Regulation of Vitamin D Metabolism

The main physiological function of vitamin D is in the control of calcium homeostasis, and vitamin D metabolism is regulated largely by the state of calcium balance. The main regulation of vitamin D metabolism is by control of the activities of calcidiol 1-hydroxylase and 24-hydroxylase, and hence the fate of calcidiol. In general, factors that increase the activity of one of the hydroxylases simultaneously reduce the activity of the other. Although plasma calcitriol is relatively constant throughout the year, 24-hydroxycalcidiol shows a seasonal fluctuation that reflects that of calcidiol.

3.2.8.1 Calcitriol The major determinant of the relative activities of calcidiol 1-hydroxylase and 24-hydroxylase is the availability of calcitriol. In vitamin D-deficient animals, with low circulating concentrations of calcitriol, the activity of 1-hydroxylase in the kidneys is maximal. There is little or no detectable 24-hydroxylase activity. Both in vivo and in isolated kidney cells in culture, the addition of calcitriol results in induction of the 24-hydroxylase and repression of 1-hydroxylase; removal of calcitriol from the culture medium results in induction of 1-hydroxylase and repression of 24-hydroxylase.

3.2.8.2 Parathyroid Hormone Parathyroid hormone raises plasma calcium by direct effects on bone resorption and renal reabsorption of calcium, and indirectly by regulating the metabolism of vitamin D. It is a peptide and acts via cell surface G-protein receptors linked to adenylate cyclase. The parathyroid glands have G-protein cell surface calcium receptors linked to phospholipase C, and parathyroid hormone is secreted in response to hypocalcemia. Magnesium is required for secretion of the hormone, which may explain the development of hypocalcemia in premature infants who are magnesium deficient.

In the kidneys, parathyroid hormone increases 1-hydroxylation of calcidiol and reduces 24-hydroxylation. This is not the result of de novo enzyme synthesis, but an effect on the activity of the preformed enzymes, mediated by cAMP-dependent protein kinases. In turn, calcitriol has a direct role in the control of parathyroid hormone, acting to repress expression of the gene. In chronic renal failure, there is reduced synthesis of calcitriol, leading to the development of secondary hyperparathyroidism that results in excess mobilization of bone mineral, hypercalcemia, hypercalciuria, hyperphosphaturia, and the development of calcium phosphate renal stones.

3.2.8.3 Calcitonin Calcitonin is secreted by the C cells of the thyroid gland in response to hypercalcemia. Its primary action is to oppose the actions of parathyroid hormone by suppressing osteoclast actions. It also stimulates calcidiol 1-hydroxylation in the kidney. Two separate mechanisms seem to be involved: (1) a rapid increase in the activity of 1-hydroxylase, mediated by a cAMP-dependent protein kinase, and (2) a slower response that involves de novo enzyme synthesis. Isolated kidney cells in culture do not respond to calcitonin. The effect is not seen when calcitonin is given to thyro-para-thyroidectomized animals. This suggests that calcitonin may act indirectly, via actions on the parathyroid gland and parathyroid hormone secretion, rather than directly on calcidiol hydroxylases.

3.2.8.4 Plasma Concentrations of Calcium and Phosphate Although the main response to changes in plasma calcium is a change in the secretion of parathyroid hormone, the activity of calcidiol 1-hydroxylase in kidney slices is decreased directly by high concentrations of calcium in the incubation medium. Calcium has no direct effect on the activity of calcidiol 24-hydroxylase under these conditions. Strontium and cadmium also inhibit calcidiol 1-hydroxylase.

The serum concentration of calcitriol varies inversely with phosphate throughout the day. Feeding subjects on low phosphate diets leads to a fall in serum phosphate and an increase in circulating calcitriol. It is not clear whether or not this is a direct effect of phosphate on the kidney hydroxylases.

3.3 METABOLIC FUNCTIONS OF VITAMIN D

The principal physiological role of vitamin D is in the maintenance of the plasma concentration of calcium. Calcitriol acts to increase intestinal absorption of calcium, to reduce its excretion by increasing reabsorption in the distal renal tubule, and to mobilize the mineral from bone - of the 25 mol of calcium in the adult body, 99% is in bone. The daily intake of calcium is around 25 mmol, and intestinal secretions add an additional 7 mmol to the intestinal contents; 10 to 14 mmol of this is normally absorbed, with 18 to 22 mmol excreted in feces. Bone turnover accounts for exchange of 10 mmol of calcium between bone and plasma daily. The kidneys filter some 240 mmol of calcium daily, almost all of which is reabsorbed; urinary excretion of calcium is about 3 to 7 mmol per day.

Calcitriol acts like a steroid hormone, binding to, and activating, nuclear receptors that modulate gene expression. More than 50 genes are known to be regulated by calcitriol (see Table 3.3), but vitamin D response elements have only been identified in a relatively small number, including: calcidiol 1-hydroxylase and 24-hydroxylase; calbindin, a calcium binding protein in the

Table 3.3 Genes Regulated by Calcitriol Increased Expression

Decreased Expression

Vitamin D

Calcitriol receptor

metabolism

Calcidiol 1-hydroxylase

Calcidiol 24-hydroxylase

Mineral

Calbindin D

Preproparathyroid hormone

metabolism

Osteocalcin

Transferrin receptor

Osteopontin

Plasma membrane calcium pump

Metallothionein

Energy

Glyceraldehyde 3-phosphate

Fatty acid binding protein

metabolism

dehydrogenase

ATP synthase

NADH dehydrogenase subunit I

NADH dehydrogenase subunit II

NADH dehydrogenase subunit IV

Cytochrome oxidase

Cytochrome b

Protein kinase C

Protein kinase inhibitor

Ferredoxin

Regulatory

Nerve growth factor

Histone H4

peptides

Interleukin I

Interleukin II

Interleukin 6

Interleukin III receptor

Cachexin (tumor necrosis factor-a)

7 -Interferon

Monocyte-derived

Granulocyte-macrophage

neutrophil-activating peptide

colony stimulating factor

Cytoskeleton

Fibronectin

a-tubulin

Osteoclast integrin

Oncogenes

c-fms, c-fos, c-ki-ras, c-myc

c-myc

Type I collagen

Source: From data reported by Hannah and Norman, 1994.

intestinal mucosa and other tissues; the vitamin K-dependent protein osteocalcin in bone (Section 5.3.3); and osteopontin, which permits the attachment of osteoclasts to bone surfaces and the osteoclast cell membrane isoform of integrin. In addition, calcitriol affects the secretion of insulin and the synthesis and secretion of parathyroid and thyroid hormones - these actions may be secondary to changes in intracellular calcium concentrations resulting from induction of calbindin.

Calcitriol also has a role in the regulation of cell proliferation and differentiation. In addition to genomic actions, it has a variety of actions that are because of interaction with cell surface G-protein receptors.

24-Hydroxycalcidiol is also biologically active. In hypocalcemic vitamin D-deficient chicks, calcitriol alone does not reverse the hypertrophy of the parathyroid gland; 24-hydroxycalcidiol, together with calcitriol, does - although alone it has no effect (Henry et al., 1977). In hens raised to maturity with calcitriol as the sole source of vitamin D, although the fertility of the eggs is unimpaired, hatchability is greatly reduced and can be restored by feeding 24-hydroxycalcidiol, together with calcitriol (Henry and Norman, 1978). 24-Hydroxycalcidiol also has biological activity in cartilage. Isolated chondrocytes show increased formation of proteoglycans in response to both calcitriol and 24-hydroxycalcidiol. Studies of knockout mice lacking the 24-hydroxylase show that 24-hydroxycalcidiol has a role in intramembranous bone formation during development (St-Arnaud, 1999; van Leeuwen et al., 2001).

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