From disease model to therapeutic insight: An engineered hydrogel reveals the role of matrix viscous dissipation in intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain. Although the mechanical functions of the nucleus pulposus (NP) critically relies on its viscous dissipation, the role of this property in IVDD remains unclear. Here, we established a correlation between reduced NP viscous dissipation and disease severity in both clinical specimens and a rat model. Using engineered hydrogels that independently mimic the viscous dissipation properties of healthy and degenerated NP, we found that decreased viscous dissipation induces NP cells (NPCs) senescence by suppressing YAP. Further mechanistic investigation revealed that NPCs likely sense changes in extracellular matrix (ECM) viscous dissipation primarily through ITGB1, which subsequently regulate cell adhesion and inhibit YAP activity. Downstream of YAP, reduced viscous dissipation leads to decreased nuclear envelope integrity and aberrant accumulation of cytosolic DNA in NPCs, thereby activating the cGAS-STING pathway and driving NPCs senescence. The senescence of NPCs induced by these events changed the components of ECM, which may further reduce viscous dissipation, potentially creating a vicious cycle. By pharmacological activation of YAP and the implantation of a mechanically biomimetic hydrogel, we alleviated the vicious cycle and suppressed IVDD progression in vivo. These findings provide important insights into the pathogenesis of IVDD and suggest promising therapeutic strategies.