Aberrant Growth Plate Development in VDR/RXR Gamma Double Null Mutant Mice

Endocrinology. 2001 Dec;142(12):5332-41. doi: 10.1210/endo.142.12.8544.

Abstract

VDR forms heterodimers with one of three RXRs, RXR alpha, RXR beta, and RXR gamma, and it is thought that RXR ligands can also modulate the trans-activation function of VDR/RXR heterodimers. In the present study we generated VDR/RXR gamma double null mutant mice to examine the convergent actions of vitamin D and vitamin A signaling and to explore the possibility of a functionally redundant VDR. Although RXR gamma(-/-) mice exhibited no overt abnormalities, VDR(-/-)/RXR gamma(-/-) mice appeared similar to VDR(-/-) mice, showing features typical of vitamin D-dependent rickets type II, including growth retardation, impaired bone formation, hypocalcemia, and alopecia. However, compared to VDR(-/-) mice, growth plate development in VDR(-/-)/RXR gamma(-/-) mutant mice was more severely impaired. Normalizing mineral ion homeostasis through dietary supplementation with high calcium and phosphorous effectively prevented rachitic abnormalities, except for disarranged growth plates in VDR(-/-)/RXR gamma(-/-) mutant mice, and alopecia in both VDR(-/-) and VDR(-/-)/RXR gamma(-/-) mutant mice. Histological analysis of VDR(-/-)/RXR gamma(-/-) growth plates revealed that development of the hypertrophic chondrocytes was selectively impaired. Thus, our findings indicated that the combined actions of VDR- and RXR gamma-mediated signals are essential for the normal development of growth plate chondrocytes, and raised the possibility that a functionally redundant VDR is present on chondrocytes as a heterodimer with RXR gamma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Bone and Bones / pathology
  • Bone and Bones / physiopathology
  • Chondrocytes / pathology
  • Diet
  • Growth Plate / growth & development*
  • Growth Plate / pathology
  • Homeostasis
  • Hypertrophy
  • Mice
  • Mice, Knockout / genetics
  • Minerals / administration & dosage
  • Minerals / metabolism
  • Osteoclasts / physiology
  • Phenotype
  • Receptors, Calcitriol / deficiency*
  • Receptors, Calcitriol / genetics
  • Receptors, Retinoic Acid / deficiency*
  • Receptors, Retinoic Acid / genetics
  • Retinoid X Receptors
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics

Substances

  • Minerals
  • Receptors, Calcitriol
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors