From mechanical triggering to metabolic-inflammatory driving: a new paradigm of knee osteoarthritis pathogenesis

Abstract

Background – Knee osteoarthritis (KOA) is a global public health crisis and a leading cause of disability among middle-aged and elderly populations. Historically characterized as a passive “wear-and-tear” process, the understanding of KOA has undergone a fundamental paradigm shift. While aberrant biomechanical loading remains a primary initiator of joint damage, it is increasingly recognized that systemic metabolic dysfunction and chronic low-grade inflammation act as the critical forces driving sustained disease progression. Main body – Abnormal mechanical loading is the primary initiator of KOA, inducing chondrocyte micro-injury and ultrastructural extracellular matrix disruption. Mechanotransduction via integrins and ion channels activates pro-inflammatory and degradative pathways, such as NF-κB and Wnt/β-catenin, tilting the joint toward a catabolic state. While traditional views emphasize physical attrition, emerging evidence suggests that mechanical stress may be perpetuated by systemic metabolic factors. Obesity potentially acts as a pathophysiological bridge, where the infrapatellar fat pad (IFP) might function as a metabolic hub, possibly translating endocrine signals into local joint inflammation through adipokine secretion and extracellular vesicle communication. Furthermore, molecular investigations into the lipid metabolism axis, including the CH25H-CYP7B1-RORα signaling pathway, provide preliminary evidence for metabolic influence on chondrocyte senescence. While clinical evidence for these metabolic drivers is still evolving, synovial fluid metabolomics is being actively explored to identify potential biomarkers. Conclusions – The evolving pathological landscape of KOA necessitates a transition in clinical management from isolated symptomatic relief toward integrated metabolic regulatory strategies. This new paradigm—defined by “mechanical initiation, metabolic-inflammatory driving, and heightened mechanical sensitivity”—provides a rigorous theoretical foundation for developing innovative, disease-modifying prevention and therapeutic models, including targeted nutritional interventions and metabolic-modulating pharmacology.