Wu Hao, Yan Jinhong, Zhang Qian, Cheng Gong, Cao Zhilin
Department of Sports Medicine, Yantaishan Hospital, No.10087 Science and Technology Avenue, Laishan District, Yantai, 264003, Shandong, China.
Department of Orthopaedics, Yantai Yuhuangding Hospital, Yantai, Shandong, China.
Hum Cell. 2025 Aug 13;38(5):142. doi: 10.1007/s13577-025-01272-1.
Knee osteoarthritis (KOA) is a degenerative joint disorder characterized by articular cartilage degeneration and synovial inflammation. Dysfunction mediated by autophagy-related protein 5 (ATG5) represents a key driver of KOA pathogenesis, while the cGAS-STING-NLRP3 signaling axis is closely associated with inflammation and apoptosis. Therefore, this study aims to explore the regulatory effect of ATG5 on the cGAS-STING-NLRP3 axis and its specific role in KOA. HE staining, Safranin O-fast green staining were used to assess the degree of cartilage degeneration in KOA rats. TUNEL staining were applied to observe the apoptosis of chondrocytes in cartilage tissues. Levels of inflammatory factors in serum of rats and cells were detected by ELISA. Expression of proteins levels was analyzed using western blot and immunofluorescence assay. Flow cytometry was used to investigate the apoptosis. In cartilage tissues of KOA rats, ATG5 was lowly expressed, while cGAS, STING and NLRP3 were overexpressed. Co-localization was observed between ATG5 and STING. Overexpression of ATG5 led to decreased expression of inflammatory factors, cGAS, STING, NLRP3, p62 and Cleaved caspase-1, a reduced Mankin score, and increased Beclin1 expression. However, knockout of ATG5 reversed these changes. Additionally, overexpression of ATG5 decreased the apoptosis rate of chondrocytes, whereas inhibition of ATG5 promoted chondrocyte apoptosis. In conclusion, ATG5 regulates the cGAS-STING-NLRP3 axis, thereby promoting chondrocyte autophagy and inhibiting inflammation, which in turn protects chondrocytes and alleviates KOA. In conclusion, ATG5 modulates the cGAS-STING-NLRP3 axis, thereby enhancing chondrocyte autophagy and suppressing inflammation, which collectively protects chondrocytes and alleviates the progression of KOA.
膝关节骨关节炎（KOA）是一种以关节软骨退变和滑膜炎症为特征的退行性关节疾病。自噬相关蛋白5（ATG5）介导的功能障碍是KOA发病机制的关键驱动因素，而cGAS-STING-NLRP3信号轴与炎症和细胞凋亡密切相关。因此，本研究旨在探讨ATG5对cGAS-STING-NLRP3轴的调控作用及其在KOA中的具体作用。采用苏木精-伊红（HE）染色、番红O-固绿染色评估KOA大鼠软骨退变程度。应用TUNEL染色观察软骨组织中软骨细胞的凋亡情况。采用酶联免疫吸附测定（ELISA）检测大鼠血清和细胞中炎症因子水平。运用蛋白质免疫印迹法和免疫荧光分析法分析蛋白表达水平。采用流式细胞术研究细胞凋亡情况。在KOA大鼠软骨组织中，ATG5低表达，而cGAS、STING和NLRP3高表达。观察到ATG5与STING存在共定位。ATG5过表达导致炎症因子、cGAS、STING、NLRP3、p62和裂解的半胱天冬酶-1表达降低，曼金评分降低，Beclin1表达增加。然而，敲除ATG5可逆转这些变化。此外，ATG5过表达降低了软骨细胞的凋亡率，而抑制ATG5则促进软骨细胞凋亡。总之，ATG5调节cGAS-STING-NLRP3轴，从而促进软骨细胞自噬并抑制炎症，进而保护软骨细胞并减轻KOA。总之，ATG5调节cGAS-STING-NLRP3轴，从而增强软骨细胞自噬并抑制炎症，共同保护软骨细胞并减轻KOA的进展。
