title: Cutting Edge: EZH2 Promotes Osteoclastogenesis by Epigenetic Silencing of the Negative Regulator IRF8.
abstract: Osteoclasts are resorptive cells that are important for homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic mechanisms in osteoclastogenesis. A recent study showed that epigenetic silencing of the negative regulator of osteoclastogenesis Irf8 by DNA methylation is required for osteoclast differentiation. In this study, we investigated the role of EZH2, which epigenetically silences gene expression by histone methylation, in osteoclastogenesis. Inhibition of EZH2 by the small molecule GSK126, or decreasing its expression using antisense oligonucleotides, impeded osteoclast differentiation. Mechanistically, EZH2 was recruited to the IRF8 promoter after RANKL stimulation to deposit the negative histone mark H3K27me3 and downregulate IRF8 expression. GSK126 attenuated bone loss in the ovariectomy mouse model of postmenopausal osteoporosis. Our findings provide evidence for an additional mechanism of epigenetic IRF8 silencing during osteoclastogenesis that likely works cooperatively with DNA methylation, further emphasizing the importance of IRF8 as a negative regulator of osteoclastogenesis.
authors.affiliation: Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.
authors.forename: Celestia
authors.initials: C
authors.lastname: Fang
authors.affiliation: Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.
authors.forename: Se Hwan
authors.initials: SH
authors.lastname: Mun
authors.affiliation: Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.
authors.forename: Min Joon
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.
authors.forename: Koichi
authors.initials: K
authors.lastname: Murata
authors.affiliation: Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.
authors.forename: Seyeon
authors.initials: S
authors.lastname: Bae
authors.affiliation: Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.|Department of Medicine Weill Cornell Medical College.
authors.forename: Baohong
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.|Department of Medicine Weill Cornell Medical College.
authors.forename: Kyung-Hyun
authors.initials: KH
authors.lastname: Park-Min
authors.affiliation: Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.|Department of Medicine Weill Cornell Medical College.|Graduate Program in Immunology and Microbial Pathogenesis Weill Cornell Graduate School of Medical Sciences.
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics*; D000099185:Interferon Regulatory Factor-8
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8; C498409:EZH2 protein, human