Cao Xiankun, Yang Xiao, Zhang Pu, Xu Jianguang, Zhao Jie, Yang Erzhu
Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China.
Department of Orthopedics Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China.
Cell Death Discov. 2025 Mar 20;11(1):110. doi: 10.1038/s41420-025-02394-z.
Osteoarthritis (OA) inflammatory microenvironment triggered glucose metabolism and mitochondrial dysfunction in chondrocytes, leading to a shift of metabolic tendency between oxidative phosphorylation and anaerobic glycolysis. Thioredoxin-interacting protein (Txnip) increased production of reactive oxygen species (ROS), which exacerbates oxidative stress, inflammation and further accelerates cartilage degeneration and extracellular matrix (ECM) degradation. Txnip expression is also positively correlated with several critical pathological glucose and lipid metabolism processes beyond inflammation and endoplasmic reticulum stress (ERS). While the role of Txnip-mediated chondrocyte metabolic reprogramming in OA has not been explored. This study focuses on the unexplored role of Txnip-mediated chondrocyte metabolic reprogramming in chondrogenesis and ECM deposition. The study reveals that upregulated glycolysis after Txnip knockdown significantly contributes to mouse chondrogenesis and ECM deposition. Moreover, verapamil, a clinically used drug that targets Txnip, shows potential for treating mouse OA. These findings suggest that targeting Txnip-mediated metabolic reprogramming could offer a novel therapeutic strategy for OA treatment.
骨关节炎（OA）的炎症微环境引发软骨细胞中的葡萄糖代谢和线粒体功能障碍，导致氧化磷酸化和无氧糖酵解之间的代谢倾向发生转变。硫氧还蛋白相互作用蛋白（Txnip）增加活性氧（ROS）的产生，这会加剧氧化应激、炎症，并进一步加速软骨退变和细胞外基质（ECM）降解。Txnip的表达还与炎症和内质网应激（ERS）之外的几个关键病理葡萄糖和脂质代谢过程呈正相关。然而，Txnip介导的软骨细胞代谢重编程在OA中的作用尚未得到探索。本研究聚焦于Txnip介导的软骨细胞代谢重编程在软骨生成和ECM沉积中尚未被探索的作用。该研究表明，Txnip敲低后糖酵解上调显著促进小鼠软骨生成和ECM沉积。此外，维拉帕米是一种临床上用于靶向Txnip的药物，显示出治疗小鼠OA的潜力。这些发现表明，靶向Txnip介导的代谢重编程可为OA治疗提供一种新的治疗策略。
