EZH2/miR-142-3p/HMGB1 axis mediates chondrocyte pyroptosis by regulating endoplasmic reticulum stress in knee osteoarthritis  

作　　者：Yang Chen Shanshan Dong Xin Zeng Qing Xu Mingwei Liang Guangneng Liao Lan Li Bin Shen Yanrong Lu Haibo Si 

机构地区：[1]Department of Orthopedic Surgery&Key Laboratory of Transplant Engineering and Immunology,Regenerative Medicine Research Center,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China [2]Department of Discipline Construction,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China [3]Institute of Clinical Pathology,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China [4]Experimental Animal Center,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China

出　　处：《Chinese Medical Journal》2025年第1期79-92,共14页中华医学杂志(英文版)

基　　金：supported by the National Natural Science Foundation of China(No.81802210);the Science&Technology Department of Sichuan Province(No.2021YFS0122);the Health Commission of Sichuan Province(No.20PJ056);the National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(No.Z2018B20).

摘　　要：Background:Knee osteoarthritis(OA)is still challenging to prevent or treat.Enhanced endoplasmic reticulum(ER)stress and increased pyroptosis in chondrocytes may be responsible for cartilage degeneration.This study aims to investigate the effect of ER stress on chondrocyte pyroptosis and the upstream regulatory mechanisms,which have rarely been reported.Methods:The expression of the histone methyltransferase enhancer of zeste homolog 2(EZH2),microRNA-142-3p(miR-142-3p),and high mobility group box 1(HMGB1)and the levels of ER stress,pyroptosis,and metabolic markers in normal and OA chondrocytes were investigated by western blotting,quantitative polymerase chain reaction,immunohistochemistry,fluorescence in situ hybridization,fluorescein amidite-tyrosine-valine-alanine-aspartic acid-fluoromethyl ketone(FAM-YVAD-FMK)/Hoechst 33342/propidium iodide(PI)staining,lactate dehydrogenase(LDH)release assays,and cell viability assessments.The effects of EZH2,miR-142-3p,and HMGB1 on ER stress and pyroptosis and the hierarchical regulatory relationship between them were analyzed by chromatin immunoprecipitation,luciferase reporters,gain/loss-of-function assays,and rescue assays in interleukin(IL)-1β-induced OA chondrocytes.The mechanistic contribution of EZH2,miR-142-3p,and HMGB1 to chondrocyte ER stress and pyroptosis and therapeutic prospects were validated radiologically,histologically,and immunohistochemically in surgically induced OA rats.Results:Increased EZH2 and HMGB1,decreased miR-142-3p,enhanced ER stress,and activated pyroptosis in chondrocytes were associated with OA occurrence and progression.EZH2 and HMGB1 exacerbated and miR-142-3p alleviated ER stress and pyroptosis in OA chondrocytes.EZH2 transcriptionally silenced miR-142-3p via H3K27 trimethylation,and miR-142-3p posttranscriptionally silenced HMGB1 by targeting the 3′-UTR of the HMGB1 gene.Moreover,ER stress mediated the effects of EZH2,miR-142-3p,and HMGB1 on chondrocyte pyroptosis.In vivo experiments mechanistically validated the hierarchical regulatory

关 键 词：OSTEOARTHRITIS EZH2 MicroRNA-142-3p HMGB1 Endoplasmic reticulum stress PYROPTOSIS 

分 类 号：R684.3[医药卫生—骨科学]