Semaglutide alleviates osteoarthritis in mice via GLP-1R-mediated autophagy, independent of weight loss

Osteoarthritis (OA) is a debilitating joint disease characterized by cartilage degeneration, often linked to systemic metabolic disorders. Current therapeutic strategies for OA primarily focus on symptom management, with a notable lack of disease-modifying treatments that simultaneously address metabolic abnormalities and inflammatory responses. Glucagon-like peptide-1 receptor (GLP-1R) agonists, like semaglutide, are established for diabetes and weight management, but their potential to directly impact OA pathology, especially independent of weight loss, represents a significant therapeutic gap. This study explores semaglutide's direct effects on OA and its underlying molecular mechanisms.

Researchers first screened several hypoglycemic drugs using a zebrafish cartilage injury repair model to identify pro-regenerative effects. For in vivo studies, OA was induced in C57BL/6 mice via destabilization of the medial meniscus (DMM) surgery. The effects of semaglutide treatment on joint structure, function, and pain behaviors were systematically evaluated in both wild-type (WT) and systemic Glp-1r knockout mice. To investigate cellular mechanisms, RNA sequencing was performed on IL-1β-stimulated primary mouse chondrocytes treated with semaglutide. Functional loss was verified using the GLP-1R antagonist Exendin (9-39) and the autophagy inhibitor Bafilomycin A1.

Drug screening in the zebrafish cartilage injury model revealed that semaglutide exerted the most significant pro-regenerative effects, markedly promoting cartilage repair. In WT mice with DMM-induced OA, semaglutide treatment significantly improved gait abnormalities and mechanical hyperalgesia. Crucially, these benefits occurred without significantly affecting body weight. Treatment also alleviated cartilage destruction, synovitis, and subchondral bone sclerosis associated with abnormal chondrocyte metabolism. Mechanistically, RNA sequencing indicated that semaglutide regulated extracellular matrix metabolism and activated autophagy through AKT/mTOR inhibition in IL-1β-stimulated chondrocytes. The protective effects of semaglutide on chondrocyte metabolism and its therapeutic efficacy in OA were completely abolished by GLP-1R inhibition with Exendin (9-39) or by Glp-1r gene knockout. Furthermore, Glp-1r gene deficiency itself exacerbated cartilage degeneration and bone structural damage, highlighting the receptor's intrinsic role.

In wild-type 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.