Physical Activity Alleviates Obesity-Related Osteoarthritis Risk: Multi-Dimensional Analysis From Population Data

Osteoarthritis (OA) is a major global health concern. Obesity and sedentary behavior increase OA risk, while physical activity (PA) is protective. However, how sedentary behavior and PA regulate the obesity-OA relationship and underlying molecular mechanisms remain unclear. To address this gap, we combined cross-sectional data analyses with genetic causal inference, defining obesity by relative fat mass. Multivariable logistic regression assessed obesity-OA associations, while Mendelian randomization (MR) and linkage disequilibrium score regression examined genetic correlations and causality among key factors. Transcriptome-wide association studies (TWAS), colocalization, and summary-data-based MR (SMR) explored molecular mechanisms. Obesity was associated with a 39.6% higher OA risk (OR = 1.396, p < 0.001), and PA significantly attenuated this association (low PA: OR = 0.625, p = 0.009; high PA: OR = 0.663, p = 0.024). MR analyses indicated obesity increased OA risk (OR = 1.752, p < 0.001) and hospital-diagnosed OA risk (OR = 2.009, p < 0.001), while TWAS, colocalization, and SMR identified protein arginine methyltransferase 6 (PRMT6) as a key molecular mediator. MR also revealed sedentary behavior elevates OA (OR = 1.293) and obesity risks (OR = 1.271, both p < 0.001), while PA is protective (OA: OR = 0.844, p = 0.026; obesity: OR = 0.827, p < 0.001), with obesity mediating 44%-63% of PA and sedentary effects on OA. In conclusion, reducing sedentary time and increasing PA lower OA risk by alleviating obesity burden and regulating PRMT6-mediated mechanisms, providing novel evidence for the precise prevention and management of obesity-associated OA and supporting a dual-target intervention strategy.