Abstract
Despite being a leading cause of chronic pain and disability, the underlying mechanisms of intervertebral disc (IVD) degeneration (IVDD) remain unclear. Emerging evidence suggests that mechanosensation (the ability of the skeletal system to perceive mechanical and biochemical signals) mediated by abnormal mechanical loading plays a critical role in the regulation of IVD health. This review examines the complex interactions amongIVDs, intraosseous sensory mechanisms, and the central nervous system (CNS), with a particular focus on the roles of pathways such as PGE2/EP4, Wnt/β-catenin, and NF-κB. This review elucidates the manner in which mechanical stress and aberrant signaling disrupt the homeostasis of the nucleus pulposus (NP), cartilaginous endplate (CEP) and annulus fibrosus (AF), thereby driving degeneration and exacerbating pain. Furthermore, targeted therapeutic strategies, including the modulation of skeletal interoception and dynamic mechanical loading, present novel avenues for reversing IVDD progression. By integrating skeletal biology with spinal pathology, this work offers a novel perspective on the pathogenesis of IVDD and identifies promising strategies for clinical intervention. These findings highlight the potential of targeting skeletal interoception to mitigate IVDD and associated pain, paving the way for innovative, mechanism-driven therapies.