Pan Yi-Nan, Jia Chao, Yu Jia-Pei, Wu Zhou-Wei, Xu Guo-Chao, Huang Yi-Xing
Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
Int Immunopharmacol. 2023 Jan;114:109606. doi: 10.1016/j.intimp.2022.109606. Epub 2022 Dec 19.
Osteoarthritis (OA) is a degenerative and progressive disease that affects joints. Pathologically, it is characterized by oxidative stress-mediated excessive chondrocyte apoptosis and mitochondrial dysfunction. Fibroblast growth factor 9 (FGF9) has been shown to exert antioxidant effects and prevent degenerative diseases by activating ERK-related signaling pathways. However, the mechanism of FGF9 in the pathogenesis of OA and its relationship with anti-oxidative stress and related pathways are unclear. In this study, mice with medial meniscus instability (DMM) were used as the in vivo model whereas TBHP-induced chondrocytes served as the in vitro model to explore the mechanism underlying the effects of FGF9 in OA and its association with anti-oxidative stress. Results showed that FGF9 reduced oxidative stress, apoptosis, and mitochondrial dysfunction in TBHP-treated chondrocytes and promoted the nuclear translocation of Nrf2 to activate the Nrf2/HO1 signaling pathway. Interestingly, silencing the Nrf2 gene or blocking the ERK signaling pathway abolished the antioxidant effects of FGF9. FGF9 treatment reduced joint space narrowing, cartilage ossification, and synovial thickening in the DMM model mice. In conclusion, the present findings demonstrate that FGF9 can inhibit TBHP-induced oxidative stress in chondrocytes through the ERK and Nrf2-HO1 signaling pathways and prevent the progression of OA in vivo.
骨关节炎（OA）是一种影响关节的退行性和进行性疾病。在病理上，其特征在于氧化应激介导的软骨细胞过度凋亡和线粒体功能障碍。成纤维细胞生长因子9（FGF9）已被证明具有抗氧化作用，并通过激活ERK相关信号通路预防退行性疾病。然而，FGF9在OA发病机制中的作用及其与抗氧化应激和相关通路的关系尚不清楚。在本研究中，以内侧半月板不稳定（DMM）小鼠作为体内模型，而以叔丁基过氧化氢（TBHP）诱导的软骨细胞作为体外模型，以探讨FGF9在OA中的作用机制及其与抗氧化应激的关联。结果表明，FGF9可降低TBHP处理的软骨细胞中的氧化应激、凋亡和线粒体功能障碍，并促进Nrf2的核转位以激活Nrf2/HO1信号通路。有趣的是，沉默Nrf2基因或阻断ERK信号通路可消除FGF9的抗氧化作用。FGF9治疗可减轻DMM模型小鼠的关节间隙变窄、软骨骨化和滑膜增厚。总之，本研究结果表明，FGF9可通过ERK和Nrf2-HO1信号通路抑制TBHP诱导的软骨细胞氧化应激，并在体内预防OA的进展。
