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

Obesity was associated with a significantly higher risk of osteoarthritis in cross-sectional analysis.

• Obesity defined by relative fat mass was associated with a 39.6% higher OA risk (OR = 1.396, p < 0.001).
• Multivariable logistic regression was used to assess the obesity-OA association.
• Analysis was based on population cross-sectional data.

Physical activity significantly attenuated the association between obesity and osteoarthritis risk.

• Low PA was associated with reduced obesity-OA association (OR = 0.625, p = 0.009).
• High PA was also associated with reduced obesity-OA association (OR = 0.663, p = 0.024).
• Both low and high PA levels showed statistically significant attenuation of the obesity-OA relationship.

Mendelian randomization analyses confirmed a genetic causal relationship between obesity and increased osteoarthritis risk.

• MR analysis showed obesity increased OA risk (OR = 1.752, p < 0.001).
• Obesity also increased hospital-diagnosed OA risk (OR = 2.009, p < 0.001).
• Linkage disequilibrium score regression was used alongside MR to examine genetic correlations and causality.

Sedentary behavior elevated both osteoarthritis and obesity risks in Mendelian randomization analyses.

• Sedentary behavior elevated OA risk (OR = 1.293, p < 0.001).
• Sedentary behavior also elevated obesity risk (OR = 1.271, p < 0.001).
• Both associations were statistically significant at p < 0.001.

Physical activity was protective against both osteoarthritis and obesity in Mendelian randomization analyses.

• PA was associated with reduced OA risk (OR = 0.844, p = 0.026).
• PA was associated with reduced obesity risk (OR = 0.827, p < 0.001).
• These findings were derived from genetic causal inference using MR methodology.

Obesity mediated a substantial proportion of the effects of physical activity and sedentary behavior on osteoarthritis risk.

• Obesity mediated 44%–63% of the PA and sedentary behavior effects on OA.
• This mediation was identified through MR-based mediation analyses.
• The finding suggests obesity is a key pathway through which lifestyle behaviors influence OA risk.

TWAS, colocalization, and summary-data-based MR identified PRMT6 as a key molecular mediator in the obesity-OA pathway.

• Protein arginine methyltransferase 6 (PRMT6) was identified as a key molecular mediator.
• PRMT6 was identified through a combination of transcriptome-wide association studies (TWAS), colocalization analysis, and summary-data-based MR (SMR).
• This represents a proposed molecular mechanism linking obesity to OA risk.