title: The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway.
abstract: 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.
authors.affiliation: Department of orthopedics, Second affiliated hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
authors.forename: Linwei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of orthopedics, Second affiliated hospital, Wenzhou Medical university, Wenzhou, Zhejiang Province, China.
authors.forename: Yaosen
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of orthopedics, Second affiliated hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of pediatrics, Second affiliated hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of orthopedics, Second affiliated hospital, Wenzhou Medical university, Wenzhou, Zhejiang Province, China.
authors.forename: Liaojun
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of orthopedics, Second affiliated hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
authors.forename: Fangcai
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D020219:Chondrogenesis / Q000187:drug effects*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D010003:Osteoarthritis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics; D000099274:Frizzled-Related Proteins
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; D006023:Glycoproteins; D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D011728:Pyridones; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C495270:CTNNB1 protein, human; C578195:EPZ005687; C498409:EZH2 protein, human