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

Abstract

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-articular injection of Erastin induced ferroptosis in mouse chondrocytes, and Met eliminated the ferroptosis effects induced by Erastin and protected articular cartilage. In addition, the results of the present study demonstrated that Met alleviated the microstructural changes of subchondral osteosclerosis and reduced heterotypic angiogenesis in DMM mice. Conclusion Met alleviates the pathological changes of OA by inhibiting ferroptosis in OA chondrocytes, alleviating subchondral sclerosis and reducing abnormal angiogenesis in subchondral bone in advanced OA.

Metformin regulates bone marrow stromal cells to accelerate bone healing in diabetic mice

“…Besides its effects on bone formation, there are also interests in studying the effects of metformin on chondrocytes, especially in the context of osteoarthritis development. Limited reference showing that metformin is protective against development of osteoarthritis by reducing chondrocyte apoptosis and alleviating chondrocyte degeneration [27][28][29]. Consistent with the above reports, our data suggest that metformin promoted the cartilage formation in the endochondral ossification at day 14 post-fracture in T2D mice.…”

Recent Therapeutic Strategies for Excessive Chondrocyte Death in Osteoarthritis: A Review

“…Cheng et al found that stigmasterol can inhibit ferroptosis induced by IL‐1βand improved cell viability through negatively regulating sterol regulatory element binding transcription factor 2 (SREBTF2) 215 . In addition, metformin has shown potential in the treatment of OA, as demonstrated by downregulating Gpx4 to inhibit chondrocyte ferroptosis, alleviate OA, and, to a certain extent, improve subchondral bone sclerosis and reduce angiogenesis in mice 216 …”

Metformin as a Promising Anti-Aging Agent in the Treatment of Osteoarthritis

“…In experimental mouse models of advanced OA, metformin was found to suppress ferroptosis and pyroptosis in OA chondrocytes resulting in the reduction of disease alterations such as chondrocyte degradation, subchondral sclerosis and abnormal angiogenesis in the subchondral bone [30,31]. On another note, change in the microarchitecture of subchondral bone is a characteristic feature in patients with OA.…”