Nongenomic effects of 1α,25-dihydroxyvitamin D on cartilage formation deduced from comparisons between Cyp27b1 and Vdr knockout mice.

The active form of vitamin D, 1α,25-dihydroxyvitamin D (1α,25D), plays an important role in the maintenance of calcium (Ca) homeostasis, bone formation, and cell proliferation and differentiation via nuclear vitamin D receptor (VDR). It is formed by the hydroxylation of vitamin D at the 1α position by 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) in the kidney. However, Cyp27b1 mice, deficient in CYP27B1, and VDR-deficient mice (Vdr) have not been extensively examined, particularly in a comparative framework. To clarify the physiological significance of 1α,25D and VDR, we produced Cyp27b1 mice and compared their phenotypes with those of Vdr mice. Cyp27b1 mice exhibited hypocalcemia, growth defects, and skeletogenesis dysfunction, similar to Vdr mice. However, unlike Cyp27b1 mice, Vdr mice developed alopecia. Cyp27b1 mice exhibited cartilage mass formation and had difficulty walking on hindlimbs. Furthermore, a phenotypic analysis was performed on Cyp27b1 mice provided a high Ca diet to correct for the Ca metabolic abnormality. In addition, the effects of 1α,25D that are not mediated by Ca metabolic regulatory activity were investigated. Even when the blood Ca concentration was corrected, abnormalities in growth and cartilage tissue formation did not improve in Cyp27b1 mice. These results suggested that 1α,25D directly controls chondrocyte proliferation and differentiation. Using Cyp27b1 mice produced in this study, we can analyze the physiological effects of novel vitamin D derivatives in the absence of endogenous 1α,25D. Accordingly, this study provides a useful animal model for the development of novel vitamin D formulations that are effective for the treatment and prevention of osteoporosis.