Metformin alleviates osteoarthritis in mice by inhibiting chondrocyte ferroptosis and improving subchondral osteosclerosis and angiogenesis

作者：Jiangbo Yan, Gangning Feng, Long Ma, Zhirong Chen, Qunhua Jin · 发表于：Journal of Orthopaedic Surgery and Research · 年份：2022 · DOI：10.1186/s13018-022-03225-y · 被引用次数：65 · 研究领域：Ferroptosis and cancer prognosis、Bone Metabolism and Diseases、Osteoarthritis Treatment and Mechanisms

BACKGROUND: Osteoarthritis (OA) is the most common musculoskeletal disease, and it has a complex pathology and unknown pathogenesis. Chondrocyte ferroptosis is closely associated with the development of OA. As a common drug administered for the treatment of type 2 diabetes, metformin (Met) is known to inhibit the development of ferroptosis. However, its therapeutic effect in OA remains unknown. The present study aimed to explore the effects of Met on cartilage and subchondral bone in a mouse OA model and to explore the potential underlying mechanisms. METHODS: A mouse OA model was induced using destabilization of the medial meniscus (DMM) surgery, chondrocyte ferroptosis was induced using an intra-articular injection of Erastin, and Met (200 mg/kg/day) was intragastrically administered for 8 weeks after surgery. H&E and Safranin O‑fast green staining were used to evaluate cartilage degeneration, and μ‑computed tomography was used to evaluate changes in subchondral bone microarchitecture. Moreover, immunohistochemical staining was performed to detect mechanistic metalloproteinases 13, type II collagen, glutathione peroxidase 4, acyl-CoA synthetase long-chain family member 4, solute carrier family 7 member 11 and p53. Runt-associated transcription factor 2 and CD31 were detected using immunofluorescent staining. RESULTS: Met protected articular cartilage and reversed the abnormal expression of ferroptosis-related proteins in the chondrocytes of DMM mice. Moreover, intra-articul...