Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathway

Osteoarthritis (OA) is characterized by cartilage destruction, chronic inflammation, and local pain. Evidence showed that retinoic acid receptor-related orphan receptor-alpha (ROR alpha) is crucial in cartilage development and OA pathogenesis. Here, we investigated the role and molecular mechanism of ROR alpha, an important member of the nuclear receptor family, in regulating the development of OA pathologic features. Investigation into clinical cartilage specimens showed that ROR alpha expression level is positively correlated with the severity of OA and cartilage damage. In an in vivo OA model induced by anterior crucial ligament transaction, intra-articular injection of si-Rora adenovirus reversed the cartilage damage. The expression of cartilage matrix components type II collagen and aggrecan were elevated upon ROR alpha blockade. RNA-seq data suggested that the IL-6/STAT3 pathway is significantly downregulated, manifesting the reduced expression level of both IL-6 and phosphorylated STAT3. ROR alpha exerted its effect on IL-6/STAT3 signaling in two different ways, including interaction with STAT3 and IL-6 promoter. Taken together, our findings indicated the pivotal role of the ROR alpha/IL-6/STAT3 axis in OA progression and confirmed that ROR alpha blockade improved the matrix catabolism in OA chondrocytes. These results may provide a potential treatment target in OA therapy.

Automated summary

Evidence suggests that ROR alpha plays a crucial role in cartilage development and OA pathogenesis by regulating the expression of cartilage matrix components. Blocking ROR alpha can reverse cartilage damage and elevate the expression of cartilage matrix components. Additionally, ROR alpha affects the IL-6/STAT3 signaling pathway, highlighting its potential as a treatment target in OA therapy.