Department of Orthopedic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
Endocrinology. 2010 Jan;151(1):14-22. doi: 10.1210/en.2009-0969. Epub 2009 Dec 4.
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.
维生素 D 代谢物是骨和矿物质稳态的重要效应物。在几种细胞类型中，肾脏外的 25-羟维生素 D（25OHD）向维生素 D 的生物活性形式 1α,25-二羟维生素 D [1,25(OH)(2)D]的转化由 1α-羟化酶（CYP27B1）催化，但关于人骨中 CYP27B1 的表达或调节知之甚少。我们检查了人骨髓基质细胞（hMSCs，也称为间充质干细胞）是否参与维生素 D 代谢，以及 hMSCs 中的维生素 D 羟化酶是否受到 hMSCs 来源个体维生素 D 状态的影响。我们还研究了维生素 D 代谢物对成骨细胞分化的影响以及 IGF-I 在调节 CYP27B1 中的作用。在一系列 27 名受试者中，hMSCs 中的维生素 D 羟化酶表达水平不同，并与血清 25OHD、1,25(OH)(2)D 和 PTH 相关。体外用 25OHD 处理可上调 hMSCs 中的 CYP27B1 和 IGF-I；IGF-I 还上调 CYP27B1 表达并刺激成骨细胞分化。当用细胞色素 P450 抑制剂酮康唑阻断 25OHD 的羟化时，25OHD 不再能够诱导 CYP27B1 表达。总之，这些发现表明人骨髓基质细胞具有代谢和响应维生素 D 的分子机制。我们提出，循环 25OHD 通过其在 hMSCs 中由基础 CYP27B1 催化的局部转化为 1,25(OH)(2)D，通过 IGF-I 的上调放大维生素 D 信号，从而通过正反馈机制诱导 CYP27B1，以增强 IGF-I 启动的成骨细胞分化。
