Generation of 1, 25-dihydroxyvitamin D3 in Cyp27b1 knockout mice by treatment with 25-hydroxyvitamin D3 rescued their rachitic phenotypes. Issue 185 (January 2019)

• Record Type: Journal Article
• Authors: Nishikawa, Miyu; Yasuda, Kaori; Takamatsu, Masashi; Abe, Keisuke; Nakagawa, Kimie; Tsugawa, Naoko; Hirota, Yoshihisa; Tanaka, Kazuma; Yamashita, Shigeaki; Ikushiro, Shinichi; Suda, Tatsuo; Okano, Toshio; Sakaki, Toshiyuki
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 185(2019)
• Page Start: 71
• Page End: 79
• Publication Date: 2019-01
• Subjects: 25OHD3 25-hydroxyvitamin D3 -- 125(OH)2D3 1α, 25-dihydroxy vitamin D3 -- VDR vitamin D receptor -- PTH parathyroid hormone -- ADX adrenodoxin -- ADR adrenodoxin reductase -- CKD chronic kidney disease; Vitamin D -- 1α-hydroxylase -- CYP27B1 -- CYP27A1 -- Knockout mouse; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2018.07.012
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Daily treatment with 25(OH)D3 rescued rachitic phenotypes in the Cyp27b1 KO mice. 1, 25(OH)2 D3 was detected at a normal level in the plasma of Cyp27b1 KO mice. The most probable candidate of another 1α-hydroxylase is Cyp27a1. 25(OH)D3 may be useful for the treatment and prevention of osteoporosis. Abstract: We have reported that 25-hydroxyvitamin D3 [25(OH)D3 ] binds to vitamin D receptor and exhibits several biological functions directly in vitro. To evaluate the direct effect of 25(OH)D3 in vivo, we used Cyp27b1 knockout (KO) mice, which had no detectable plasma 1α, 25-dihydroxyvitamin D3 [1, 25(OH)2 D3 ] when fed a diet containing normal Ca and vitamin D. Daily treatment with 25(OH)D3 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)D3 administration. An elevated Cyp24a1 mRNA expression was observed in the kidneys, and plasma concentrations of Cyp24a1-dependent metabolites of 25(OH)D3 were increased. To our surprise, 1, 25(OH)2 D3 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)D3 showed normal growth, normal plasma levels of Ca, P, and parathyroid hormone, and normal bone mineral density. The curative effect of 25(OH)D3 was considered to depend on the de novo synthesis of 1, 25(OH)2 D3 in the Cyp27b1 KO mice. This suggests that another enzyme than Cyp27b1 is present for the 1, 25(OH)2 D3 synthesis. Interestingly, the liver mitochondrial fraction prepared from Cyp27b1 KO mice converted 25(OH)D3 to 1, 25(OH)2 D3 . The most probable candidate is Cyp27a1. Our findings suggest that 25(OH)D3 may be useful for the treatment and prevention of osteoporosis for patients with chronic kidney disease.