The Orphan Nuclear Estrogen Receptor-Related Receptor-α Regulates Cartilage Formationin Vitro: Implication of Sox9

We report for the first time the expression of estrogen receptor-related receptor (ERR)-alpha in fetal and adult rat chondrocytes in growth plate and articular cartilage and the rat chondrogenic cell line C5.18 cells in vitro. ERRalpha mRNA and protein were expressed from proliferating chondrocyte to mature chondrocyte stages. We show that overexpressing ERRalpha in C5.18 cell cultures induces an increase in Sry-type high-mobility-group box transcription factor (Sox)-9 expression, a master gene in cartilage formation. In parallel, we report Sox9 promoter regulation by ERRalpha in C5.18 cells. To assess a functional role for ERRalpha in chondrogenesis, its expression was blocked by antisense oligonucleotides in C5.18 cell cultures, and this led to inhibition of cartilage formation associated with down-regulation of Sox9 and Indian hedgehog expression and maturation of proliferating chondrocytes into hypertrophic chondrocytes in vitro. Together these results implicate ERRalpha in the formation and maintenance of cartilage and also suggest that agonists and antagonists of ERRalpha may be useful as therapeutic agents in a wide variety of diseases affecting cartilage and joints.