Swimming exercise induces redox-lipid crosstalk to ameliorate osteoarthritis progression
Yubin Wu, Mingzhuang Hou, Yaoge Deng, Xiaowei Xia, Yang Liu, Jianfeng Yu, Chenqi Yu, Huilin Yang, Yijian Zhang, Xuesong Zhu
Abstract
Conventional pharmacotherapy exhibits limited efficacy in halting cartilage degeneration, whereas exercise interventions have demonstrated promising protective effects against osteoarthritis (OA), albeit with unclear underlying mechanisms. This study investigated the beneficial effects of swimming in mitigating local joint damage through the enhancement of systemic antioxidant capacity. We found that overexpression of superoxide dismutase 3 (SOD3) could promote the elimination of extracellular reactive oxygen species (ROS) and preserve the cartilage extracellular matrix (C-ECM). Conversely, genetic deletion of SOD3 accelerated the loss of C-ECM and contributed to OA due to an imbalance in extracellular oxidative stress. Further investigation revealed that SOD3 could interact with CCAAT/enhancer binding protein β (C/EBPβ), leading to the inhibition of apolipoprotein E (APOE) transcription and subsequent APOE-induced cholesterol transport. Ultimately, we developed targeted extracellular vesicles (EVs) with high cartilage affinity for efficient and precise delivery of SOD3. Overall, this study elucidated the potential of exercise for degenerative joint disorders through SOD3-mediated extracellular antioxidation and cholesterol redistribution. Swimming exercise confers protection against cartilage degeneration, thereby impeding the progression of OA. • Swimming exercise mitigates cartilage degeneration and protects against OA by enhancing extracellular antioxidant capacity. • Swimming exercise-induced SOD3 activation exerts chondroprotective effects through the scavenging of extracellular free radicals. • SOD3 indirectly reduces intracellular lipid accumulation and regulates cholesterol transport via the C/EBPβ-APOE axis. • Engineered extracellular vesicles (EVs) precisely deliver SOD3 to chondrocytes, offering beneficial effects for OA prevention and therapy.