Mechanistic study of the regulation of mitochondrial function by the GPNMB/Nrf2/NF-κB signaling pathway mediated by Quzhi Tang to alleviate chondrocyte senescence

ETHNOPHARMACOLOGICAL RELEVANCE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.