Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1

作     者：Yu Jin Zhen Liu Zhenxia Li Hairui Li Cheng Zhu Ruomei Li Ting Zhou Bing Fang Yu Jin;Zhen Liu;Zhenxia Li;Hairui Li;Cheng Zhu;Ruomei Li;Ting Zhou;Bing Fang

作者机构：Department of OrthodonticsShanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghaiChina 

出 版 物：《International Journal of Oral Science》 (国际口腔科学杂志（英文版）)

年 卷 期：2022年第14卷第3期

页      面：396-409页

核心收录：

学科分类：1003[医学-口腔医学] 1002[医学-临床医学] 100210[医学-外科学(含：普外、骨外、泌尿外、胸心外、神外、整形、烧伤、野战外)] 10[医学] 

基　　金：supported by National Natural Science Foundation of China(11932012,81870790 and 31801233) Science and Technology Commission of Shanghai Municipality(18441903600) Clinical Research Plan of SHDC(No.SHDC2020CR3009A) Innovative Research Team of High-level Local Universities in Shanghai(SSMU-ZDCX20180902) 

主　　题：Histone demethylase JMJD3 downregulation protects against aberrant force induced osteoarthritis through epigenetic control of NR4A1 

摘      要：Osteoarthritis(OA)is a prevalent joint disease with no effective treatment *** mechanical stimuli was demonstrated to be an essential factor for OA *** multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains *** demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and ***,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still *** this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in ***,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte *** investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its *** experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory *** vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was *** importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably *** together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA *** work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.