The active form of
vitamin D, 1α,25-dihydroxyvitamin D3 (1α,25D3), 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,25D3 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,25D3 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,25D3 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,25D3. 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.