CDK5 regulates PPARγ/NF-κB signaling to exacerbate obesity-related osteoarthritis via modulating macrophage polarization and chondrocyte apoptosis

BACKGROUND: Obesity is an important risk factor for osteoarthritis (OA), but the mechanisms associated with OA progression are still not fully understood. The aim of this study was to investigate the role of cyclin-dependent kinase 5 (CDK5) in regulating the peroxisome proliferator-activated receptor gamma (PPARγ)/nuclear factor-κB (NF-κB) signaling pathway and its effect on obesity-related OA. METHODS: By analyzing tissue samples from obese and nonobese patients with OA in conjunction with a high-fat diet (HFD)-induced obese mouse model of OA, we investigated the expression level of CDK5 and its effects on inflammation and apoptosis. The role of CDK5 in macrophage polarization and chondrocyte apoptosis was further explored by gene knockdown and pharmacological intervention. RESULTS: CDK5 levels were found to be significantly elevated in obese patients with OA, promoting M1 macrophage infiltration and chondrocyte apoptosis. In the model, CDK5 knockdown attenuated cartilage damage and inhibited PPARγ phosphorylation and NF-κB signaling. In vitro experiments showed that overexpression of CDK5 facilitated M1 macrophage polarization and chondrocyte apoptosis, and PPARγ agonists reversed these effects. Mechanically, CDK5 binds to PPARγ to regulate the NF-κB signaling pathway. CONCLUSION: CDK5 promotes the progression of obesity-associated OA through the PPARγ/NF-κB pathway and is a potential therapeutic target in OA, especially in obese patients.