Jie Lishi, Zhang Chaofeng, Liu Yujiang, Huang Zeling, Xu Bo, Zhu Zaishi, Li Yuwei, Wang Peimin, Shi Xiaoqing
Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210023, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210023, China.
Department of Orthopaedics and Traumatology, Suzhou Hospital of Traditional Chinese Medicine, Suzhou, China.
J Ethnopharmacol. 2025 Jan 31;340:119165. doi: 10.1016/j.jep.2024.119165. Epub 2024 Nov 29.
Quzhi Tang (QZT) is a compound formula consisting of six traditional Chinese medicinal herbs. It has achieved good clinical results in the treatment of knee osteoarthritis (KOA), and the potential drug mechanisms involved are worth exploring in depth.
Using single-cell transcriptome analysis, this study identified the key target of senescence, GPNMB. Then, it investigated the mechanism by which QZT regulates the GPNMB/Nrf2/NF-κB signaling pathway to repair mitochondrial damage and ameliorate the process of chondrocyte senescence.
We collected cartilage tissues from mice and identified GPNMB as a key target of chondrocyte senescence by combining transcriptomics, histopathology, molecular biology, and immunology methods. The effects of QZT on the level of chondrocyte senescence in mice and its ameliorative effect on KOA were studied. In in vivo experiments, we explored the mechanism of GPNMB in the development of senescence in detail and revealed that, after siRNA-GPNMB interference, chondrocytes exhibited reduced impairment of mitochondrial function and senescence under equal amounts of stimuli, increasing Nrf2 expression and reducing NF-κB expression. In addition, the level of oxidative stress increased in chondrocytes overexpressing GPNMB after lentiviral infiltration, aggravating the impairment of mitochondrial function. After treatment with QZT, chondrocytes overexpressing GPNMB were able to increase Nrf2 expression, decrease NF-κB expression, repair mitochondrial damage, and improve the degree of chondrocyte aging.
We concluded that the GPNMB/Nrf2/NF-κB signaling pathway plays an important role in chondrocyte senescence and that QZT was able to reduce intracellular oxidative stress and restore impaired mitochondrial function by regulating the expression level of the GPNMB/Nrf2/NF-κB signaling pathway, reducing the level of chondrocyte senescence in the KOA process.
祛湿汤（QZT）是一种由六种传统中药组成的复方。它在治疗膝关节骨关节炎（KOA）方面取得了良好的临床效果，其潜在的药物作用机制值得深入探索。
本研究采用单细胞转录组分析，确定了衰老的关键靶点GPNMB。然后，研究了QZT调节GPNMB/Nrf2/NF-κB信号通路以修复线粒体损伤和改善软骨细胞衰老过程的机制。
我们从小鼠收集软骨组织，并通过转录组学、组织病理学、分子生物学和免疫学方法相结合，确定GPNMB为软骨细胞衰老的关键靶点。研究了QZT对小鼠软骨细胞衰老水平的影响及其对KOA的改善作用。在体内实验中，我们详细探讨了GPNMB在衰老发展中的作用机制，发现siRNA-GPNMB干扰后，软骨细胞在等量刺激下线粒体功能损伤和衰老减少，Nrf2表达增加，NF-κB表达降低。此外，慢病毒浸润后过表达GPNMB的软骨细胞氧化应激水平升高，加重了线粒体功能损伤。QZT处理后过表达GPNMB的软骨细胞能够增加Nrf2表达，降低NF-κB表达，修复线粒体损伤，改善软骨细胞衰老程度。
我们得出结论，GPNMB/Nrf2/NF-κB信号通路在软骨细胞衰老中起重要作用，QZT能够通过调节GPNMB/Nrf2/NF-κB信号通路的表达水平，降低细胞内氧化应激，恢复受损的线粒体功能，降低KOA过程中软骨细胞衰老水平。
