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

Abstract

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.

Lysine-specific histone demethylase 1B (LSD2/KDM1B) represses p53 expression to promote proliferation and inhibit apoptosis in colorectal cancer through LSD2-mediated H3K4me2 demethylation

“…These findings indicate that LSD2 induces tumor proliferation and inhibits apoptosis via p53 expression. We found that the knockdown of LSD2 caused G1/S arrest in CRC cell lines, and the effect of p53 on cell cycle arrest is mainly dependent on the p53-p21-Rb pathway [ 31 ]. Therefore, we detected the expression of p21 and RB in this pathway, and found that LSD2 regulates the cell cycle distribution of CRC through the p53-p21-Rb pathway in vivo and in vitro, which promotes the proliferation and growth of CRC.…”

Compromised nuclear envelope integrity drives tumor cell invasion

“…In these tissues, NE ruptures are associated with senescence and aging phenomena that affect cell proliferation, survival, and ultimately tissue function. NE ruptures are often accompanied by DNA damage of unknown underlying mechanism(s) ( 2,3,12,14,15 ). Here, we investigated the consequences of nuclear deformation and rupture associated with cell migration in crowded tissues, focusing on mammary duct carcinoma.…”

Autophagy protects nucleus pulposus cells from cyclic mechanical tension‑induced apoptosis

“…ROS levels in NP cells subjected to 20% CMT are increased by 3-MA. Our previous study indicated that cMT had minimal effect on the production of ROS in NP cells (22). In the present study, the ROS levels of NP cells pretreated with 3-MA or rapamycin following cMT were measured at 24 h. The results showed that the level of ROS in NP cells was increased significantly in the combined CMT and 3-MA group (P<0.05), with no significant differences observed among other groups (Fig.…”

“…These results suggest that maintaining the autophagy level of disc cells is conducive to alleviating apoptosis caused by mechanical stress and may assist in delaying the process of Idd. However, the cellular biological response to mechanical stress depends on different factors, including the duration, frequency and magnitude of mechanical stress, in addition to the disc cell type (22,34,35), and further experiments are warranted to clarify these issues.…”