The Bcr-Abl inhibitor DCC-2036 inhibits necroptosis and ameliorates osteoarthritis by targeting RIPK1 and RIPK3 kinases

Osteoarthritis (OA) is a chronic progressive degenerative joint disease. Owing to its complex pathogenesis, OA treatment is typically challenging. Necroptosis is a form of programmed cell death mainly mediated by the serine/threonine kinases, RIPK1 and RIPK3, and mixed lineage kinase-like domain (MLKL). In this study, we found that the multi-targeted kinase inhibitor DCC-2036 can inhibit TSZ (TNF-α, Smac mimetic, and z-VAD-FMK)-induced necroptosis of chondrocytes and synovial fibroblast cells (SFs). In addition, we found that oral DCC-2036 inhibited chondrocyte damage in a rat model of OA induced by intra-articular injection of monosodium iodoacetate (MIA). A mechanistic study showed that DCC-2036 directly inhibited the activities of RIPK1 and RIPK3 kinases to block necroptosis, inhibiting the inflammatory response and protecting chondrocytes. In summary, our research suggests that DCC-2036, a new necroptosis inhibitor targeting RIPK1 and RIPK3 kinase activity, may be useful for the clinical treatment of OA and provides a new direction for the research and treatment of OA. [Display omitted] •DCC-2036 ameliorates TSZ-induced necroptosis of chondrocytes.•DCC-2036 alleviates cartilage damage in MIA-induced OA model.•DCC-2036 inhibits necroptosis by targeting RIPK1 and RIPK3 kinase activity.•DCC-2036 improves TNF-α-IFN-γ-induced cytokine shock.