions) have been broadly categorized as either fibrocar tough, why the surfaces of some synovial joints are imperfectly matched, | 169 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Body weight Fig. 5.53 The combined effect of
several muscle forces (M–M) and
1 3
Tensile force, FT body weight can be calculated by
resolving each force into two
components acting in two
Compressive force, FC M
3
a (inn a tt ho ism cic aa sl ely pm ae raa ln lein
l
g af nu dl directions
perpendicular to the mid plane of
the lumbosacral intervertebral
M 1 disc). The components acting in
these two directions are then
summed to give the total
C compressive (C) and shear (S)
Resultant force, M 2 forces acting on the disc. The
R magnitude and direction of the
S
A B C resultant force (R), which
represents the combined effect of
Torsional moment or torque, T all four forces, can be calculated
using trigonometry.
Shear force, FS Bending moment, M
Ultimate strength Ultimate failure
D E F
Fig. 5.52 The effects of different types of loading on a solid object (A) are
illustrated in B–F.
and why some tendons insert closer to joints than others. The emerging
subject of ‘mechanobiology’ considers how cells adapt their matrix to
prevailing mechanical demands and explains why some tissues are
better at doing this than others.
MECHANICAL CONCEPTS
Forces, moments and torques
A force is an action that deforms an object, or that causes it to move,
and can be termed compressive, tensile or shear, according to the 0
Deformation (mm)
manner in which it deforms that object (Fig. 5.52). A force F acting at
the end of a lever of length L will generate a bending moment (F × L) Fig. 5.54 A typical force-deformation graph for a skeletal structure
acting about the pivot point of the lever. A torque or torsional moment subjected to mechanical loading. In the initial ‘toe region’, deformation
increases rapidly with force, but this is followed by a linear region in
(Fig. 5.52F) may be quantified in similar terms. The combined influ
which the deformation increases more slowly, and in proportion to the
ence of several forces can be calculated as shown in Figure 5.53. If the
applied force. The gradient of the graph indicates the stiffness of the
forces all act in the same direction, they may be added. However, if they
structure at any given load. Strength is the force at which an object
act in different directions, each force must be resolved into two imagi
becomes damaged, and this is usually interpreted either as the force at
nary components that act in two anatomically convenient directions at
which the gradient first reduces (the elastic limit) or as the force when the
90° to each other, using simple trigonometry. All components acting
gradient falls to zero (the ultimate strength).
in the same direction are added to form two forces (S and C in
Fig. 5.53), which can be used to calculate the magnitude and direction
of the single resultant force (which has a similar effect to all of the
individual forces combined). Forces acting on a stationary object are
analysed according to the principle that all forces acting in any given
direction must balance each other (i.e. add to zero), and all moments
or torques acting about a given pivot point must also balance each
other.
Mechanical properties of structures
Most anatomical structures deform readily when a sufficient force is
applied to them, but their resistance to deformation increases steadily
as the magnitude of the force increases. The resulting graph of force
against deformation resembles the one shown in Figure 5.54. Stiffness
is the ratio of force to deformation (typical units N/mm) and so is
represented by the gradient of the graph. The initial region of low stiff
ness, or ‘toe region’, is followed by a stiffer region in which the graph
is almost linear. In many biological structures, the ‘toe region’ can be
explained by the straightening out of the zigzag ‘crimped’ structure of
collagen type I fibres, whereas the linear region represents direct stretch
ing of the straightened collagen fibres and some slipping between them.
If the deformed structure springs back immediately to its original
)N(
ecroF
Elastic limit
y
Stiffness = ––
x
‘Linear’ region
y
‘Toe’ region
x
dimensions when the deforming force is removed, the deformation is
termed ‘elastic’; a deformation that shows no sign of recovering is
plastic; a deformation that recovers eventually, but gradually, is visco
elastic (see below). ‘Strength’ is the force at which an object becomes
damaged, and is usually interpreted either as the force at which the
gradient of the graph first reduces (the elastic limit) or as the force when
the gradient falls to zero (the ultimate strength).
Properties of materials
The properties of materials must be expressed in such a way that they
are independent of the size and shape of the structure they constitute.
A force divided by the area over which that force is applied gives a stress
value (force per unit area); the resulting deformation divided by the
original length of the object gives a strain value (fractional or percentage
deformation). Stress divided by strain is the sizeindependent material
equivalent of the stiffness of an object, and is an important physical
property termed the ‘modulus’ (sometimes ‘Young’s modulus’). There
are different types of modulus but essentially they are measures of stiff
ness, or resistance to deformation. | 170 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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‘Hysteresis energy’
‘Strain energy’
0
Deformation (mm)
Fig. 5.55 This force–deformation graph shows how an object deforms
when a force is applied to it (upward arrow) and how it recovers its
shape when the force is gradually released (downward arrow). The area
under the loading curve represents the strain energy that has been
expended in deforming the object. The area under the unloading curve
represents the energy that is given up when the object is allowed to
spring back to its original shape. The small area in between represents
energy that cannot be recovered but is dissipated as heat. This is the
hysteresis energy.
Energy and shock absorption
Deforming an object may require a considerable expenditure of energy.
Technically, the work done (i.e. energy expended) is proportional to
the average force exerted, multiplied by the distance moved. This is
mathematically equivalent to the area under the graph in Figure 5.55,
and is referred to as the strain energy, i.e. the energy expended in
deforming the object. If the object has elastic properties, it will spring
back to its original shape when the deforming force is removed, and
all the strain energy is then released. (This release of strain energy Viscoelasticity
explains why a stretched rope can recoil violently if it snaps.) Struc
tures such as coiled springs, which can resist high forces and also
Materials are said to be viscoelastic if they behave partly like a thick
deform extensively, are capable of storing large amounts of energy, and
(viscous) fluid and partly like an elastic solid. Viscoelastic deformations
so can act as shock absorbers when they are continually compressed
change with time, even when the deforming stress is constant, and
and stretched. Tendons act in a similar manner during locomotion:
complete recovery from such deformations also takes some time after
they store strain energy when they are stretched by muscle contraction,
the stress is removed (Fig. 5.56). In most biological materials, viscous
and release most of this energy when the muscles relax later in the gait
behaviour occurs because applied loading causes fluid to flow from the
cycle. A small fraction of the stored strain energy, the hysteresis energy,
most heavily loaded regions to the least loaded, by percolating through
is dissipated as heat (see Fig. 5.55). This heat can cause the tempera
very small (nanometrescale) pores in the matrix, a process that can
ture to rise by several degrees centigrade in large tendons that are
take hours; for this reason, the term poroelastic is often preferred to
involved in vigorous repetitive activity. Any material or structure that is
viscoelastic when referring to tissues such as cartilage.
capable of absorbing large amounts of strain energy before failure is
Creep and stress relaxation are two important manifestations of
termed tough; otherwise it is brittle. From Figure 5.55 it is apparent
viscoelasticity. Creep may be described as continuing deformation
that tough materials must be both strong and extensible. In contrast,
under constant load (see Fig. 5.56), whereas stress relaxation is a
brittle materials such as glass and tooth enamel undergo minimal
gradual decrease in force resisted by a viscoelastic material when it is
deformation and so absorb little strain energy, even though they are
initially deformed by a certain amount, and then held with the same
strong. The shockabsorbing characteristics of tendons are important
constant deformation. Creep can reduce the thickness of loaded articu
during locomotion, making movements smoother and reducing meta
lar cartilage and intervertebral discs, typically by 20% in 5 minutes and
bolic cost (Alexander 1988).
3 hours, respectively. Creep deformation is reversed over a similar time
scale when the compressive loading is reduced and water is reabsorbed.
Liquids Bone creeps at a much slower rate, but in old osteoporotic vertebrae,
creep probably contributes to vertebral deformity (Luo et al 2012).
A liquid has negligible rigidity and so deforms readily to take the shape
of its container. When compressed, it maintains practically the same
MATERIAL PROPERTIES OF SKELETAL TISSUES
volume, but it flows to equalize the intensity of loading within it. As a
result, a static liquid under load exhibits a single internal pressure (force
The material properties of several skeletal tissues are compared in
per unit area) that does not vary with location or direction. Even deli
cate objects are not deformed when immersed in a highpressure liquid Table 5.3.
if they themselves are filled with liquid, because the internal and exter
Bone
nal pressures on them are exactly equal; this explains why cells can
survive high pressures in liquids without damage to their delicate
plasma membrane. Of the musculoskeletal tissues, only the nucleus Bone consists mainly of collagen type I and microcrystals of the mineral
pulposus of intervertebral discs exhibits true liquid behaviour (Adams hydroxyapatite. Collagen gives bone considerable tensile strength, and
2013). Some other tissues, including bone and cartilage, contain liquid renders it very tough when fractured, whereas the mineral component
that is able to move through pores in the solid matrix. gives bone a very high compressive modulus and high compressive
)N(
ecroF
0
Time
Fig. 5.56 The deformation of viscoelastic materials varies with time. In
this example, a load is applied at zero time, which causes an immediate
elastic deformation, followed by a slowly increasing time-dependent
deformation (creep). When the load is removed, some deformation is
recovered immediately, but full recovery is achieved only slowly.
noitamrofeD
Load removed
Creep deformation
Recovery
Elastic deformation
Table 5.3 Tensile material properties of skeletal tissues*
Cortical bone Tendon (ligament) Articular cartilage
Strength (MPa) 130 50–110 5–20?
Modulus (MPa) 17,000 500–1800 (150–800) 4–10
Failure strain (%) 1–2.5 10–20 30–100
*For comparison, alloy steel has a strength of 600 MPa and a modulus of 20,000 MPa. | 171 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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strength. Rigidity (stiffness) is the defining characteristic of bone; it MECHANICAL PROPERTIES OF
enables the tissue to provide precisely shaped surfaces in synovial joints SKELETAL STRUCTURES
that will deform very little under load, and it also enables fast locomo
tion when muscles pull on bones. If bones were strong and tough but Long bones
not rigid, rapid muscle contractions would cause them to bend alarm
ingly and would slow the angular movement of limbs.
Long bones are characterized by enlarged ends covered in cartilage, a
long hollow shaft and various bony protuberances. The enlarged ends
Tendon, ligament and fascia serve to reduce contact stress where long bones meet in synovial joints,
and to increase the stability of such joints (Fig. 5.58). A different rela
Tendons, ligaments and fascia consist primarily of densely packed col tionship between stability and mobility can exist in different anatomi
lagen type I fibres, giving these tissues high tensile strength. The crimped cal planes, even for the same joint, e.g. the knee joint favours stability
nature of the collagen fibres allows them to be stretched by up to 15% in the frontal plane and mobility in the sagittal plane. The hollow shaft
before failure, and this combination of strength and extensibility of a long bone confers high strength in bending for a given mass of
enables tendons, ligaments and fascia to absorb more strain energy per material, but also minimizes bone mass and so increases the speed of
unit weight than any other biological material. An important difference movement. Bending strength is increased by having as much bone mass
between tendons and ligaments is that ligaments often contain bundles as possible far from the axis of bending (Fig. 5.59). The precise cross
of collagen fibres orientated in a range of directions, presumably sectional shape of a long bone therefore gives a clear indication of the
because bones can be moved apart in a range of directions, whereas the planes in which the shaft is most likely to be subjected to severe
fibres in a tendon are all aligned with the direction of muscle tension. bending. Bony prominences or processes on long bones serve to
Fascia usually contains collagen fibres aligned in adjacent sheets to increase the lever arm of muscles that are attached to them: if a large
resist forces in at least two different directions. prominence is close to the centre of rotation of a joint, then it can
increase the lever arm by over 100%, and the maximum torque devel
oped by the muscle about that centre of rotation would increase by the
Hyaline cartilage
same amount.
Hyaline cartilage consists mainly of very fine collagen type II fibrils and
large proteoglycan molecules, which have the property of attracting
water and swelling. Collagen gives cartilage its tensile strength and stiff Stability
ness, and the proteoglycans give the tissue a high water content that
confers compressive ‘turgor’. During growth and healing, proteoglycans
enable the growing cartilage to swell and occupy space that later will
be strengthened by other components of the matrix. Articular cartilage
is a particular type of hyaline cartilage that covers the ends of articulat
ing bones; its high water content enables it to distribute loading evenly
on the underlying bone. Since cartilage is softer than bone, it deforms
more when loaded, increasing the area of contact between articular
surfaces and reducing contact stress (Fig. 5.57). Cartilage creep (see
above) causes the area of contact to increase, and further reduces
contact stress. Creep in articular cartilage also causes water to be exuded
into the joint cavity, assisting in fluidfilm lubrication (see below).
Articular cartilage ‘wear’ (loss of material) during high and repetitive
loading is minimized because the collagen type II fibrils in the super
ficial zone are aligned parallel to the surface, an arrangement that
provides maximal resistance to surface splitting and the subsequent
loss of tissue. A B C
Mobility
Fibrocartilage and elastic cartilage
Fig. 5.58 In synovial joints, the shapes of the opposing bone ends largely
Fibrocartilage and elastic cartilage combine the high proteoglycan and determine how much movement is possible, and the stability of the joint.
water content that characterizes cartilage with a high proportion of Tapered bone ends (A) lead to high mobility but low stability (in the plane
either collagen type I (fibrocartilage) or elastin (elastic cartilage). Col of the page). Conversely, very wide bone ends (C) lead to low mobility
lagen type I confers extra tensile strength and toughness, whereas elastin and high stability. Some joints resemble (A) in one plane but (B) or (C) in
fibres provide elastic recoil, i.e. the ability to spring back to shape after others.
large deformations.
A
D
A B
Bone Cartilage
B
C
Fig. 5.59 A cross-section through the shaft of a long bone, showing how
the irregular shape gives information about the bone’s strength in bending
about different axes. Strength will be greatest about the axis A–B
Fig. 5.57 Articular cartilage in a synovial joint is not as stiff as the because a high proportion of bone mass is located a long distance from
underlying bone, so the presence of cartilage in a loaded joint increases this axis, and so will resist bending very strongly. Strength will be minimal
the area of contact (B) compared to a joint without cartilage (A). about the axis C–D for a similar reason. | 172 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Synovial joints MUSCLES AND LEVER SYSTEMS
Typically, synovial joints are designed for full and free movements, but Collagenous architecture of muscle
they must also provide some stability in specific planes (see Fig. 5.58).
In a joint with a small range of movement, intrinsic stability provided Muscles are supported by a hierarchy of collagenous sheaths (endomy
by the articular surfaces and ligaments of that joint may be more impor sium, perimysium and epimysium), which surround individual muscle
tant than the extrinsic stability provided by surrounding muscles. Low fibres, fascicles and whole muscles respectively. Muscles are bound
friction movement is facilitated by the smooth surfaces of articular together into functional groups by collagenous fascia. Together, these
cartilage being made slippery by the presence of the boundary lubricant sheaths create a strong honeycomb structure that contributes to the
lubricin, which is bound to the cartilaginous surfaces. This boundary muscle’s resistance to tension. When muscle is stretched during eccen
lubrication reduces friction during slow movements, especially when tric (lengthening) contractions, high tensile forces in the collagenous
forces are high. During rapid movements, microscopic undulations in structures add to the tension generated by muscle fibre contraction,
the cartilage surface trap small quantities of synovial fluid between the leading to high and potentially damaging forces acting on the musc
articular surfaces, so that fluidfilm lubrication (akin to aquaplaning) ulotendinous junction.
can also occur (Fig. 5.60), and friction and wear are greatly reduced.
The sticky, viscous nature of synovial fluid enables it to persist between Internal muscle forces
the cartilage surfaces for longer than water, which would be squeezed
out much too quickly. Fluidfilm lubrication is assisted by joint incon
Generally speaking, muscle forces exert greater mechanical loading on
gruity, in which the opposing articular surfaces have slightly different
the skeleton than does body weight. For example, during relaxed
curvatures (Fig. 5.61), producing a potential fluidfilled gap that moves
standing, 50% of the compressive force acting on the lumbar spine
as the joint moves, washing synovial fluid across the cartilage surfaces.
arises from the antagonistic activity of the muscles of the back and
Incongruity can also help to reduce peak loading on the apex of the
abdomen, and 50% comes from superincumbent body weight (Adams
joint.
2013). However, when bending the trunk to lift weights from the
ground, more than 90% of the compressive force acting on the spine
Intervertebral discs
can be attributed to muscle tension (Fig. 5.62). Similarly, muscle
forces acting on the knee can exceed body weight by a factor of 200–
Intervertebral discs are composed of three tissues: the anulus fibrosus 400% during stair climbing and during deep squatting movements.
(fibrocartilage), the nucleus pulposus (a hydrated collagen–proteoglycan Muscle forces can exceed the strength of adjacent bones if they contract
gel) and the endplates (hyaline cartilage). The water content of the in alarm, so that normal inhibitory reflexes are suppressed; it is not
nucleus pulposus can reach 90% in children and young adults, enabling uncommon for vertebrae to be crushed by muscle tension during
the tissue to behave like a fluid. When compressive loading is applied major epileptic fits. According to Newton’s 2nd Law of motion (force
to the vertebral column, the fluid pressure in the nucleus presses evenly = mass × acceleration), muscle forces also rise to high levels when
on the adjacent vertebral bodies, even when they are orientated at small attempting to accelerate body parts, e.g. during jumping or throwing.
angles to each other. The anulus resists radial expansion of the nucleus It follows that any attempt to achieve maximum acceleration will natu
and can deform vertically to facilitate spinal bending in various planes. rally require maximal muscle tension. The size and potential dangers
The relatively dense hyaline cartilage endplate helps to maintain a fluid of internal muscle forces are often overlooked, leading some authors
pressure in the nucleus by slowing down water loss into the vertebral to draw spurious distinctions between weightbearing and nonweight
body through perforations in the vertebral endplate. Nevertheless, discs bearing joints, and to suggest erroneously that only the former are
lose approximately 20% of their water gradually, in the course of each subjected to high loading. It is likely that a watchmaker’s finger joints
day. This net loss of water is regained at night when, in recumbency, are subjected to stresses as high, and as often, as those applied to his
the load on the spine is relieved. Diurnal variations in disc water ankles.
content cause adults to be approximately 2 cm taller in the early
morning, and more flexible in the evening.
D
Contact between asperities
Synovial fluid
Cartilage Boundary lubricant
O F
d
1 µm
Fig. 5.60 The articular cartilage surfaces of synovial joints contain
microscopic undulations that trap small quantities of synovial fluid
between the surfaces, enabling fluid-film lubrication to occur. Boundary
lubrication at the points of contact between cartilage asperities
(roughness) is facilitated by lubricants adhering to the cartilage surface.
A B
Synovial
fluid W
F F
Fig. 5.62 During manual labour, muscle tension often rises to high levels
in order to generate sufficient bending moment to move external objects.
Fig. 5.61 Some synovial joints are incongruent in the sense that the In this example, the back muscles act only a short distance (d) from the
opposing articular surfaces have slightly different curvatures. This ensures pivot point in the intervertebral discs (O), whereas the weight being lifted
that there is a fluid-filled gap between them when the joint is subjected to acts on a much bigger lever arm (D). In order for the moments to balance,
low loading (A). Under high loading (B) this gap disappears, but peak the back muscle tension (F) must exceed the weight being lifted (W) by
loading at the apex of the joint remains lower than it would be if the the ratio of D/d. In practice, this can lead to the lumbar spine being
surfaces had the same curvature, and this is a major advantage for an compressed by approximately 500 kg during moderate manual handling.
incongruent joint. The shape of the concave articular surface is (For simplicity, the above analysis disregards the weight of the upper
sometimes referred to as a Gothic arch. Abbreviation: F = loading force. body.) | 173 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Fig. 5.63 Muscle lever systems can be
Force
classified as first-class (A), second-class (B) or
A First-class lever
Motion third-class (C), according to the relative
positions of the fulcrum (or pivot), the muscle
insertion, and the externally applied load.
Fulcrum
Load
B Second-class lever
Motion Force
Load
Fulcrum
C Third-class lever Force
Load
Motion Fulcrum
Muscle lever systems
Muscle tension generates bending moments and torques about joints. A
Moments and torques depend on lever arms as well as muscle forces.
It is conventional (although not particularly illuminating) to distin
guish between three types of muscle lever system (Fig. 5.63). Generally,
the length of the lever arm (the perpendicular distance between the line
of action of the muscle and the centre of rotation of the joint) is more
important than lever type (Fig. 5.64). If the lever arm is short, then a
given muscle contraction will move the joint through a large angle, so
the lever system is suited to large and/or rapid movements of that joint.
Conversely, a long lever arm leads to small and/or slow movements but
F
greater moment generation. Elite weightlifters may have muscle inser d
tions with particularly large lever arms about particular joints.
MOVEMENTS
Movements of bones
B
Movement of a bone is referred to as translation if it does not involve
any change in orientation relative to a fixed frame of reference (or to
another bone). A pure rotation involves no translation, merely a pivot
ing of the bone about some fixed point or centre of rotation. Spin is
the rotation of a bone about its mechanical axis, which for a long bone
would coincide with its long axis. Spin can occur in conjunction with F
other joint rotations (Fig. 5.65). Most body movements involve some
combination of rotation, translation and spin, although the transla d
tional component is often small. 2
Movements at articular surfaces
Fig. 5.64 The precise location of a muscle insertion relative to a joint
greatly influences the function of that joint. A, If the perpendicular
Opposing joint surfaces are never perfectly congruent, but substantial distance (d) between the muscle’s line of action and the centre of rotation
regions of these surfaces may fit together exactly in a certain position of the joint (•) is large, then the joint is suited to slow but forceful
known as the closepacked position, in which the joint is most stable. movements. B, If d is small, then the joint is suited to rapid but less
For example, the closepacked position of the knee joint corresponds forceful movements. Abbreviation: F, force, showing line of muscle action. | 174 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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(90° + 90°+ 90°) - (90° + 90°) = 90° Table 5.4 The close- and loose-packed positions of joints
Joint Close-packed position Loose-packed position
Shoulder Abduction + lateral rotation Semi-abduction
Ulnohumeral Extension Semi-flexion
Radiohumeral Semi-flexion + semi-pronation Extension + supination
Wrist Dorsiflexion Semi-flexion
A 2nd–5th Full flexion Semi-flexion + ulnar deviation
metacarpophalangeal
Interphalangeal (fingers) Extension Semi-flexion
90° 1st carpometacarpal Full opposition Neutral position of thumb
Hip Extension + medial rotation Semi-flexion
Knee Full extension Semi-flexion
Ankle Dorsiflexion Neutral position
Tarsal joints Full supination Semi-pronation
90° 90° Metatarsophalangeal Dorsiflexion Neutral position
Interphalangeal (toes) Dorsiflexion Semi-flexion
B C Intervertebral Extension Neutral position
Data from MacConaill MA, Basmajian JV 1977 Muscles and Movements, 2nd edn. New York: Kriger.
Fig. 5.65 Complex movements of the body’s joints are sometimes
required to produce apparently simple movements of the limbs. In this
example, moving the hand as shown from A to B to C requires a hidden
‘spin’ movement of the arm of 90° about its mechanical (long) axis.
Spin Roll Slide
CoR
Fig. 5.66 The surfaces of incongruent joints move relative to each other
by various combinations of spin, roll and slide. Fig. 5.67 When a bone is rotated, the centre of rotation (CoR) can be
located by drawing lines between the initial and final positions of
anatomical landmarks on the bone, and then determining where the
to full extension. In other (loosepacked) positions, the surfaces of perpendicular bisectors of these lines meet. The CoR may not correspond
incongruent joints are not perfectly matched, and are able to move rela to a precise anatomical landmark.
tive to each other by a combination of spin, roll and slide (Fig. 5.66).
In final closepacking, surfaces are fully congruent, in maximal contact be included in Table 5.4. However, most of the positions given do cor
and tightly compressed or ‘screwed home’, the fibrous capsule and liga respond with postures adopted when maximal stress is encountered.
ments are maximally spiralized and tensed, and no further movement
is possible. Closepacked surfaces cannot be separated by normal exter Centre of rotation
nal force (as they may be in other positions), and bones can be regarded
as temporarily locked, as if no joint existed. Closepacking is a final, The centre of rotation is a theoretical concept and may not correspond
limiting position, and any force that tends to further change can only closely to any anatomical landmark or natural pivot. For a finite move
be resisted by contraction of appropriate muscles. Failure to stop further ment of one bone relative to a fixed reference (perhaps an anatomical
movement results in injury to joint structures. Therefore, movement just plane), the centre of rotation can be located by drawing theoretical lines
short of closepacking is physiologically most important. between the initial and final positions of two anatomical landmarks on
Ligaments and articular cartilage are, to a small degree, elastically the bone, and determining where the perpendicular bisectors of these
deformable: in the final stages of closepacking the articular position is two lines meet (Fig. 5.67). Real movements of real joints often involve
an equilibrium between the external moments and torques applied varying combinations of rotation and translation as the movement
(often by gravity) and resistance to tissue deformation by the tense, progresses. It can be instructive to break the whole movement down
twisted capsule and compressed cartilage surfaces. In symmetrical into a series of small movements, calculate the centre of rotation for
standing, the knee and hip joints approach closepacked positions suf each one, and then join up the centres to create the locus of the instan
ficiently to maintain an erect posture with minimal energy. In all other taneous centre of rotation for the whole movement. Joint disease some
positions, the articular surfaces are not congruent and parts of the times leads to an abnormally long and tortuous locus of the centre of
capsule are lax; the joint is said to be loosepacked. Close and loose rotation, because degenerative changes can reduce the restraint to
packed positions of several major joints are shown in Table 5.4 (see motion offered by one or more tissues.
MacConaill and Basmajian (1977)). Capsules are sufficiently lax near
Coupled movements
the midrange of many movements to allow separation of the articulat
ing surfaces by external forces. Opinions may vary in connection with An attempt to move a joint in one plane sometimes causes articular
some of the positions in Table 5.4, e.g. a closepacked position may surfaces to meet at an oblique angle, creating small rotations in other
possibly occur in occasional joints at both extremes of the range of planes. These secondary rotations, which are usually smaller than the
movement. It is difficult to assess the situation in small tarsal and carpal primary rotations, are referred to as coupled movements, e.g. lateral
joints and the first carpometacarpal joints. Intervertebral movements bending of the lumbar spine, which occurs in the coronal plane, also
are the result of integrated simultaneous changes at all elements that normally produces coupled axial rotations. Joint pathology can lead to
make up the intervertebral articular complex, and perhaps should not abnormal coupled movements. | 175 | Gray's Anatomy | temp.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PDFPlumberTextLoader |
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Increased matrix
Matrix deposition
modulus (stiffness)
Decreased Cell Increased
Low strain Adaptive remodelling High strain
mechanical loading Matrix mechanical loading
Reduced matrix
Matrix resorption
modulus (stiffness)
Fig. 5.68 Adaptive remodelling is the process by which musculoskeletal tissues adapt to prevailing mechanical demands. If a tissue is subjected to
increased mechanical loading (right), it deforms more. Cells respond to this increased strain by depositing more matrix and increasing its modulus
(stiffness) until strain levels return to normal. Similarly, reduced loading leads to reduced tissue strain (left), reduced modulus and reduced matrix
deposition until strain levels rise to normal.
MECHANOBIOLOGY to tissue strain, possibly by detecting the resulting fluid flow within the
microscopic canaliculi of the matrix. Cells in cartilage and ligaments
Adaptive remodelling also detect tissue strain, possibly because it deforms the cells in shear
(see Fig. 5.52). Cells in articular cartilage and in the nucleus pulposus
of intervertebral discs appear to be able to detect hydrostatic pressure
Skeletal tissues are generally able to adapt their mechanical properties
in their surrounding medium, although only the cells in the nucleus
to match the forces applied to them. This process is best understood
pulposus would normally experience such a pressure in life. (The pore
for bone, and bone biologists refer to this general principle as Wolff’s
pressure in a ‘biphasic’ solid such as articular cartilage can vary from
Law. As illustrated in Figure 5.68, the amount of deformation of a tissue
place to place and is not equivalent to a single hydrostatic pressure.)
(i.e. the strain) is proportional to the mechanical loading to which it is
Muscle cells respond to strain and microinjury, possibly disturbing
subjected. Cells detect this increased strain and respond by producing
intracellular proteins such as titin. Mechanotransduction appears to be
more extracellular matrix, which increases the modulus (stiffness) of
mediated by matrix molecules such as fibronectin pulling on trans
the tissue and returns strain levels to normal. Similarly, reduced loading
membrane proteins such as integrins, which in turn disturb the cell
leads to reduced tissue strain, reduced matrix synthesis and reduced
cytoskeleton.
modulus, so that tissue strain increases to normal values. This negative
feedback system ensures that bone adapts (remodels) to suit its mechan
Degeneration, injury and frustrated repair
ical environment (Currey 2002). Animal experiments suggest that as
few as 36 relatively severe loading cycles per day are sufficient to
produce a maximal hypertrophic response in bone, whereas fewer than Numerous theories have been propounded to explain degenerative
four loading cycles per day leads to tissue resorption (Rubin and Lanyon changes in skeletal tissues. Most presume that the cells behave abnor
1984). Evidently, bone cells respond to maximal loading rather than mally, possibly because of an unfavourable genetic inheritance, so that
timeaveraged loading. There is some experimental evidence that carti the matrix becomes weakened and physically disrupted. Alternatively,
lage adapts similarly to its mechanical environment (Hall et al 1991). degenerative changes may represent an attempt by the cells to repair a
It would be unlikely that they did not, because the mechanical proper matrix where the primary cause of damage has been excessive mechani
ties of adjacent tissues would rapidly become mismatched, increasing cal loading (Adams et al 2013). Excessive loading does not necessarily
the risk of damage to one of them. However, it is equally evident that imply trauma; normal loading is excessive if the matrix has become
different tissues cannot adapt at the same rates. Highly vascularized abnormally weak on account of an unfavourable genetic inheritance or
tissues such as muscle and bone have the potential to adapt rapidly, age. In poorly vascularized tissues, such as cartilage and tendon, low
whereas poorly vascularized tissues such as large tendons do not. Avas cell density and inadequate transportation of metabolites could lead to
cular tissues such as articular cartilage and intervertebral discs can adapt a vicious circle of minor injury, frustrated repair, tissue weakening and
only very slowly, so that turnover times for some matrix macromole further injury.
cules can be as long as 100 years. Large differences in adaptive potential
between adjacent musculoskeletal tissues could lead to problems in the
less wellvascularized tissue when levels of mechanical loading increase
abruptly (Adams et al 2013). Bonus e-book image
Mechanotransduction
Fig. 5.40 B, The arrangement of titin and nebulin in a skeletal
Various mechanisms have been proposed to explain how cells in mus muscle sarcomere.
culoskeletal tissues detect mechanical loading. Cells in bone respond
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