FGF21 Promotes Senescence, Apoptosis, and Extracellular Matrix Degradation in Osteoarthritis via the AMPK Signaling Pathway

Background: Fibroblast growth factor 21 (FGF21) is a peptide hormone synthesized by multiple organs that regulates energy homeostasis. However, the FGF21 function is complicated and well debated due to its different sites of production and actions. Here, for first time, we demonstrate FGF21 therapy can reduce the progression of osteoarthritis (OA) in animal models and in vitro studies. Methods: Western blot analysis, RT-qPCR and immunofluorescence staining were used to detect the changes in gene and protein levels in the vitro experiment. To explore the molecular mechanism of FGF21, TFEB knockdown experiments were performed with lentivirus in vitro. Finally, X-ray and tissue staining were used to assess imageology and histomorphology differences of mouse knee joint. Findings: FGF21 administration led to an upregulation of autophagy and reduced the apoptosis, senescence and extracellular matrix degradation of the chondrocytes induced by tert-butyl hydroperoxide (TBHP). However, 3-methyladenine (3MA), an autophagy inhibitor, could reverse the protective effect of FGF21, Mechanistically, it was observed that FGF21-induced autophagy enhancement was mediated by the dephosphorylation and nuclear translocation of TFEB, which occurs due to the activation of the AMPK-mTOR signal pathway. The in vivo experiments demonstrated that FGF21 treatment could ameliorate OA in the DMM model. Interpretations: Collectively, our study reveals FGF21 protects chondrocytes from apoptosis and senescence via autophagy up-regulation and also ameliorates OA development in vivo, demonstrating its potential as a therapeutic agent for OA. Funding: This study is supported by National 685 Natural Science Foundation of China (81401772) Declaration of Interest: The authors have declared that no competing interest exists. Ethical Approval: All experimental procedures and the protocols for animal use and care were in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and were approved by the Animal Care and Use Committee of Wenzhou Medical University.