Evidence that both 1 alpha,25-dihydroxyvitamin D-3 and 24-hydroxylated D-3 enhance human osteoblast differentiation and mineralization

M. van Driel, M. Koedam, C. J. Buurman, M. Roelse, F. Weyts, H. Chiba, A. G. Uitterlinden, H. A. P. Pols, J. P. T. M. Van Leeuwen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Vitamin D playsa 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 1 alpha,25-(OH)(2)D-3 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 1 alpha,25-(OH)(2)D-3 and the 24-hydroxylated metabolites 24R,25-(OH)(2)D-3 and 1 alpha,24R,25-(OH)(3)D-3 induced gene transcription. All metabolites dose-dependently increased alkaline phosphatase (ALP) activity and osteocalcin (OC) production (protein and RNA), and directly enhanced mineralization. 1 alpha,24R,25-(OH)(3)D-3 stimulated ALP activity and OC production most potently, while for mineralization it was equipotent to 1 alpha,25(OH)(2)D-3. The nuclear VDR antagonist ZK159222 almost completely blocked the effects of all metabolites. Interestingly, 1 beta,25-(OH)(2)D-3, an inhibitor of membrane effects of 1 alpha,25-(OH)(2)D-3 in the intestine, induced gene transcription and increased ALP activity, OC expression and mineralization. In conclusion, not only 1 alpha,25-(OH)(2)D-3, but also the presumed 24-hydroxylated "degradation" products stimulate differentiation of human osteoblasts. 1 alpha,25-(OH)(2)D-3 aswell as the 24-hydroxylated metabolites directly enhance mineralization, with the nuclear VDR playing a central role. The intestinal antagonist 1 beta,25-(OH)(2)D-3 acts in bone as an agonist and directly stimulates mineralization in a nuclear VDR-dependent way.
Original languageEnglish
Pages (from-to)922-935
Number of pages14
JournalJournal of Cellular Biochemistry
Volume99
Issue number3
DOIs
Publication statusPublished - 15 Oct 2006

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