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ObjectiveBoth obesity and synovitis are independently associated with knee osteoarthritis (KOA) progression. We examined whether synovitis mediates the relationship between body mass index (BMI) and KOA radiographic progression in the Osteoarthritis Initiative (OAI) cohort.DesignWe conducted a case-control study within the OAI. Cases (n = 315) were right knees with an increase of ≥1 Kellgren-Lawrence from baseline to 48 months of follow-up. Controls (n = 315) were right knees with no KL change. Cases and controls were matched by age, sex, race, and baseline KL. MRI Osteoarthritis Knee Score (MOAKS) at baseline and at 2 years was used for a semi-quantitative scoring (0-3) of effusion-synovitis and Hoffa-synovitis. Conditional logistic regression estimated associations between BMI and synovitis with KOA progression. Mediation analysis was used to assess the mediating effects of synovitis.ResultsThe mean age of participants was 61 years, 70.8% were women, and 87% were White. KOA progression was associated with higher BMI (adjusted OR 1.05; 95%CI 1.01-1.09) and effusion-synovitis relative to no effusion-synovitis (adjusted OR 2.2; 95%CI 1.6-3.1). Associations between effusion-synovitis worsening and KOA progression were more pronounced among obese individuals (OR 34.1; 95%CI 4.2-274.8; P = 0.001) compared to normal weight (OR 3.2; 95%CI 0.8-12.8, P=0.096) individuals. Effusion-synovitis at 2 years, but not at baseline, mediated the relationship between BMI and KOA progression over a 4-year period.ConclusionsWe found that effusion-synovitis worsening mediated the association between BMI and KOA progression and was associated with increased risk of KOA progression, particularly among obese individuals.