Mechanotransduction in intervertebral disc degeneration: from compartment-specific sensors to translational frontiers.

Intervertebral disc degeneration is a major structural correlate of low back pain and is increasingly viewed as a disorder of mechanobiological dysregulation rather than simple mechanical overload. Over the past decade, disc cells have been shown to engage a diverse mechanosensory repertoire, including Piezo1, transient receptor potential channels, integrin-focal adhesion complexes, acid-sensing ion channels, primary cilia, and cytoskeletal-nuclear signaling axes. These upstream sensors converge on a more limited set of downstream hubs, most notably Yes-associated protein and transcriptional co-activator with PDZ-binding motif and mitogen-activated protein kinase/nuclear factor kappa B, which then shape cell-fate programs such as senescence, autophagy, pyroptosis, and ferroptosis. The extracellular matrix functions both as the substrate and as the output of mechanotransduction, creating a self-reinforcing loop in which degenerative matrix changes amplify pathological mechanosensing. Despite substantial molecular progress, mechanistic understanding remains concentrated in nucleus pulposus models, whereas matched cross-compartment analyses involving the annulus fibrosus, cartilage endplate, and vertebral interface remain limited. As a result, the relative importance of mechanosensors across compartments and loading contexts is still unresolved. Multiscale platforms, including finite element modeling, tunable hydrogels, organ culture, and quantitative magnetic resonance imaging, have strengthened causal interrogation, but translational progress remains largely preclinical. The clearest advance to date has come from biomaterial-based strategies, supported by early human feasibility data for injectable hydrogel implants. In this Review, we synthesize mechanotransduction in intervertebral disc degeneration, summarize the relative maturity of current mechanistic understanding across compartments and signaling branches, and discuss the importance of systematic cross-compartment comparison alongside single-sensor, single-compartment studies.