The Role of Calcitriol in Bone Metabolism

In addition to the role of bone mineral as a structural component of bone, it can be regarded as a major reserve of calcium for the body. In an adult, the skeleton contains 25 mol of calcium, whereas the total extracellular fluids contain only about 25 mmol. Parathyroid hormone, calcitonin, and calcitriol regulate the intestinal absorption and renal excretion of calcium, and the mobilization and deposition of bone calcium, maintaining the plasma concentration in a narrow range between 2.2 to 2.55 mmol per L. Of this, 0.7 mmol per L is bound to albumin and therefore not readily diffusible; a further 0.25 mmol per L is chelated, for example, by citrate. The metabolically important fraction is the remaining 1.3 mmol per L that is present as free Ca2+ ions.

Bone mineral is largely calcium phosphate, in the form of hydroxyapatite [Ca10(PO4)6(OH)2], although it also contains carbonate and citrate, as well as magnesium and traces of fluoride and strontium. The mineral has a very fine crystal structure, and hence a large surface area; as discussed in Section 5.3.3, the function of osteocalcin, the y -carboxyglutamate-containing calcium binding protein in the bone matrix, is to modify crystallization of bone mineral. The maintenance of bone structure is because of the balanced activity of os-teoclasts, which erode existing bone mineral and organic matrix. Osteoblasts synthesize and secrete the proteins of the bone matrix and also have resorptive activity. Mineralization of the organic matrix seems to be largely controlled by the availability of adequate concentrations of calcium and phosphate, modulated by osteocalcin.

Osteoblasts also synthesize and secrete into the bone matrix a variety of compounds that modify the responsiveness of osteoclasts to inhibition by calcitonin and prostaglandins. They have both nuclear and cell surface receptors for calcitriol, as well as receptors for parathyroid hormone, glucocorticoids, epidermal growth factor, prostaglandins, estrogens, and androgens. They are susceptible to multiple hormonal modulation of activity. In response to cal-citriol, they show decreased synthesis of collagen and alkaline phosphatase, and increased synthesis of osteocalcin and osteopontin. These are genomic responses associated with nuclear receptors. There are also rapid (nongenomic) responses mediated by cell surface receptors that include activation of voltage-gated calcium channels, induction of phospholipid and sphingolipid turnover, an increase in intracellular calcium, and priming of parathyroid hormonesensitive ion channels, as well as second messenger cascades. There is also a slower, nongenomic response to calcitriol, with a time course of 1 to 3 hours and phosphorylation of a variety of secreted proteins, including osteopontin (Farach-Carson and Ridall, 1998).

Physiologically, the response of bone to calcitriol is resorption of bone mineral and matrix protein. Both calcitriol and parathyroid hormone increase bone resorption in vivo and in bone organ culture, but have no effect on the activity of isolated osteoblasts. In addition to direct stimulation of the resorptive activity of osteoblasts, calcitriol increases osteoclastic activity. This is not because of a direct effect of calcitriol on osteoclasts, which lack calcitriol receptors, but rather an increase in the differentiation of osteoclast precursor cells into mature osteoclasts. It is not known whether osteoclast precursors respond directly to calcitriol, or whether the effect is indirect, mediated by calcitriol-responsive leukocytes or osteoblasts. Osteoblasts stimulated by calcitriol or parathyroid hormone secrete one ormore smallproteins thatincrease the activity of osteoclasts (Bar-Shavit et al., 1983).

Osteoclastic activity is inhibited by calcitonin and prostaglandins I2, E1, and E2, all of which act directly on the osteoclast; there is some evidence that osteoblasts may synthesize and secrete some of the osteoclast inhibitory prostaglandins. Calcitriol and parathyroid hormone stimulation of osteoblast resorptive activity also cause the synthesis and release of a variety of growth factors from the osteoblasts. These accumulate in the bone and act as delayed activators of osteoblast proliferation and activation. Although the immediate response of osteoblasts to calcitriol is repression of the synthesis of collagen and alkaline phosphatase (Rowe and Kream, 1982), between 24 to 48 hours after calcitriol administration there is increased collagen synthesis, with both new mRNA synthesis and an increased rate of translation of the existing mRNA, and induction of alkaline phosphatase and osteocalcin (Franceschi et al., 1988; Boyan et al., 1989). Alkaline phosphatase may have an important role in mineralization by hydrolyzing pyrophosphate and ATP in the bone matrix, both of which are inhibitors of mineralization; inhibition of alkaline phosphatase inhibits calcification of cartilage in culture. The combined effect of the delayed autocrine activators of osteoblast proliferation released by parathyroid hormone or calcitriol-stimulated osteoblasts, and the delayed induction of collagen, osteocalcin, and alkaline phosphatase synthesis is thus to promote the formation and mineralization of new bone matrix to replace that resorbed.

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