Osteoclastic Metabolism of 25(OH)-Vitamin D3: A Potential Mechanism for Optimization of Bone Resorption
Vitamin D plays an important role in the maintenance of optimal bone mineralization. Besides its role in phosphate and calcium homeostasis, it is now recognized that vitamin D acts directly on bone cells. 1alpha,25 hydroxyvitamin D3 (1,25D), which is produced by the hydroxylation of 25 hydroxyvitamin D3 (25D) by the enzyme 1-alpha-hydroxylase, directly stimulates bone resorption and increases osteoblast-mediated osteoclastogenesis. The major site of vitamin D hydroxylation is the kidney. However, several cell types, including osteoblasts, express 1-alpha-hydroxylase, thereby enabling local production of the fully active 1,25D. Whether osteoclasts are able to convert 25D directly to 1,25D and the function of such a conversion in bone homeostasis remain undetermined.
Kogawa and co-workers [1] investigated the expression and function of 1-alpha-hydroxylase in osteoclasts. In vitro, osteoclasts differentiated from peripheral blood mononuclear cells express 1-alpha-hydroxylase and are able to convert 25D to 1,25D. Moreover, addition of 25D enhances osteoclast size as well as the expression of several key osteoclast genes including Nfat1c, c-Fos, type II carbonic anhydrase, and OSCAR. Accordingly, 1-alpha-hydroxylase gene knockdown with short hairpin RNA reduces in vitro osteoclast differentiation. Surprisingly, whereas 1,25D and 25D favor osteoclast differentiation, both reduce bone resorption by osteoclasts in vitro. Similarly, osteoclasts from mice lacking the gene for vitamin D receptor have increased bone-resorbing activity when compared with those from wild-type mice.
These results suggest that intrinsic vitamin D metabolism influences osteoclast differentiation and activity.
- Kogawa M, et al. Endocrinology. 2010;151:4613-4625
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