Regulation of serum calcium The<unk>  gland releases<unk>  which keeps calcium in homeostasis. A diagrammatic representation of the movements of calcium ions into and out of the blood plasma (the central square labeled PLASMA Ca2+) in an adult in calcium balance: The widths of the red arrows indicating movement into and out of the plasma are roughly in proportion to the daily amounts of calcium moved in the indicated directions. The size of the central square in not in proportion to the size of the diagrammatic bone, which represents the calcium present in the skeleton, and contains about 25,000 mmol (or 1 kg) of calcium compared to the 9 mmol (360 mg) dissolved in the blood plasma. The differently colored narrow arrows indicate where the specified<unk> s act, and their effects (“+” means stimulates; “-“ means inhibits) when their plasma levels are high.<unk>  is<unk> , 1,25 OH VIT D3 is calcitriol or 1,25 dihydroxyvitamin D3, and CALCITONIN is a<unk>  secreted by the thyroid gland when the plasma ionized calcium level is high or rising. The diagram does not show the extremely small amounts of calcium that move into and out of the cells of the body, nor does it indicate the calcium that is bound to the extracellular proteins (in particular the plasma proteins) or to plasma phosphate.<unk>  regulates serum calcium through its effects on bone, kidney, and the intestine: In bone,<unk>  enhances the release of calcium from the large reservoir contained in the bones. Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by<unk> . Stimulation is indirect since osteoclasts do not have a receptor for<unk> ; rather,<unk>  binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their secretion of osteoprotegerin (OPG). Free OPG competitively binds to RANKL as a decoy receptor, preventing RANKL from interacting with RANK, a receptor for RANKL. The binding of RANKL to RANK (facilitated by the decreased amount of OPG available for binding the excess RANKL) stimulates osteoclast precursors, which are of a monocyte lineage, to fuse. The resulting multinucleated cells are osteoclasts, which ultimately mediate bone resorption. Estrogen also regulates this pathway through its effects on<unk> . Estrogen suppresses T cell TNF production by regulating T cell differentiation and activity in the bone marrow, thymus, and peripheral lymphoid organs. In the bone marrow, estrogen downregulates the proliferation of hematopoietic stem cells through an IL-7 dependent mechanism. In the kidney, around 250 mmol of calcium ions are filtered into the glomerular filtrate per day. Most of this (245 mmol/d) is reabsorbed from the tubular fluid, leaving about 5 mmol/d to be excreted in the urine. This reabsorption occurs throughout the tubule (most, 60-70%, of it in the proximal tubule), except in the thin segment of the loop of Henle. Circulating<unk>  only influences the reabsorption that occurs in the distal tubules and the renal collecting ducts (but see Footnote). A more important effect of<unk>  on the kidney is, however, its inhibition of the reabsorption of phosphate (HPO42−) from the tubular fluid, resulting in a decrease in the plasma phosphate concentration. Phosphate ions form water-insoluble salts with calcium. Thus, a decrease in the phosphate concentration of the blood plasma (for a given total calcium concentration) increases the amount of calcium that is ionized. A third important effect of<unk>  on the kidney is its stimulation of the conversion of 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D (calcitriol), which is released into the circulation. This latter form of vitamin D is the active<unk>  which stimulates calcium uptake from the intestine. Via the kidney,<unk>  enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D. Vitamin D activation occurs in the kidney.<unk>  up-regulates 25-hydroxyvitamin D3 1-alpha-hydroxylase, the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to its active form (1,25-dihydroxy vitamin D). This activated form of vitamin D increases the absorption of calcium (as Ca2+ ions) by the intestine via calbindin.<unk>  was one of the first<unk> s to be shown to use the G-protein adenylyl cyclase second messenger system. Regulation of serum phosphate<unk>  reduces the reabsorption of phosphate from the proximal tubule of the kidney, which means more phosphate is excreted through the urine. However,<unk>  enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, absorption of both calcium and phosphate is mediated by an increase in activated vitamin D. The absorption of phosphate is not as dependent on vitamin D as is that of calcium. The end result of<unk>  release is a small net drop in the serum concentration of phosphate. Vitamin D synthesis<unk>  upregulates the activity of 1-α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol, the major circulating form of inactive vitamin D, into 1,25-dihydroxycholecalciferol, the active form of vitamin D, in the kidney. Interactive pathway map
Parathyroid hormone
Calcitriol
Growth hormone
Calcitonin
Thyroglobulin
Orexin
Calcitonin gene-related peptide
Estrogen 