Excessive reactive oxygen species (ROS) generation in degenerative intervertebral disc (IVD) indicates the contribution of oxidative stress to IVD degeneration (IDD), giving a novel insight into the pathogenesis of IDD. ROS are crucial intermediators in the signaling network of disc cells. They regulate the matrix metabolism, proinflammatory phenotype, apoptosis, autophagy, and senescence of disc cells. Oxidative stress not only reinforces matrix degradation and inflammation, but also promotes the decrease in the number of viable and functional cells in the microenvironment of IVDs. Moreover, ROS modify matrix proteins in IVDs to cause oxidative damage of disc extracellular matrix, impairing the mechanical function of IVDs. Consequently, the progression of IDD is accelerated. Therefore, a therapeutic strategy targeting oxidative stress would provide a novel perspective for IDD treatment. Various antioxidants have been proposed as effective drugs for IDD treatment. Antioxidant supplementation suppresses ROS production in disc cells to promote the matrix synthesis of disc cells and to prevent disc cells from death and senescence in vitro. However, there is not enough in vivo evidence to support the efficiency of antioxidant supplementation to retard the process of IDD. Further investigations based on in vivo and clinical studies will be required to develop effective antioxidative therapies for IDD.
Senescence is a crucial driver of intervertebral disc degeneration (IDD). Disc cells are exposed to high oxygen tension due to neovascularization in degenerative discs. However, the effect of oxygen tension on disc cell senescence was unknown. Herein, rat nucleus pulposus (NP) cells were cultured under 20% O2 or 1% O2. Consequently, ROS induced by 20% O2 caused DNA damage and then activated p53-p21-Rb and p16-Rb pathways via ERK signaling to induce NP cell senescence. It also induced catabolic and proinflammatory phenotype of NP cells via MAPK and NF-κB pathways. Furthermore, 20% O2 was found to upregulate Nox4 in NP cells. Small interfering RNA against Nox4 reduced ROS production induced by 20% O2 and consequently suppressed premature senescence of NP cells. On the contrary, NP cells overexpressing Nox4 produced more ROS and rapidly developed senescent signs. In consistent with the in vitro studies, the expression of Nox4, p21, and Rb was upregulated in rat degenerative discs. This study, for the first time, demonstrates that Nox4 is an oxygen-sensing enzyme and a main ROS source in NP cells. Nox4-dependent ROS are genotoxic and a potent trigger of NP cell senescence. Nox4 is a potential therapeutic target for disc cell senescence and IDD.
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.
Intervertebral disc (IVD) cell senescence is a recognized mechanism of intervertebral disc degeneration (IDD). Elucidating the molecular mechanisms underlying disc cell senescence will contribute to understanding the pathogenesis of IDD. We previously reported that N-acetylated proline-glycine-proline (N-Ac-PGP), a matrikine, is involved in the process of IDD. However, its roles in IDD are not well understood. Here, using rat nucleus pulposus (NP) cells, we found that N-Ac-PGP induced premature senescence of NP cells by binding to CXCR1. N-Ac-PGP induced DNA damage and reactive oxygen species accumulation in NP cells, which resulted in activation of the p53-p21-Rb and p16-Rb pathways. Moreover, the RT profiler PCR array showed that N-Ac-PGP down-regulates the expression of antioxidant genes in NP cells, suggesting a decline in the antioxidants of NP cells. On the other hand, N-Ac-PGP up-regulated the expression of matrix catabolic genes and inflammatory genes in NP cells. Concomitantly, N-Ac-PGP reinforced the destructive effects of senescent NP cells on the homeostasis of the IVDs in vivo. Our study suggests that N-Ac-PGP plays critical roles in the pathogenesis of IDD through the induction of premature senescence of disc cells and via the activation of catabolic and inflammatory cascades in disc cells. N-Ac-PGP also deteriorates the redox environment of disc cells. Hence, N-Ac-PGP is a new potential therapeutic target for IDD.
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