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

Sci Rep. 2020 Mar 30;10(1):5677. doi: 10.1038/s41598-020-62048-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics
  • Animals
  • Calcifediol / genetics
  • Calcifediol / metabolism
  • Calcitriol / pharmacology
  • Disease Models, Animal
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, Calcitriol / genetics*
  • Receptors, Calcitriol / metabolism*
  • Rickets / metabolism
  • Vitamin D / analogs & derivatives
  • Vitamin D / genetics
  • Vitamin D / metabolism*
  • Vitamin D3 24-Hydroxylase / genetics


  • Receptors, Calcitriol
  • dihydroxy-vitamin D3
  • Vitamin D
  • 1,25-dihydroxyvitamin D
  • Vitamin D3 24-Hydroxylase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • Calcitriol
  • Calcifediol