Metabolic pathways linking air pollution to osteoarthritis: Insights from a prospective cohort

Abstract

Objective To investigate metabolic pathways linking air pollution exposure to osteoarthritis (OA) development and quantify their mediating role in disease pathogenesis. Methods This prospective cohort study utilized UK Biobank data from 220,872 participants. Air pollution exposure was assessed using land use regression models for PM₂.₅, PM₁₀, PM₂.₅ ₋ ₁₀, NO₂, and NOₓ, with composite scores constructed. Nuclear magnetic resonance metabolomics profiling quantified 251 circulating metabolites. Elastic net regression identified air pollution-related metabolic signatures. Cox proportional hazards models assessed associations of air pollution related metabolic profiles with incident OA. Causal mediation analysis quantified metabolic pathway mediation using counterfactual methods. Results During follow-up, 40,399 participants (18.3%) developed incident OA. Elastic net regression identified 50 metabolites associated with air pollution scores, encompassing lipoprotein subclasses (26%), fatty acids (16%), amino acids (12%), and inflammatory biomarkers. Air pollution-related metabolic signatures showed stronger associations with OA risk (HR 1.095, 95% CI: 1.082–1.108 per IQR increase) than air pollution scores alone (HR 1.030, 95% CI: 1.018–1.042). Effects were most pronounced for knee OA (HR 1.140, 95% CI: 1.118–1.162). Causal mediation analysis revealed that metabolic signatures mediated 21.04% (95% CI: 16.52%−41.95%) of the air pollution-OA association. Conclusion Metabolic pathways significantly mediate air pollution-OA associations, providing novel insights into environmental contributions to musculoskeletal health and identifying potential therapeutic targets for prevention strategies.