EZH2-H3K27me3-Mediated Epigenetic Silencing of DKK1 Induces Nucleus Pulposus Cell Pyroptosis in Intervertebral Disc Degeneration by Activating NLRP3 and NAIP/NLRC4

被引：1

作者：

Yao, Qijun ^{[1
]}

Lei, Yue ^{[1
]}

Zhang, Yongxu ^{[1
]}

Chen, Haoran ^{[1
]}

Dong, Xiaowei ^{[1
]}

Ye, Zhiqiang ^{[1
]}

Liang, Haidong ^{[1
]}

机构：

[1] Dalian Med Univ, Hosp 2, Dept Bone & Soft Tissue Repair & Reconstruct Surg, 467 Zhongshan Rd, Dalian 116000, Liaoning, Peoples R China

来源：

INFLAMMATION | 2025年 / 48卷 / 02期

关键词：

Intervertebral disc degeneration; Enhancer of zeste homologue 2; Dickkopf1; Histone methylation; Inflammasomes; Pyroptosis; INFLAMMASOME; SENESCENCE; EZH2;

D O I：

10.1007/s10753-024-02096-1

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Nucleus pulposus (NP) cell pyroptosis is crucial for intervertebral disc degeneration (IDD). However, the precise mechanisms underlying pyroptosis in IDD remain elusive. Therefore, this study aimed to investigate how dickkopf-1 (DKK1) influences NP cell pyroptosis and delineate the regulatory mechanisms of IDD. Behavioral tests and histological examinations were conducted in rat IDD models to assess the effect of DKK1 on the structure and function of intervertebral discs. Detected pyroptosis levels using Hoechst 33,342/propidium iodide (PI) double staining, and determined pyroptosis-related protein expression via western blotting. The cellular mechanisms of DKK1 in pyroptosis were explored in interleukin (IL)-1 beta-induced NP cells transfected with or without DKK1 overexpression plasmids (oe-DKK1). In addition, IL-1 beta-treated NP cells transfected with sh-EZH2 and/or sh-DKK1 were utilized to clarify the interplay between the enhancer of zeste homologue 2 (EZH2) and DKK1 in pyroptosis. Additionally, the epigenetic regulation of DKK1 by EZH2 was explored in NP cells treated with the EZH2 inhibitors GSK126/DZNep. DKK1 expression decreased in IDD rats. Transfection with oe-DKK1 reduced pro-inflammatory factors and extracellular matrix markers in IDD rats. In IL-1 beta-induced NP cells, DKK1 overexpression suppressed pyroptosis and inhibited the NLRP3 and NAIP/NLRC4 inflammasome activation. EZH2 knockdown increased DKK1 expression and reduced pyroptosis-related proteins. Conversely, DKK1 downregulation reversed the inhibitory effects of EZH2 knockdown on pyroptosis. Furthermore, EZH2 suppressed DKK1 expression via H3K27 methylation at the DKK1 promoter. EZH2 negatively regulates DKK1 expression via H3K27me3 methylation, promoting NP cell pyroptosis in IDD patients. This regulatory effect involves the activation of NLRP3 and NAIP/NLRC4 inflammasomes.Graphical AbstractThe potential mechanism of IL-1 beta induced pyroptosis NP cells. EZH2-H3K27me3-mediated epigenetic silencing of DKK1 induces nucleus pulposus cell pyroptosis in intervertebral disc degeneration by activating NLRP3 and NAIP/NLRC4

引用

页码：902 / 918

页数：17

共 46 条

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