Aberrant growth plate development in VDR/RXR gamma double null mutant mice

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-acti vation 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 funct ionally redundant VDR. Although RXR gamma (-/-) mice exhibited no overt abn ormalities, VDR-/-/RXR gamma (-/-) mice appeared similar to VDR-/- mice, sh owing features typical of vitamin D-dependent rickets type II, including gr owth retardation, impaired bone formation, hypocalcemia, and alopecia. Howe ver, compared to VDR-/- mice, growth plate development in VDR-/-/RXR gamma (-/-) mutant mice was more severely impaired. Normalizing mineral ion homeo stasis through dietary supplementation with high calcium and phosphorous ef fectively prevented rachitic abnormalities, except for disarranged growth p lates in VDR-/-/RXR gamma (-/-) mutant mice, and alopecia in both VDR-/- an d VDR-/-RXR gamma (-/-) mutant mice. Histological analysis of VDR-/-/RXR ga mma (-/-) growth plates revealed that development of the hypertrophic chond rocytes was selectively impaired. Thus, our findings indicated that the com bined actions of VDR- and RXR gamma -mediated signals are essential for the normal development of growth plate chondrocytes, and raised the possibilit y that a functionally redundant VDR is present on chondrocytes as a heterod imer with RXR gamma.