title: BET Inhibitor JQ1 Blocks Inflammation and Bone Destruction.
abstract: BET proteins are a group of epigenetic regulators controlling transcription through reading acetylated histone tails and recruiting transcription complexes. They are considered as potential therapeutic targets in many distinct diseases. A novel synthetic bromodomain and extraterminal domain (BET) inhibitor, JQ1, was proved to suppress oncogene transcription and inflammatory responses. The present study was aimed to investigate the effects of JQ1 on inflammatory response and bone destruction in experimental periodontitis. We found that JQ1 significantly suppressed lipopolysaccharide (LPS)-stimulated inflammatory cytokine transcription, including interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α), as well as receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast markers, such as c-Fos, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP) and cathepsin K in vitro. JQ1 also inhibited toll-like receptors 2/4 (TLR2/4) expression and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation. Chromatin immunoprecipitation and quantitative polymerase chain reaction (ChIP-qPCR) revealed that JQ1 neutralized BRD4 enrichment at several gene promoter regions, including NF-κB, TNF-α, c-Fos, and NFATc1. In a murine periodontitis model, systemic administration of JQ1 significantly inhibited inflammatory cytokine expression in diseased gingival tissues. Alveolar bone loss was alleviated in JQ1-treated mice because of reduced osteoclasts in periodontal tissues. These unprecedented results suggest the BET inhibitor JQ1 as a prospective new approach for treating periodontitis.
authors.affiliation: Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA 02111, USA State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu 610041, China.
authors.forename: S
authors.initials: S
authors.lastname: Meng
authors.affiliation: Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA 02111, USA State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu 610041, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA 02111, USA State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu 610041, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA 02111, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Tu
authors.affiliation: Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA 02111, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA 02111, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA 02111, USA.
authors.forename: D
authors.initials: D
authors.lastname: Murray
authors.affiliation: Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA 02111, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Cancer Preventive Material Development Research Center (CPMDRC) & Institute, College of Oriental Medicine, Kyunghee University, Seoul, 130-701 South Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu 610041, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA 02111, USA Department of Anatomy and Cell Biology, Tufts University School of Medicine, Sackler School of Graduate Biomedical Sciences, Boston, MA 02111, USA jk.chen@tufts.edu.
authors.forename: J
authors.initials: J
authors.lastname: Chen
mesh_terms: D000135:Acid Phosphatase / Q000187:drug effects; D016301:Alveolar Bone Loss / Q000517:prevention & control*; D000818:Animals; D056657:Cathepsin K / Q000187:drug effects; D002454:Cell Differentiation; D002460:Cell Line; D053583:Interleukin-1beta / Q000187:drug effects; D007527:Isoenzymes / Q000187:drug effects; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects; D050778:NFATC Transcription Factors / Q000187:drug effects; D009687:Nuclear Proteins / Q000627:therapeutic use*; D010010:Osteoclasts / Q000187:drug effects; D010518:Periodontitis / Q000517:prevention & control*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D050783:Proto-Oncogene Proteins c-ets / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects; D053245:RANK Ligand / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors; D018808:Transcription Factor AP-1 / Q000187:drug effects; D014157:Transcription Factors / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects; D000092468:Bromodomain Containing Proteins
chemical_list: D000135:Acid Phosphatase; D056657:Cathepsin K; D053583:Interleukin-1beta; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D050783:Proto-Oncogene Proteins c-ets; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D000071681:Tartrate-Resistant Acid Phosphatase; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C096031:NFAB complex; C494005:Nfatc1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C505689:Tnfsf11 protein, mouse; C000605511:Acp5 protein, mouse; C534132:Ctsk protein, mouse
keywords: BRD4 protein; anti-inflammatory agents; epigenetics; experimental animal models; osteoclasts; periodontitis