Once activated,<unk> s move to areas of microfracture in the bone by chemotaxis.<unk> s lie in small cavities called Howship's lacunae, formed from the digestion of the underlying bone. The sealing zone is the attachment of the<unk> 's plasma membrane to the underlying bone. Sealing zones are bounded by belts of specialized adhesion structures called podosomes. Attachment to the bone matrix is facilitated by integrin receptors, such as αvβ3, via the specific amino acid motif Arg-Gly-Asp in bone matrix proteins, such as osteopontin. The<unk>  releases hydrogen ions through the action of carbonic anhydrase (H2O + CO2 → HCO3− + H+) through the ruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized bone matrix into Ca2+, H3PO4, H2CO3, water and other substances. Dysfunction of the carbonic anhydrase has been documented to cause some forms of osteopetrosis. Hydrogen ions are pumped against a high concentration gradient by proton pumps, specifically a unique vacuolar-ATPase. This enzyme has been targeted in the prevention of osteoporosis. In addition, several hydrolytic enzymes, such as members of the cathepsin and matrix metalloprotease (MMP) groups, are released to digest the organic components of the matrix. These enzymes are released into the compartment by lysosomes. Of these hydrolytic enzymes, cathepsin K is of most importance. Cathepsin K and other cathepsins Cathepsin K is a collagenolytic papain-like cysteine protease that is mainly expressed in<unk> s, and is secreted into the resorptive pit. Cathepsin K is the major protease involved in the degradation of type I collagen and other noncollagenous proteins. Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic disease, characterised by a lack of functional cathepsin K expression. Knockout studies of cathepsin K in mice lead to an osteopetrotic phenotype, which, is partially compensated by increased expression of proteases other that cathepsin K and enhanced<unk> ogenesis. Cathepsin K has an optimal enzymatic activity in acidic conditions. It is synthesized as a proenzyme with a molecular weight of 37kDa, and upon activation by autocatalytic cleavage, is transformed into the mature, active form with a molecular weight of ~27kDa. Upon polarization of the<unk>  over the site of resorption, cathepsin K is secreted from the ruffled border into the resorptive pit. Cathepsin K transmigrates across the ruffled border by intercellular vesicles and is then released by the functional secretory domain. Within these intercellular vesicles, cathepsin K, along with reactive oxygen species generated by TRAP, further degrades the bone extracellular matrix. Several other cathepsins are expressed in<unk> s including cathepsins B, C, D, E, G, and L. The function of these cysteine and aspartic proteases is generally unknown within bone, and they are expressed at much lower levels than cathepsin K. Studies on cathepsin L knockout mice have been mixed, with a report of reduced trabecular bone in homozygous and heterozygous cathepsin L knockout mice compared to wild-type and another report finding no skeletal abnormalities. Matrix metalloproteinases The matrix metalloproteinases (MMPs) comprise a family of more than 20 zinc-dependent endopeptidases. The role of matrix metalloproteinases (MMPs) in<unk>  biology is ill-defined, but in other tissue they have been linked with tumor promoting activities, such as activation of growth factors and are required for tumor metastasis and angiogenesis. MMP9 is associated with the bone microenvironment. It is expressed by<unk> s, and is known to be required for<unk>  migration and is a powerful gelatinase. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, and fracture repair. MMP-13 is believed to be involved in bone resorption and in<unk>  differentiation, as knockout mice revealed decreased<unk>  numbers, osteopetrosis, and decreased bone resorption. MMPs expressed by the<unk>  include MMP-9, -10, -12, and -14. apart from MMP-9, little is known about their relevance to the<unk> , however, high levels of MMP-14 are found at the sealing zone.<unk>  physiology In the 1980s and 90s the physiology of typical<unk> s was studied in detail. With the isolation of the ruffled border, ion transport across it was studied directly in biochemical detail. Energy-dependent acid transport was verified and the postulated proton pump purified. With the successful culture of<unk> s, it became apparent that they are organized to support the massive transport of protons for acidification of the resorption compartment and solubilization of the bone mineral. This includes ruffled border Cl− permeability to control membrane potential and basolateral Cl−/HCO3− exchange to maintain cytosolic pH in physiologically acceptable ranges. The effectiveness of its ion secretion depends upon the<unk>  forming an effective seal around the resorption compartment. The positioning of this "sealing zone" appears to be mediated by integrins expressed on the<unk>  surface. With the sealing zone in place, the multinucleated<unk>  reorganizes itself. Developing the highly invaginated ruffled membrane apposing the resorption compartment allows massive secretory activity. In addition, it permits the vesicular transcytosis of the mineral and degraded collagen from the ruffled border to the free membrane of the cell, and its release into the extracellular compartment. This activity completes the bone resorption, and both the mineral components and collagen fragments are released to the general circulation. Regulation<unk> s are regulated by several hormones, including parathyroid hormone (PTH) from the parathyroid gland, calcitonin from the thyroid gland, and growth factor interleukin 6 (IL-6). This last hormone, IL-6, is one of the factors in the disease osteoporosis. Osteoporosis<unk> curs when there is an imbalance between the bone resorption activities of<unk> s and the bone formation activities of<unk> s.<unk>  activity is also mediated by the interaction of two molecules produced by<unk> s, namely osteoprotegerin and RANK ligand. Note that these molecules also regulate differentiation of the<unk> .
Osteoclast
Lymphoblast
Prolymphocyte
Plasma cell
Dendritic cell
Podocyte
Progenitor cell
Monocyte