Semaglutide alleviates osteoarthritis independent of weight loss via GLP-1R-mediated activation of autophagy through AKT/mTOR inhibition.

OBJECTIVE: The development of osteoarthritis (OA) is closely associated with systemic metabolic disorders, yet there remains a lack of disease-modifying therapeutic strategies that simultaneously target metabolic abnormalities and inflammatory responses. This study aims to systematically evaluate the therapeutic potential of semaglutide, a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist used for diabetes management, in OA and to elucidate its underlying molecular mechanisms. METHODS: We utilized a zebrafish cartilage injury repair model to screen and assess the impact of several hypoglycemic drugs on cartilage regeneration. OA was induced in C57BL/6 mice by destabilization of the medial meniscus (DMM) surgery. Using systemic knockout mice, we systematically evaluated the effects of semaglutide on joint structure, function, and pain-related behaviors . RNA sequencing was performed to explore the regulator effects of semaglutide on extracellular matrix metabolism, associated signaling pathways, and autophagy in IL-1β-stimulated primary mouse chondrocytes. To verify the functional loss, the GLP-1R antagonist Exendin (9-39) and the autophagy inhibitor Bafilomycin A1 were employed. RESULTS: Drug screening using a zebrafish cartilage injury model demonstrated that semaglutide exerted the most significant pro-regenerative effects, markedly promoting cartilage repair. In wild-type (WT) mice with DMM-induced OA, semaglutide treatment significantly improved gait abnormalities and mechanical hyperalgesia without significantly affecting body weight, and alleviated cartilage destruction, synovitis, and subchondral bone sclerosis associated with abnormal chondrocyte metabolism. However, GLP-1R inhibition or knockout completely abolished the protective effects of semaglutide on chondrocyte metabolism and its therapeutic efficacy in OA. Moreover, gene deficiency exacerbated cartilage degeneration and bone structural damage, indicating that GLP-1R signaling is indispensable for maintaining cartilage homeostasis. Mechanistically, semaglutide inhibited the AKT/mTOR pathway through GLP-1R activation, thereby reversing IL-1β- and DMM-induced autophagy suppression and restoring the balance of extracellular matrix metabolism in chondrocytes. CONCLUSION: Semaglutide exerts protective effects against OA by activating GLP-1R in chondrocytes, inhibiting the AKT/mTOR pathway, and enhancing chondrocyte autophagy. It alleviates abnormal cartilage metabolism in OA independently of body weight changes.: This study demonstrates, for the first time, that semaglutide exerts protective effects against OA independent of weight loss by directly activating chondrocyte GLP-1R, inhibiting the AKT/mTOR pathway, and enhancing autophagy. These findings provide robust preclinical evidence supporting the repositioning of semaglutide as a disease-modifying therapy, particularly for patients with OA and comorbid metabolic disorders such as diabetes. Furthermore, they indicate that GLP-1R and its downstream signaling pathways may represent potential therapeutic targets for OA, thereby opening new avenues for drug repurposing and precision interventions in metabolic OA.