title: Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in arthritis.
abstract: OBJECTIVE
  Histone deacetylase 1 (HDAC1) is highly expressed in the synovium of RA patients. Thus we aimed to investigate a novel HDAC inhibitor (HDACi), NW-21, designed to target HDAC1. The effect of NW-21 on osteoclast formation and activity, cytokine and chemokine expression in vitro and arthritis in mice was assessed.
  
  
  METHODS
  The effects on human osteoclast formation and activity derived from human blood monocytes stimulated with receptor activator of nuclear factor κB ligand (RANKL) and M-CSF were assessed. The anti-inflammatory activity of NW-21 was assessed using human monocytes stimulated with either TNF-α or lipopolysaccharide for 24 h. mRNA expression of monocyte chemotactic protein 1 (MCP-1), TNF-α, macrophage inflammatory protein 1α (MIP-1α), IL-1 and RANTES (regulated on activation, normal T cell expressed and secreted) was assessed. The effect of NW-21 in the collagen antibody-induced arthritis model was assessed following daily oral administration at 5 mg/kg/day. The HDAC1 inhibitors NW-21 and MS-275 were compared with a broad-acting HDACi, 1179.4b. Effects on inflammation and bone were assessed using paw inflammation scoring, histology and live animal micro-CT.
  
  
  RESULTS
  NW-21 suppressed osteoclast formation and activity as well as significantly reducing mRNA expression of MCP-1 and MIP-1α in monocytes stimulated by lipopolysaccharide or TNF-α (P < 0.05) in vitro. Only inhibitors that targeted HDAC1 (NW-21 and MS-275) reduced inflammation and bone loss in the arthritis model.
  
  
  CONCLUSIONS
  The results indicate that inhibitors targeting HDAC1, such as NW-21 and MS-275, may be useful for treating RA, as such drugs can simultaneously target both inflammation and bone resorption.
authors.affiliation: Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA, melissa.cantley@adelaide.edu.au.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Cantley
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, and.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: Colgate Australian Clinical Dental Research Centre, School of Dentistry, University of Adelaide, Adelaide, SA, Australia.
authors.forename: P Mark
authors.initials: PM
authors.lastname: Bartold
authors.affiliation: Colgate Australian Clinical Dental Research Centre, School of Dentistry, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Victor
authors.initials: V
authors.lastname: Marino
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, and.
authors.forename: Praveer K
authors.initials: PK
authors.lastname: Gupta
authors.affiliation: Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA.
authors.forename: David R
authors.initials: DR
authors.lastname: Haynes
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications* / Q000188:drug therapy; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001862:Bone Resorption / Q000517:prevention & control*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D007249:Inflammation / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001549:Benzamides; D018925:Chemokines; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; C000602889:NW-21 compound; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C118739:entinostat; D056284:Histone Deacetylase 1
keywords: bone loss; collagen antibody–induced arthritis; histone deacetylase 1; inflammation; osteoclasts