Generation of 1,25-dihydroxyvitamin D3 in Cyp27b1 knockout mice by treatment with 25-hydroxyvitamin D3 rescued their rachitic phenotypes

Miyu Nishikawa, Kaori Yasuda, Masashi Takamatsu, Keisuke Abe, Kimie Nakagawa, Naoko Tsugawa, Yoshihisa Hirota, Kazuma Tanaka, Shigeaki Yamashita, Shinichi Ikushiro, Tatsuo Suda, Toshio Okano, Toshiyuki Sakaki

Research output: Contribution to journalArticle

2 Citations (Scopus)

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)2D3] 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)2D3 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)2D3 in the Cyp27b1 KO mice. This suggests that another enzyme than Cyp27b1 is present for the 1,25(OH)2D3 synthesis. Interestingly, the liver mitochondrial fraction prepared from Cyp27b1 KO mice converted 25(OH)D3 to 1,25(OH)2D3. 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.

Original languageEnglish
JournalJournal of Steroid Biochemistry and Molecular Biology
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Calcifediol
Calcitriol
Plasmas
Minerals
Bone
Calcitriol Receptors
Nutrition
Metabolites
Parathyroid Hormone
Vitamin D
Liver
Messenger RNA
Enzymes

Keywords

  • 1α-hydroxylase
  • CYP27A1
  • CYP27B1
  • Knockout mouse
  • Vitamin D

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Generation of 1,25-dihydroxyvitamin D3 in Cyp27b1 knockout mice by treatment with 25-hydroxyvitamin D3 rescued their rachitic phenotypes. / 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.

In: Journal of Steroid Biochemistry and Molecular Biology, 01.01.2018.

Research output: Contribution to journalArticle

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. / Generation of 1,25-dihydroxyvitamin D3 in Cyp27b1 knockout mice by treatment with 25-hydroxyvitamin D3 rescued their rachitic phenotypes. In: Journal of Steroid Biochemistry and Molecular Biology. 2018.
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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)2D3] 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)2D3 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)2D3 in the Cyp27b1 KO mice. This suggests that another enzyme than Cyp27b1 is present for the 1,25(OH)2D3 synthesis. Interestingly, the liver mitochondrial fraction prepared from Cyp27b1 KO mice converted 25(OH)D3 to 1,25(OH)2D3. 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.",
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AU - Nishikawa, Miyu

AU - Yasuda, Kaori

AU - Takamatsu, Masashi

AU - Abe, Keisuke

AU - Nakagawa, Kimie

AU - Tsugawa, Naoko

AU - Hirota, Yoshihisa

AU - Tanaka, Kazuma

AU - Yamashita, Shigeaki

AU - Ikushiro, Shinichi

AU - Suda, Tatsuo

AU - Okano, Toshio

AU - Sakaki, Toshiyuki

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KW - Knockout mouse

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