Vitamin D metabolism and action in human bone marrow stromal cells.
Vitamin D metabolites are important effectors of bone and mineral homeostasis. Extrarenal conversion of 25-hydroxyvitamin D (25OHD) to the biologically active form of vitamin D, 1 alpha,25-dihydroxyvitamin D [1,25(OH)(2)D] is catalyzed in several cell types by the 1 alpha-hydroxylase (CYP27B1), but little is known about the expression or regulation of CYP27B1 in human bones. We examined whether human bone marrow stromal cells (hMSCs, also known as mesenchymal stem cells) participate in vitamin D metabolism and whether vitamin D hydroxylases in hMSCs are influenced by the vitamin D status of the individual from whom the hMSCs were obtained. We also investigated the effects of vitamin D metabolites on osteoblast differentiation and the role of IGF-I in the regulation of CYP27B1. In a series of 27 subjects, vitamin D hydroxylases in hMSCs were expressed at different levels and were correlated with serum 25OHD, 1,25(OH)(2)D, and PTH. In vitro treatment with 25OHD up-regulated CYP27B1 and IGF-I in hMSCs; IGF-I also up-regulated CY27B1 expression and stimulated osteoblast differentiation. When hydroxylation of 25OHD was blocked by ketoconazole, a cytochrome P450 inhibitor, 25OHD was no longer able to induce CYP27B1 expression. In summary, these findings show that human bone marrow stromal cells have the molecular machinery both to metabolize and respond to vitamin D. We propose that circulating 25OHD, by virtue of its local conversion to 1,25(OH)(2)D catalyzed by basal CYP27B1 in hMSCs, amplifies vitamin D signaling through IGF-I up-regulation, which in turn induces CYP27B1 in a feed-forward mechanism to potentiate osteoblast differentiation initiated by IGF-I.
Zhou
Shuanhu
S
Department of Orthopedic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
LeBoff
Meryl S
MS
Glowacki
Julie
J
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002112:Calcifediol / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014807:Vitamin D / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology* / Q000502:physiology
D014807:Vitamin D; D007334:Insulin-Like Growth Factor I; D013250:Steroid Hydroxylases; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol