Li Xiao-Tong, Li Zhi-Ling, Li Pei-Lin, Wang Fei-Yan, Zhang Xiao-Yu, Wang Yu-Xing, Zhao Zhi-Dong, Yin Bo-Feng, Hao Rui-Cong, Mao Ning, Xia Wen-Rong, Ding Li, Zhu Heng
Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
Stem Cells. 2024 Apr 15;42(4):360-373. doi: 10.1093/stmcls/sxad097.
Recent investigations have shown that the necroptosis of tissue cells in joints is important in the development of osteoarthritis (OA). This 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, the rat anterior cruciate ligament transection OA model was 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 necroptotic 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 α-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 of the subchondral osteoblast necroptosis, which suggests that necroptotic subchondral osteoblasts in joints may be possible targets to treat OA by stem cell therapy.
近期研究表明，关节组织细胞的坏死性凋亡在骨关节炎（OA）的发展过程中起重要作用。本研究旨在探讨外源性骨骼干细胞（SSCs）对OA中软骨下成骨细胞坏死性凋亡的潜在影响。使用从人胫骨平台分离的人SSCs和软骨下成骨细胞进行蛋白质免疫印迹、实时定量PCR、RNA测序、基因编辑和坏死性凋亡检测试验。此外，采用大鼠前交叉韧带横断OA模型评估SSCs在体内对成骨细胞坏死性凋亡的影响。显微CT和病理数据显示，关节内注射SSCs可显著改善OA大鼠软骨下小梁骨的微观结构。此外，SSCs可抑制OA大鼠和坏死性凋亡细胞模型中软骨下成骨细胞的坏死性凋亡。对肿瘤坏死因子α刺激或未刺激的SSCs进行的大量RNA测序结果表明，SSCs衍生的肿瘤坏死因子α诱导蛋白3（TNFAIP3）与细胞坏死性凋亡相关。此外，SSCs来源的TNFAIP3有助于在体内和体外抑制软骨下成骨细胞的坏死性凋亡。此外，关节内注射过表达TNFAIP3的SSCs可进一步改善OA大鼠软骨下小梁骨的重塑。因此，我们报道SSCs来源的TNFAIP3有助于抑制软骨下成骨细胞的坏死性凋亡，这表明关节中坏死性凋亡的软骨下成骨细胞可能是通过干细胞疗法治疗OA的潜在靶点。
