Johannes P T M van Leeuwen Marjolein van Driel and Hulbert A P Pols


Vitamin D is the major regulator of calcium homeostasis and protects the organism from calcium deficiency via effects on the intestine, kidney, parathyroid gland, and bone. Disturbances in the vitamin D endocrine system, for example, vitamin D-dependent rickets type I and type II, result in profound effects on the mineralization of bone. Also, recent studies with vitamin D receptor (VDR) knockout mice show effects on bone. It is questioned whether vitamin D has a direct effect on bone formation and mineralization. In rickets and in particular vitamin D receptor knockout mice, calcium supplementation restores bone mineralization. However, the vitamin D receptor (see Vitamin D Receptor section) is present in osteoblasts, and vitamin D affects the expression of various genes in osteoblasts (see Introduction: Osteoblasts and Effects of Vitamin D on Osteoblast Function and Mineralization sections). Vitamin D regulates the expression of genes and osteoblast activity not in an independent manner but often in interaction with other hormones and/or growth factors (see section titled Interaction of Vitamin D with Other Factors).

The most biologically active vitamin D molecule is 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), which is formed after two consecutive hydroxylations in the liver (C-25 position) and kidney (C-1a position) of skin-derived vitamin D3 (cholecalciferol). The vitamin D3 molecule can also be hydroxy-lated at the C-24 position resulting in 24,25-(OH)2D3 or 1,24,25-(OH)3D3. The 24-hydroxylation was generally considered the first step in the degradation cascade of vitamin D3. However, over the years data have accumulated that also metabolites formed in the C-24 hydroxylation cascade have biological activity (see Metabolism: 24-Hydroxylase Activity section).

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