Signaling pathways and ion channels in osteoarthritis: a review of recent advances

The understanding of osteoarthritis (OA) has gradually evolved from the traditional perspective of it being a mere "wear-and-tear" joint disease to a more comprehensive view that characterizes it as a degenerative joint disease marked by chronic low-grade inflammation and immune imbalance. The progression of OA is closely linked to abnormal mechanical loading and the activation of the innate immune system. This narrative review examines the role of mechanosensory-immune signaling networks in OA, with a specific focus on ion channels as receptors for upstream mechanical and chemical stimuli. These channels facilitate signal transduction through ion fluxes, such as Ca²⁺, to key inflammatory pathways, including nuclear factor κB (NF-κB), cyclic guanosine monophosphate-adenylate synthase-interferon gene stimulator (cGAS-STING), adenylate-activated protein kinase (AMPK), and the NLRP3 inflammasome. Furthermore, it integrates signaling axes such as the protein kinase/Yes-related protein (Hippo/YAP) pathway, the Wnt/β-catenin pathway, and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling axes, analyzing their context-dependent bidirectional regulation during cartilage homeostasis maintenance and the degeneration process. The primary contributions of this study include the construction of an integrated mechanobiological-immunological transduction network framework that encompasses "ion channels-signaling pathways-immune responses." This framework highlights the hierarchical crosstalk and positive feedback amplification effects among these pathways, while exploring their dynamic and reversible regulatory characteristics under varying mechanical and inflammatory microenvironments. Ultimately, this framework facilitates a systems-level understanding of the pathological progression of OA and provides a theoretical foundation for the development of multi-target synergistic therapies and stage-specific precision intervention strategies.