The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway

Sci Rep. 2016 Aug 19;6:29176. doi: 10.1038/srep29176.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Chondrocytes / drug effects
  • Chondrocytes / pathology
  • Chondrogenesis / drug effects*
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
  • Enhancer of Zeste Homolog 2 Protein / genetics*
  • Gene Expression Regulation / drug effects
  • Glycoproteins / genetics
  • Humans
  • Indazoles / administration & dosage*
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Osteoarthritis / drug therapy*
  • Osteoarthritis / genetics
  • Osteoarthritis / pathology
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Pyridones / administration & dosage*
  • Wnt Signaling Pathway / drug effects
  • beta Catenin / genetics


  • CTNNB1 protein, human
  • EPZ005687
  • Glycoproteins
  • Indazoles
  • Intracellular Signaling Peptides and Proteins
  • Pyridones
  • WD repeat containing planar cell polarity effector
  • beta Catenin
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein