The Retinoid X Receptor Alpha Modulator K-80003 Suppresses Inflammatory And Catabolic Responses In A Rat Model Of Osteoarthritis

Osteoarthritis (OA), a most common and highly prevalent joint disease, is closely associated with dysregulated expression and modification of RXR alpha. However, the role of RXR alpha in the pathophysiology of OA remains unknown. The present study aimed to investigate whether RXR alpha modulator, such as K-80003 can treat OA. Experimental OA was induced by intra-articular injection of monosodium iodoacetate (MIA) in the knee joint of rats. Articular cartilage degeneration was assessed using Safranin-O and fast green staining. Synovial inflammation was measured using hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay (ELISA). Expressions of MMP-13, ADAMTS-4 and ER alpha in joints were analyzed by immunofluorescence staining. Western blot, RT-PCR and co-Immunoprecipitation (co-IP) were used to assess the effects of K-80003 on RXR alpha-ER alpha interaction. Retinoid X receptor alpha (RXR alpha) modulator K-80003 prevented the degeneration of articular cartilage, reduced synovial inflammation, and alleviated osteoarthritic pain in rats. Furthermore, K-80003 markedly inhibited IL-1 beta-induced p65 nuclear translocation and I kappa B alpha degradation, and down-regulate the expression of HIF-2 alpha, proteinases (MMP9, MMP13, ADAMTS-4) and pro-inflammatory factors (IL-6 and TNF alpha) in primary chondrocytes. Additionally, knockdown of ER alpha with siRNA blocked these effects of K-80003 in chondrocytes. In conclusion, RXR alpha modulators K-80003 suppresses inflammatory and catabolic responses in OA, suggesting that targeting RXR alpha-ER alpha interaction by RXR alpha modulators might be a novel therapeutic approach for OA treatment.