Systemic implications of osteoarthritis: from local degeneration to systemic metabolic Dysregulation

Background Traditionally viewed as a localized “wear-and-tear” pathology, osteoarthritis (OA) is now increasingly recognized as a complex systemic disorder driven by metabolic and inflammatory dysregulation. This review synthesizes emerging evidence to redefine the pathogenesis of OA from a “whole-joint” to a “whole-body” perspective. Main body We first examine local degradation mechanisms, identifying synovial macrophage polarization, mitochondrial dysfunction, and autophagy defects as critical drivers of a pro-inflammatory milieu. Furthermore, we elucidate the mechanism of inflammatory “spillover,” wherein intra-articular cytokines (e.g. IL-1β, TNF-α) and extracellular vesicles (EVs) enter the circulation, contributing to a state of low-grade systemic inflammation. This systemic inflammatory burden is closely associated with a cascade of comorbidities, including endothelial dysfunction and atherosclerosis potentially mediated by shared mechanisms such as the “bone-vascular axis,” sarcopenia through the pain-disuse cycle, and central sensitization coupled with HPA axis dysregulation. Conversely, systemic metabolic disorders, particularly obesity-induced “metaflammation” and insulin resistance, exacerbate joint degeneration through adipokines (e.g. leptin, resistin), forming a vicious bidirectional cycle. Conclusions We conclude by discussing how this systemic paradigm necessitates a shift in therapeutic strategies, moving from symptomatic management to holistic interventions. These include targeting metabolic pathways (e.g. metformin), clearing senescent cells (senolytics), and adopting a multidisciplinary precision medicine approach based on inflammatory and metabolic phenotyping.