DNA methylation changes following rapid maxillary expansion in children.

Osteoarthritis (OA) is the most prevalent musculoskeletal disease, affecting over 7% of the global population and ranking among the leading causes of disability worldwide []. The convergence of obesity and OA epidemics poses an escalating public health challenge: by 2035, over 4 billion people will be overweight [], with obesity conferring a 2.6–6.8 fold increased OA risk []. As populations age and obesity rates climb, these intertwined epidemics amplify one another, driving unsustainable disability and healthcare costs. Traditionally, OA has been attributed to mechanical overload and age-related degeneration []. However, emerging evidence defines obesity-induced OA as a distinct metabolic phenotype, with features that transcend simple biomechanical stress []. Unlike age-related OA, this metabolic phenotype affects both weight-bearing (knee, hip) and non-weight-bearing (hand, temporomandibular) joints, implicating metabolic drivers beyond mechanical load. Dysfunctional adipose depots secrete pro-inflammatory cytokines and adipokines that establish chronic low-grade inflammation []. Metabolic dysfunction precedes [] and drives structural joint changes, rather than resulting from mechanical damage. Critically, obesity-induced OA shows potential for prevention and even reversal through targeted metabolic interventions []. These defining features suggest that understanding the molecular and cellular mechanisms underlying this disease is essential for developing mechanism-based therapeutic approaches. Recent reviews have examined various aspects of the obesity-OA relationship, including inflammatory mediators and metabolic dysregulation [, ]. Our synthesis advances this field by integrating depot-specific adipose tissue dysfunction with convergent molecular signalling networks and detailed cellular crosstalk, bridging tissue-level pathology with cellular heterogeneity that previous work has addressed separately. We extensively incorporate single-cell RNA sequencing and spatial transcriptomics findings to characterise the functional diversity of synovial macrophages, fibroblasts, and chondrocytes within the obesity-affected joint microenvironment [–]. Beyond mechanistic insights, we organize therapeutic interventions within a temporal framework spanning early metabolic dysfunction through advanced structural disease, providing stage-appropriate treatment strategies []. Critically, we establish obesity-induced OA as a distinct metabolic disease phenotype that affects joints, and where targeted metabolic interventions demonstrate potential for disease prevention and reversal. This comprehensive, mechanistically grounded synthesis connects molecular pathways with cellular dynamics and clinical translation, advancing both understanding and treatment of obesity-induced OA.