Mechanobiology in Osteoarthritis: From Crosstalk of Mechanosensitive Signaling Pathways to the Intervention Mechanisms and Therapeutic Potential of Exercise

Osteoarthritis (OA) is the most prevalent joint degeneration globally. Once considered passive "wear and tear", it is now recognized as a metabolically active, whole-joint disease driven by genetic, metabolic, inflammatory, and mechanical factors. The core pathology is failed mechanotransduction, where a dysregulated mechanosensitive signaling network disrupts joint homeostasis, causing cartilage degradation, synovitis, and pain. This review re-examines OA pathogenesis through network biology, highlighting that OA stems from the dysregulation of a complex mechanosensitive network-including Piezo, Transient Receptor Potential Vanilloid 4 (TRPV4), Integrin-Focal Adhesion Kinase (integrin-FAK), Hippo/yes-associated protein-transcriptional coactivator with PDZ-binding motif (Hippo/YAP-TAZ), and Wingless/Integrated /β-catenin (Wnt/β-catenin) pathways. These pathways engage in extensive crosstalk via shared secondary messengers (calcium ions, reactive oxygen species) to determine cell fate. Furthermore, exercise acts as a physiological "mechanotherapy" to recalibrate this network, shifting cellular responses from catabolic/inflammatory states to anabolic/homeostatic ones. We also explore the translational potential of restoring network balance using precision mechanotherapy, advanced drug delivery, and biomaterials. OA is fundamentally a systemic network failure from failed mechanotransduction. Future therapies should shift from single-target interventions to systemic reprogramming of the dysregulated network. Utilizing biomaterials, smart drug delivery, and personalized exercise can advance OA management from symptomatic relief to active tissue regeneration and disease reversal.