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Evidence that both 1α,25-dihydroxyvitamin D and 24-hydroxylated D enhance human osteoblast differentiation and mineralization

Journal of Cellular Biochemistry, ISSN: 0730-2312, Vol: 99, Issue: 3, Page: 922-935
2006
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Vitamin D plays a major role in the regulation of mineral homeostasis and affects bone metabolism. So far, detailed knowledge on the vitamin D endocrine system in human bone cells is limited. Here we investigated the direct effects of 1α,25-(OH)D on osteoblast differentiation and mineralization. Also, we studied the impact of 24-hydroxylation, generally considered as the first step in the degradation pathway of vitamin D, as well as the role of the nuclear and presumed membrane vitamin D receptor (VDR). For this we used a human osteoblast cell line (SV-HFO) that has the potency to differentiate during culture forming a mineralized extracellular matrix in a 3-week period. Transcriptional analyses demonstrated that both 1α,25-(OH)D and the 24-hydroxylated metabolites 24R,25-(OH)D and 1α,24R,25-(OH)D induced gene transcription. All metabolites dose-dependently increased alkaline phosphatase (ALP) activity and osteocalcin (OC) production (protein and RNA), and directly enhanced mineralization. 1α,24R,25-(OH) D stimulated ALP activity and OC production most potently, while for mineralization itwasequipotentto 1α,25-(OH) D. The nuclear VDR antagonist ZK159222 almost completely blocked the effects of all metabolites. Interestingly, 1α,25-(OH) D, an inhibitor of membrane effects of 1α,25-(OH)D in the intestine, induced gene transcription and increased ALP activity, OC expression and mineralization. In conclusion, not only 1α,25-(OH)D, but also the presumed 24-hydroxylated "degradation" products stimulate differentiation of human osteoblasts. 1α,25-(OH)D as well as the 24-hydroxylated metabolites directly enhance mineralization, with the nuclear VDR playing a central role. The intestinal antagonist 1β,25-(OH)D acts in bone as an agonist and directly stimulates mineralization in a nuclear VDR-dependent way. © 2006 Wiley-Liss, Inc.

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