title: Aberrant growth plate development in VDR/RXR gamma double null mutant mice.
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.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yagishita
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: K
authors.initials: K
authors.lastname: Sekine
authors.forename: Y
authors.initials: Y
authors.lastname: Uematsu
authors.forename: H
authors.initials: H
authors.lastname: Murayama
authors.forename: Y
authors.initials: Y
authors.lastname: Nagai
authors.forename: W
authors.initials: W
authors.lastname: Krezel
authors.forename: P
authors.initials: P
authors.lastname: Chambon
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: S
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001842:Bone and Bones / Q000473:pathology / Q000503:physiopathology; D019902:Chondrocytes / Q000473:pathology; D004032:Diet; D006132:Growth Plate / Q000254:growth & development* / Q000473:pathology; D006706:Homeostasis; D006984:Hypertrophy; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008903:Minerals / Q000008:administration & dosage / Q000378:metabolism; D010010:Osteoclasts / Q000502:physiology; D010641:Phenotype; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000172:deficiency* / Q000235:genetics; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
chemical_list: D008903:Minerals; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors