The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway.
The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway.
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EZH2 的抑制通过 Wnt/β-连环蛋白途径改善骨关节炎的发展
DOI：
10.1038/srep29176
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发表时间：
2016-08-19
影响因子：
4.6
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Chen L;Wu Y;Wu Y;Wang Y;Sun L;Li F
本研究的目的是阐明组蛋白甲基转移酶增强子2(EZH2)在骨关节炎(OA)的病理生理学中的作用，并开发一种调控EZH2活性的策略用于骨关节炎的治疗。采用免疫印迹法比较EZH2在正常人和骨性关节炎软骨中的表达。实时荧光定量聚合酶链式反应检测EZH2基因过表达及抑制对软骨细胞肥大相关基因表达的影响；染色质免疫沉淀聚合酶链式反应分析Wnt抑制因子SFRP1启动子的组蛋白甲基化。用组织学方法评价EZH2抑制剂EPZ005687对小鼠关节的影响。我们发现，与正常人相比，骨性关节炎患者软骨细胞中EZH2水平显著升高。过表达EZH2可促进Hedgehog、MMP13、ADAMTS-5和COLX的表达，抑制EZH2则逆转这一趋势。此外，EZH2的诱导通过增加SfRP1启动子上的H3K27me3来激活β-catenin信号，而抑制EZH2则抑制β-catenin信号。最后，关节腔注射EPZ005687延缓了小鼠骨性关节炎的发育。这些结果表明，EZH2活性与骨性关节炎的发育有关。药物抑制EZH2可能是治疗骨性关节炎的有效途径。
The purpose of our study was to elucidate the role of the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in the pathophysiology of osteoarthritis (OA) and to develop a strategy to modulate EZH2 activity for OA treatment. The expression of EZH2 in normal and OA human cartilage was compared by western blotting. The effect of EZH2 overexpression and inhibition on chondrocyte hypertrophy related gene expression was examined by real-time PCR, and histone methylation on the promoter of the Wnt inhibitor SFRP1 was analyzed using a chromatin immunoprecipitation (ChIP) PCR. Histological assessment of OA mice joint was carried out to assess the in vivo effects of EZH2 inhibitor EPZ005687. We found EZH2 level was significantly increased in the chondrocytes of OA patients compared to normal humans. Overexpression of EZH2 promoted Indian Hedgehog, MMP-13, ADAMTS-5 and COLX expression, while inhibition of EZH2 reversed this trend. Furthermore, the induction of EZH2 led to β-catenin signaling activation by increasing H3K27me3 on the promoter of SFRP1, while the inhibition of EZH2 silenced β-catenin signaling. Finally, intraarticular injection of EPZ005687 delayed OA development in mice. These results implicated EZH2 activity in OA development. Pharmacological inhibition of EZH2 may be an effective therapeutic approach for osteoarthritis.