Pathological Roles of the STAT3 Pathway in the Pathogenesis of Osteoarthritis

Osteoarthritis (OA) is characterized by progressive cartilage degeneration, synovial inflammation, and subchondral bone remodeling. Mechanical stress and inflammation, mediated by activation of innate immunity and cellular senescence, may function as bidirectional, mutually reinforcing drivers of OA onset and progression. Signal transducer and activator of transcription 3 (STAT3), activated by various factors, regulates multiple intracellular pathophysiological processes. In the OA joint, sustained STAT3 activation is observed in synovial fibroblasts, chondrocytes, osteoblasts, and macrophages. This review summarizes accumulating evidence for STAT3 involvement in the onset and progression of OA and highlights the pathological roles of the STAT3 signaling pathway in OA pathogenesis. STAT3 activation stimulates the production of matrix-degrading enzymes in chondrocytes and enhances the release of proinflammatory cytokines in synovial fibroblasts. Additionally, STAT3 activation in macrophages accelerates the secretion of inflammatory mediators, thereby creating a vicious cycle that sustains chronic inflammation in the OA joint. Moreover, STAT3 activation causes abnormal bone sclerosis due to disturbances in subchondral bone remodeling. Altered subchondral bone structure may, in turn, activate the STAT3 signaling pathway in chondrocytes through changes in mechanical loading. Therefore, this exacerbating feedback loop between cartilage and subchondral bone further accelerates OA progression. Collectively, these STAT3-mediated multicellular interactions contribute to disease onset and progression throughout the joint and likely constitute a critical pathological pathway in OA development.