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

BackgroundKnee 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 bodyAbnormal 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.