Abstract
BackgroundThe senescence of nucleus pulposus (NP) cells plays a vital role in the pathogenesis of intervertebral disc (IVD) degeneration (IDD). NADPH oxidase 4 (NOX4)-associated oxidative stress has been shown to induce premature NP cell senescence. Enhancer of zeste homolog 2 (EZH2) is a crucial gene regulating cell senescence. The aim of this study was to investigate the roles of EZH2 in NOX4-induced NP cell senescence and a feedback loop between EZH2 and NOX4.ResultsThe down-regulation of EZH2 and the up-regulation of NOX4 and p16 were observed in the degenerative discs of aging rats. EZH2 regulated NP cell senescence via the H3K27me3-p16 pathway. Also, EZH2 regulated the expression of NOX4 in NP cells through the histone H3 lysine 27 trimethylation (H3K27me3) in the promoter of NOX4 gene. Furthermore, NOX4 down-regulated EZH2 expression in NP cells via the canonical Wnt/β-catenin pathway.ConclusionsA positive feedback loop between EZH2 and NOX4 is involved in regulating NP cell senescence, which provides a novel insight into the mechanism of IDD and a potential therapeutic target for IDD.
Highlights
The senescence of nucleus pulposus (NP) cells plays a vital role in the pathogenesis of intervertebral disc (IVD) degeneration (IDD)
The mean fluorescence intensity of NADPH oxidase 4 (NOX4) in 2 M were lower than 10 M significantly, but Enhancer of zeste homolog 2 (EZH2) was opposite (Additional file 1: Figure S1). p16 was significantly upregulated in 10 M compared to 2 M (Fig. 2b)
These findings were consistent with immunoblot analysis and immunohistochemistry. These results suggested the feedback loop between EZH2 and NOX4 existed and was involved in NP cell senescence
Summary
The senescence of nucleus pulposus (NP) cells plays a vital role in the pathogenesis of intervertebral disc (IVD) degeneration (IDD). The aim of this study was to investigate the roles of EZH2 in NOX4-induced NP cell senescence and a feedback loop between EZH2 and NOX4. Nucleus pulposus (NP) cell senescence plays a crucial role in the pathogenesis of IDD. The senescence-associated secretory phenotype (SASP) of NP cells includes a large number of cytokines, chemokines and matrix proteases. These factors promote extracellular matrix (ECM) degradation and induce the death or senescence of adjacent NP cells [7]. Liu et al Cell Div (2020) 15:2 senescent NP cells disturb the homeostasis of IVDs to induce IDD [8]
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