Metabolic syndrome-osteoarthritis axis: Beyond mechanical loading toward a cardiometabolic OA phenotype

Osteoarthritis (OA) has long been framed as a mechanically driven "wear-and-tear" disorder. Increasing epidemiological and translational evidence indicates that metabolic syndrome (MetS)-including obesity, insulin resistance/hyperglycaemia, dyslipidaemia, and hypertension-acts as a key disease modifier in a substantial subset of patients. MetS-related OA may represent a cardiometabolic endotype with weight-independent risk and distinct inflammatory, vascular, and lipotoxic drivers. Here, we synthesize evidence from population cohorts, imaging studies, mechanistic experiments, and emerging multi-omics research to integrate the MetS-OA axis into the broader cardiovascular-kidney-metabolic (CKM) multimorbidity framework. We highlight patterns beyond biomechanical loading, including non-weight-bearing joint involvement, multi-joint clustering, and biomarker profiles consistent with systemic metaflammation. We then map convergent pathways linking MetS to joint pathology, including adipose-tissue inflammation and adipokine imbalance, AGE-RAGE signaling and oxidative stress, microvascular dysfunction and subchondral bone hypoperfusion, lipid overload with inflammasome activation, and immune-metabolic reprogramming amplified by gut dysbiosis. We propose a trial-ready MetS-OA definition: symptomatic and imaging-confirmed OA plus standardized MetS criteria, preferably ≥ 3 metabolic abnormalities, with supportive inflammatory imaging or biomarkers. This framework integrates CKM risk with joint outcomes, enabling endotype-enriched study designs and mechanism-informed therapeutic targeting. Therapeutically, interventions that improve cardiometabolic health-ranging from lifestyle programs to metabolic pharmacotherapies-may be disease-modifying in selected MetS-OA subgroups, but require endotype-enriched randomized controlled trials with composite endpoints capturing both joint structure/symptoms and CKM risk modification. Reframing OA as a cardiometabolic joint disease in a defined subset may advance precision stratification, targeted disease modification, and integrated management across internal medicine and musculoskeletal care.