Repurposing metformin for treating osteoarthritis via leveraging Nrf2 signaling

There are currently no satisfactory effective treatments for osteoarthritis (OA), the most common degenerative joint disease leading to progressive disability in the elderly population. The effects of metformin, a first-line medication for type 2 diabetes, on OA and its underlying mechanisms remain obscure. Through a systematic review, we identified that oxidative stress played a significant role in the pathogenesis of OA, and metformin had potential antioxidative capacity in relieving various chronic inflammation-related diseases, raising the possibility of treating OA. Firstly, we observed that metformin was able to partially alleviate OA pain in the monosodium iodoacetate (MIA)-induced mouse model as assessed by animal behavior tests. Moreover, micro-CT and histological analysis demonstrated that metformin could moderately delay the progression of OA as well. Further in vitro and in vivo experiments uncovered metformin's ability to suppress oxidative stress by promoting the expression of Nuclear factor erythroid 2-related factor 2 (Nrf2). The deficiency of Nrf2 in Nrf2 knockout (KO) mice attenuated the chondroprotective effect of metformin on OA development, further affirming the core position of Nrf2 signaling during metformin fights illness as an antioxidant. Retrospective analysis of OA progress in type 2 diabetes patients showed the lower ratio of knee arthroplasty in patients treated with metformin, suggesting the possibility of clinical effectiveness. In conclusion, we found that metformin may alleviate the pathological progression of OA primarily by activating Nrf2 signaling pathway, thereby confirming the promising potential of metformin as a treatment paradigm for OA.