Calcium and Bones Endocrine Controls

1. Calcium and Bones Endocrine Controls Calcium homeostasis is important because the ion is needed to maintain nerve & muscle function & to control many cellular activities in virtually all cells. It is also a major structural component of the body in both the bone & extracellular compartments. The hormones involved in calcium metabolism in general & in bone in particular include the protein parathyroid hormone & the modified steroid calcitriol (1α,25 – dihydroxy vitamin D3; 1α,25 – dihydroxycholecalciferol), which both promote the movement of calcium ion into circulation, & the counter-balancing protein hormone calcitonin, which promotes a decrease in circulating calcium.

2. Parathyroid glands Parathyroid hormone (PTH), an 84 amino acid-long protein, is produced by processing of a longer translation product by the parathyroid glands which are embedded in the thyroid tissues in many vertebrate species. Calcitonin, a 32 amino acid-long peptide is produced by the parafollicular or C cells of the thyroid interstitium; these cells do not play a role in thyroid hormone production.

3. Calcitriol is derived from a metabolite of cholesterol, 7-dehydro-cholesterol formed in the liver. Non-ezymatic breakage of the B-ring by ultraviolet light exposure in the skin form cholecalciferol (vitamin D3) which may also be obtained in the diet, e.g., in vitamin D fortified milk. Liver hydroxylates chole-calciferol on the sidechain to form 25-hydroxycholecalciferol which is carried by the vitamin D carrier protein in serum to the kidney. In the kidney the molecule can be hydroxylated once or twice more to form the active hormone calcitriol or the inactive metabolites 24,25-dihydroxycholecalciferol or 1α, 24, 25-trihydroxycholecalciferol. PTH promotes 1α hydroxylation & activation, CT promotes 24 hydroxylation & inactivation.

4. Calcium (& phosphate) balance is achieved by actions on 3 central tissues: kidney, intestine, & bone. PTH & calcitriol elevate Ca++ in serum by stimulating kidney tubules to reabsorb Ca++ from forming urine & by stimulating osteoclasts to mobilize calcium from bone. Simultaneously, calcitriol stimulates Ca++ absorption from foods in the intestine. When serum Ca++ is too high CT blocks PTH-stimulated formation of calcitriol in the kidney & counters calcitriol & PTH actions on the kidney tubules. CT also blocks PTH & calcitriol action in osteoclasts & calcitriol actions on the intestine. CT’s actions in humans appear relatively minor with changes of PTH level in response to serum Ca++ rises or falls playing a larger role.

5. Bone is a complex tissue including inorganic, organic, & cellular components. The major inorganic component is hydroxyapatite a complex calcium salt including phosphate, carbonate, magnesium, & other ions. This is sensitive to attack by acid & forms about 2/3 of the weight of bone. It can serve as a reservoir of problematic cations such as lead, radium, strontium, or arsenic making effects of exposure more prolonged than if the ions were always free in circulation. Hydroxyapatie is interweaved with organic components such as collagens & many minor protein contributors. The cellular players are thought to be derived from blood-lineage stem cells. They include: osteoblasts that cover the surface of bone & help deposit bone mineral: osteocytes, also bone builders, which occupy interior locations in bone that eventually are walled off by mineral deposition; & osteoclasts, large multinucleate cells, which are probably modified macrophages, that act to break down & remodel bone. Other cells include vascular endothelial cells in blood vessels & nerves.

6. A sketch of a cross section of long bone near the epiphyses, growth plate, shows the various cells involved in bone remodeling in relation to the bone matrix.

7. The major hormonal target for calcium homeostasis in bone is the osteoclast which can mobilize Ca++ by secreting acid & proteolytic enzymes onto the bone matrix surface in response to stimulation by PTH & calcitriol. http://www.besthealth.com/besthealth/bodyguide/reftext/images/osteoclast.jpg CT blocks PTH (cAMP cascade) & calcitriol (nuclear receptor). Sex steroids modulate bone cell activity; androgen stimulates bone deposition, lack of estradiol causes bone loss.

8. Calcium ion movement across cells is shown. Note that the cell forms are more typical of osteoblasts which build bone and usually transport calcium toward the matrix. An osteoclast, as shown in the last two slides, would emphasize degradation of bone mineral & matrix & would pump calcium into the vasculature. Don’t believe everything you see in books!