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Aberrant growth plate development in VDR/RXR gamma double null mutant mice
N Yagishita1, Y Yamamoto, T Yoshizawa
1Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
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.
Insights
Vitamin D receptor (VDR) and RXR gamma signaling are crucial for growth plate chondrocyte development. Combined VDR and RXR gamma deficiency severely impairs chondrocyte development, suggesting functional redundancy of VDR in these cells.
Area of Science:
- Endocrinology
- Molecular Biology
- Developmental Biology
Background:
- The Vitamin D Receptor (VDR) forms heterodimers with Retinoid X Receptors (RXRs), influencing gene transcription.
- RXR ligands may modulate the activity of VDR/RXR heterodimers.
- The specific role of RXR gamma in VDR signaling and its potential functional redundancy with VDR remain unclear.
Purpose of the Study:
- To investigate the combined actions of vitamin D and vitamin A signaling pathways.
- To explore the potential functional redundancy of the VDR in chondrocytes.
- To elucidate the role of VDR/RXR gamma heterodimers in skeletal development.
Main Methods:
- Generation of VDR/RXR gamma double null mutant mice.
- Phenotypic analysis of mutant mice, including assessment of growth, bone formation, mineral ion homeostasis, and alopecia.
- Histological examination of growth plate development, focusing on chondrocyte differentiation.
Main Results:
- RXR gamma null mutant mice showed no abnormalities, while VDR/RXR gamma double null mutant mice exhibited severe rickets-like symptoms, including growth retardation, impaired bone formation, hypocalcemia, and alopecia.
- Growth plate development was more severely affected in VDR(-/-)/RXR gamma(-/-) mice compared to VDR(-/-) mice.
- Dietary supplementation normalized mineral ion homeostasis but did not fully rescue growth plate disarray or alopecia, and hypertrophic chondrocyte development was selectively impaired in double mutants.
Conclusions:
- Combined VDR and RXR gamma signaling are essential for normal growth plate chondrocyte development.
- The findings suggest a potential functional redundancy of VDR on chondrocytes, possibly through heterodimerization with RXR gamma.
- RXR gamma plays a critical role in VDR-mediated functions, particularly in chondrocyte maturation.