We have reported that 25-hydroxyvitamin D 3 [25(OH)D 3 ] binds to vitamin D receptor and exhibits several biological functions directly in vitro. To evaluate the direct effect of 25(OH)D 3 in vivo, we used Cyp27b1 knockout (KO) mice, which had no detectable plasma 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] when fed a diet containing normal Ca and vitamin D. Daily treatment with 25(OH)D 3 at 250 μg kg -1 day -1 rescued rachitic phenotypes in the Cyp27b1 KO mice. Bone mineral density, female sexual cycles, and plasma levels of Ca, P, and PTH were all normalized following 25(OH)D 3 administration. An elevated Cyp24a1 mRNA expression was observed in the kidneys, and plasma concentrations of Cyp24a1-dependent metabolites of 25(OH)D 3 were increased. To our surprise, 1,25(OH) 2 D 3 was detected at a normal level in the plasma of Cyp27b1 KO mice. The F1 to F4 generations of Cyp27b1 KO mice fed 25(OH)D 3 showed normal growth, normal plasma levels of Ca, P, and parathyroid hormone, and normal bone mineral density. The curative effect of 25(OH)D 3 was considered to depend on the de novo synthesis of 1,25(OH) 2 D 3 in the Cyp27b1 KO mice. This suggests that another enzyme than Cyp27b1 is present for the 1,25(OH) 2 D 3 synthesis. Interestingly, the liver mitochondrial fraction prepared from Cyp27b1 KO mice converted 25(OH)D 3 to 1,25(OH) 2 D 3 . The most probable candidate is Cyp27a1. Our findings suggest that 25(OH)D 3 may be useful for the treatment and prevention of osteoporosis for patients with chronic kidney disease.
|ジャーナル||Journal of Steroid Biochemistry and Molecular Biology|
|出版ステータス||Published - 2019 1|
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