Melatonin Improves Diabetic‐Accelerated Experimental Osteoarthritis by Inhibiting NLRP3‐Mediated Chondrocyte Pyroptosis via PKG/Nrf2

Recent evidence suggests a potential link between diabetes and the worsening and severity of osteoarthritis (OA) symptoms. Melatonin (MLT) has a strong ability to scavenge reactive oxygen species and lipid peroxidation, and plays a vital role in the treatment of OA. However, the role and mechanism of MLT in diabetic OA are still unclear. This study aimed to confirm that diabetes aggravates OA cartilage degeneration and to explore the specific mechanism by which MLT inhibits cell pyroptosis and alleviates OA. In this study, a model of OA combined with type 2 diabetes was established, and it was found that hyperglycemia would exacerbate the degradation of OA cartilage tissue. Secondly, we investigated the effect of MLT on OA under hyperglycemic conditions and the underlying molecular mechanisms in vivo and in vitro experiments. The results show that MLT inhibits the activation of the NLRP3 inflammasome in chondrocytes by activating PKG to mediate the Nrf2/HO-1 antioxidant defense system, thereby exerting anti-inflammatory, anti-pyroptosis, and anti-degradation effects on the cartilage extracellular matrix (ECM). Further verification revealed that silencing PKG or inhibiting Nrf2 would partially reduce the protective effect of MLT. MLT can also reduce the pain sensitivity of rats, decrease the degree of subchondral bone remodeling, and improve the microstructure of the bone. This suggests that MLT therapy may be a promising new approach for treating OA, particularly in patients with diabetes.