Exploring the therapeutic applications of metformin in articular cartilage repair: mechanistic insights and translational perspectives

• 1. The Joint Department of Orthopedics, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China

• 2. Health Science Center, Yangtze University, Jingzhou, Hubei, China

Abstract

Articular cartilage is characterized by an avascular structure and limited intrinsic regenerative capacity. The most prevalent pathological conditions that lead to cartilage damage are osteoarthritis (OA) and rheumatoid arthritis (RA). In recent decades, cartilage homeostasis has been shown to be particularly vulnerable to metabolic disturbances, especially those induced by obesity and diabetes mellitus. Metformin, a first-line antidiabetic agent and emerging antiaging therapeutic, has garnered significant attention as a promising candidate for cartilage repair that can address the unmet clinical need for treating currently irreversible cartilage damage and associated pathologies such as OA and RA. This review synthesizes preclinical and clinical evidence to elucidate the multifaceted effects of metformin on cartilage homeostasis. Cellular and animal studies have demonstrated that metformin exerts chondroprotective effects through multiple complementary mechanisms, including the activation of AMPK/SIRT1-mediated autophagy, the suppression of NF-κB signaling, the inhibition of matrix-degrading enzymes, the reduction of oxidative stress and inflammatory mediators, the modulation of macrophage polarization toward an anti-inflammatory phenotype, and the attenuation of aberrant subchondral bone remodeling. Emerging clinical evidence suggests that metformin may attenuate OA progression and ameliorate clinical symptoms. However, further large-scale, prospective trials are warranted to confirm its translation potential. By integrating findings across experimental models and clinical observations, this review highlights the role of metformin in modulating chondrocyte metabolism, mitigating inflammatory cascades, and promoting cartilage repair, thereby offering novel therapeutic strategies for cartilage-related disorders.