Retinoic Acid-Related Orphan Nuclear Receptor Alpha Promotes Cartilage Degeneration in Osteoarthritis by Activating the Wnt/β-Catenin Pathway

Osteoarthritis (OA) is the most common degenerative joint disease. Recent evidence has shown that retinoic acid-related Orphan Nuclear Receptor alpha (RORα) plays an important role in OA pathogenesis. However, its downstream regulatory mechanisms remain to be elucidated. Alterations in chondrocyte extracellular matrix (ECM) metabolism were observed by overexpressing or knocking down RORα in OA chondrocyte models. The OA mouse model was induced by unstable medial meniscus surgery (DMM), and the RORα inhibitor SR3335 or AAV virus was injected intra-articularly into the mice. Furthermore, Col2a1-creERT2: RORα^flox/flox (RORα-KO) inducible conditional knockout mice were generated to elucidate the role of RORα in OA. Moreover, mRNA Sequencing was conducted to identify potential downstream regulatory mechanisms of RORα. The overexpression of RORα in chondrocytes induced ECM degradation in mouse chondrocytes and accelerated cartilage degeneration in mice. In contrast, treatment with SR3335 or knockdown of RORα in chondrocytes alleviated ECM degradation. Similarly, less cartilage degeneration was observed in intra-articular injections of SR3335 and in the RORα-KO mice. Mechanistically, cartilage degeneration was promoted by RORα through the activation of the Wnt/β-catenin pathway and the facilitation of the nuclear translocation of β-catenin. Notably, the Wnt/β-catenin pathway inhibitor XAV-939 ameliorated RORα-induced ECM degradation in chondrocytes. The expression of RORα is increased in OA, triggering an imbalance in cartilage ECM metabolism, which leads to cartilage degeneration. Notably, the Wnt/β-catenin signaling pathway plays a critical role in RORα-mediated regulation of ECM degradation in chondrocytes. In summary, the RORα-Wnt/β-catenin pathway axis is pivotal in the pathogenesis of OA.