Metformin Alleviates TMJ Osteoarthritis By Targeting Chondrocyte Senescence Through FoxO1-Mediated Autophagy

Introduction and aims Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disorder driven by inflammation and chondrocyte senescence, leading to cartilage and bone destruction. Metformin, a medication used to treat diabetes, also exhibits anti-inflammatory and anti-aging properties. Here, we investigated the potential of metformin to mitigate TMJ-OA and its underlying mechanism. Methods Metformin (200 mg/kg) was administered to monosodium iodoacetate (MIA)-induced TMJ-OA rats via gavage. Cartilage degeneration and subchondral bone changes were assessed using histology and micro-CT. Serum levels of senescence-associated secretory phenotype (SASP) factors were measured via cytokine assays. RNA sequencing (RNA-seq) identified key pathways. In vitro , IL-1β-stimulated chondrocytes were treated with metformin, with or without Forkhead box O1 (FoxO1) inhibition (AS1842856) or the autophagy inhibitor chloroquine. Senescence markers (p53 and p21), autophagy markers, and inflammatory factors were analysed using RT-qPCR, Western Blotting, SA-β-gal staining, and immunostaining. Results Metformin significantly reduced cartilage degradation, subchondral bone loss, and SASP production in TMJ-OA rats. Metformin downregulated senescence markers (p53/p21) while enhancing autophagy. RNA-seq linked metformin’s effects to FoxO1 activation. In vitro , metformin counteracted IL-1β-induced senescence and inflammation in chondrocytes by promoting FoxO1-dependent autophagy. FoxO1 inhibition abolished these protective effects. Furthermore, chloroquine partially reversed metformin-induced changes in autophagy and cellular senescence. Conclusions Metformin attenuates TMJ-OA by suppressing inflammation-driven chondrocyte senescence via activation of autophagy. These findings highlight metformin as a promising therapeutic agent for TMJ-OA, particularly in cases where inflammaging plays a principal pathogenic role. Clinical Relevance : Given its established safety profile and widespread clinical use, metformin may represent a feasible systemic therapeutic option for TMJ-OA, particularly in patients with high-inflammaging-dominant cartilage pathology. Further clinical trials are warranted to evaluate its translational potential in TMJ-OA management.