Cyclic mechanical tension reinforces DNA damage and activates the p53-p21-Rb pathway to induce premature senescence of nucleus pulposus cells.

Intervertebral disc (IVD) degeneration (IDD) is a widely recognized contributor to low back pain. Mechanical stress is a crucial etiological factor of IDD. During the process of IDD, a vicious circle is formed between abnormal mechanical stress and the damage of disc structure and function. Notably, the pathological process of IDD is mediated by the phenotypic shift of IVD cells from an extracellular matrix anabolic phenotype to a catabolic and pro-inflammatory phenotype. Therefore, the effects of mechanical stress on the initiation and progression of IDD depend on the mechanobiology of IVD cells. Recently, disc cell senescence was identified as a new hallmark of IDD. However, the senescent response of disc cells to mechanical stress remains unknown. In this study, we found that prolonged exposure of cyclic mechanical tension (CMT) with unphysiological magnitude generated by the Flexercell tension system markedly induced premature senescence of nucleus pulposus (NP) cells. CMT augmented the DNA damage of NP cells, but did not affect the redox homeostasis of NP cells. Moreover, the p53-p21-retinoblastoma protein (Rb) pathway was activated by CMT to mediate the CMT-induced premature senescence of NP cells. The findings are beneficial to understanding the mechanism of disc cell senescence and the mechanobiology of disc cells further. It suggests that prolonged abnormal mechanical stress accelerates the establishment and progression of disc cell senescence and consequently impairs the structural and functional homeostasis of IVDs to cause IDD. Preventing the pro-senescent effect of mechanical stress on IVD cells is a promising approach to delay the process of IDD.