Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions

Miyu Nishikawa, Kaori Yasuda, Masashi Takamatsu, Keisuke Abe, Kairi Okamoto, Kyohei Horibe, Hiroki Mano, Kimie Nakagawa, Naoko Tsugawa, Yoshihisa Hirota, Tetsuhiro Horie, Eiichi Hinoi, Toshio Okano, Shinichi Ikushiro, Toshiyuki Sakaki

Research output: Contribution to journalArticle

Abstract

Recent studies have suggested that vitamin D activities involve vitamin D receptor (VDR)-dependent and VDR-independent effects of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 25-hydroxyvitamin D3 (25(OH)D3) and ligand-independent effects of the VDR. Here, we describe a novel in vivo system using genetically modified rats deficient in the Cyp27b1 or Vdr genes. Type II rickets model rats with a mutant Vdr (R270L), which recognizes 1,25(OH)2D3 with an affinity equivalent to that for 25(OH)D3, were also generated. Although Cyp27b1-knockout (KO), Vdr-KO, and Vdr (R270L) rats each showed rickets symptoms, including abnormal bone formation, they were significantly different from each other. Administration of 25(OH)D3 reversed rickets symptoms in Cyp27b1-KO and Vdr (R270L) rats. Interestingly, 1,25(OH)2D3 was synthesized in Cyp27b1-KO rats, probably by Cyp27a1. In contrast, the effects of 25(OH)D3 on Vdr (R270L) rats strongly suggested a direct action of 25(OH)D3 via VDR-genomic pathways. These results convincingly suggest the usefulness of our in vivo system.

Original languageEnglish
Article number5677
JournalScientific Reports
Volume10
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions'. Together they form a unique fingerprint.

  • Cite this

    Nishikawa, M., Yasuda, K., Takamatsu, M., Abe, K., Okamoto, K., Horibe, K., Mano, H., Nakagawa, K., Tsugawa, N., Hirota, Y., Horie, T., Hinoi, E., Okano, T., Ikushiro, S., & Sakaki, T. (2020). Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions. Scientific Reports, 10(1), [5677]. https://doi.org/10.1038/s41598-020-62048-1