Background The 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. Results The 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. Conclusions A 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.

中文翻译：

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EZH2 和 NOX4 之间的正反馈回路调节年龄相关性椎间盘退变中的髓核细胞衰老。

背景髓核（NP）细胞的衰老在椎间盘（IVD）变性（IDD）的发病机制中起着至关重要的作用。NADPH 氧化酶 4 (NOX4) 相关的氧化应激已被证明可诱导 NP 细胞过早衰老。zeste homolog 2 (EZH2) 增强子是调节细胞衰老的关键基因。本研究的目的是研究 EZH2 在 NOX4 诱导的 NP 细胞衰老中的作用以及 EZH2 和 NOX4 之间的反馈回路。结果衰老大鼠退变椎间盘中EZH2表达下调，NOX4、p16表达上调。EZH2 通过 H3K27me3-p16 途径调节 NP 细胞衰老。此外，EZH2 通过 NOX4 基因启动子中的组蛋白 H3 赖氨酸 27 三甲基化 (H3K27me3) 调节 NP 细胞中 NOX4 的表达。此外，NOX4 通过经典的 Wnt/β-catenin 途径下调 NP 细胞中 EZH2 的表达。结论 EZH2 和 NOX4 之间的正反馈回路参与调节 NP 细胞衰老，这为 IDD 的机制提供了新的见解和 IDD 的潜在治疗靶点。