THE ROLE OF RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR ALPHA IN CHONDROCYTE DIFFERENTIATION

Endochondral bone formation is regulated by transcription factors and signaling molecules. The retinoic acid receptor-related orphan receptor alpha, RORa, is involved in tissue differentiation. RORa gene expression is upregulated during chondrocyte hypertrophy. Cholesterol, a RORa ligand, promotes chondrocyte hypertrophy and stimulates expression of lipid metabolism genes. My objective was to examine the role of RORa during chondrocyte differentiation and in the regulation of lipid metabolism genes. Treatment of organ cultures with T0901317, a RORa inverse agonist, resulted in growth impairment, decreased hypertrophic zone length and delayed chondrocyte cell cycle exit. In micromass culture T0901317 treatment reduced chondrocyte differentiation and expression of hypertrophic differentiation markers. Lpl, a putative target of RORa, showed decreased expression upon T0901317 treatment in vitro. RORa overexpression in ATDC5 cells decreased Lpl expression. Overall, T0901317 treatment affects chondrocyte hypertrophy. This suggests that RORa is important for chondrocyte hypertrophy, potentially through control of lipid metabolism genes