TNFAIP3 derived from skeletal stem cells alleviated rat osteoarthritis by inhibiting the necroptosis of subchondral osteoblasts

Abstract Recent investigations have shown that the necroptosis of tissue cells in joints is important in the development of osteoarthritis (OA). The present study aimed to investigate the potential effects of exogenous skeletal stem cells (SSCs) on the necroptosis of subchondral osteoblasts in OA. Human SSCs and subchondral osteoblasts isolated from human tibia plateaus were used for Western Blotting, real-time PCR, RNA sequencing, gene editing, and necroptosis detection assays. In addition, rat anterior cruciate ligament transection OA model were used to evaluate the effects of SSCs on osteoblast necroptosis in vivo. The micro-CT and pathological data showed that intra-articular injections of SSCs significantly improved the microarchitecture of subchondral trabecular bones in OA rats. Additionally, SSCs inhibited the necroptosis of subchondral osteoblasts in OA rats and necropotic cell models. The results of bulk RNA sequencing of SSCs stimulated or not by tumor necrosis factor α suggested a correlation of SSCs derived tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and cell necroptosis. Furthermore, TNFAIP3 derived from SSCs contributed to the inhibition of the subchondral osteoblast necroptosis in vivo and in vitro. Moreover, the intra-articular injections of TNFAIP3-overexpressing SSCs further improved the subchondral trabecular bone remodeling of OA rats. Thus, we report that TNFAIP3 from SSCs contributed to the suppression on the subchondral osteoblast necroptosis, which suggest that necropotic subchondral osteoblasts in joints may be possible targets to treat OA by stem cell therapy.