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

Osteoarthritis is characterized by cartilage destruction, chronic inflammation, and subchondral sclerosis. Evidence showed that nuclear receptor family is closely associated with cartilage damage in an unclear molecular mechanism. Here, we investigated the role and molecular mechanism of the retinoic acid receptor-related orphan receptor-a (RORa), an important member of nuclear receptor, in regulating cartilage degradation and osteoarthritis pathogenesis. Investigation to osteoarthritis clinical specimen showed that the degree of RORa elevation is positively correlated with the severity of osteoarthritis and cartilage damage. In an in vivo osteoarthritis models induced by anterior crucial ligament transaction, intraarticularly injection of siRora adenovirus reversed the cartilage damage. RORa knock-down increased the protein expression level of anabolic factor such as type II collagen, Aggrecan, and decreased the expression of catabolic factor. RNA-seq data suggested IL-6/STAT3 pathway is significantly down-regulated. Mechanistically, RORa knock-down decreased the expression level of both IL-6 and phosphorylated STAT3. RORa exerted its effect on IL-6/STAT3 signaling in two different ways, which includes interaction with STAT3 and IL6 promoter. Taken together, our findings indicated the pivotal role of RORa/IL-6/STAT3 axis in osteoarthritis progression and confirmed RORa knock-down exerted therapeutic effect in human chondrocyte thus providing a potential drug target in osteoarthritis therapy. Overall design: mRNA profiles of Vehicle treated and SR3335 treated chondrocyte