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

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.