PMID- 25832610
OWN - NLM
STAT- MEDLINE
DCOM- 20151124
LR  - 20150815
IS  - 1462-0332 (Electronic)
IS  - 1462-0324 (Linking)
VI  - 54
IP  - 9
DP  - 2015 Sep
TI  - Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in 
      arthritis.
PG  - 1713-23
LID - 10.1093/rheumatology/kev022 [doi]
AB  - 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 
      kappaB ligand (RANKL) and M-CSF were assessed. The anti-inflammatory activity of 
      NW-21 was assessed using human monocytes stimulated with either TNF-alpha or 
      lipopolysaccharide for 24 h. mRNA expression of monocyte chemotactic protein 1 
      (MCP-1), TNF-alpha, macrophage inflammatory protein 1alpha (MIP-1alpha), 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-1alpha in 
      monocytes stimulated by lipopolysaccharide or TNF-alpha (P < 0.05) in vitro. Only 
      inhibitors that targeted HDAC1 (NW-21 and MS-275) reduced inflammation and bone 
      loss in the arthritis model. CONCLUSION: 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.
CI  - (c) The Author 2015. Published by Oxford University Press on behalf of the British 
      Society for Rheumatology. All rights reserved. For Permissions, please email: 
      journals.permissions@oup.com.
FAU - Cantley, Melissa D
AU  - Cantley MD
AD  - Discipline of Anatomy and Pathology, School of Medical Sciences, University of 
      Adelaide, Adelaide, SA, melissa.cantley@adelaide.edu.au.
FAU - Fairlie, David P
AU  - Fairlie DP
AD  - Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, and.
FAU - Bartold, P Mark
AU  - Bartold PM
AD  - Colgate Australian Clinical Dental Research Centre, School of Dentistry, 
      University of Adelaide, Adelaide, SA, Australia.
FAU - Marino, Victor
AU  - Marino V
AD  - Colgate Australian Clinical Dental Research Centre, School of Dentistry, 
      University of Adelaide, Adelaide, SA, Australia.
FAU - Gupta, Praveer K
AU  - Gupta PK
AD  - Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, and.
FAU - Haynes, David R
AU  - Haynes DR
AD  - Discipline of Anatomy and Pathology, School of Medical Sciences, University of 
      Adelaide, Adelaide, SA.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150331
PL  - England
TA  - Rheumatology (Oxford)
JT  - Rheumatology (Oxford, England)
JID - 100883501
RN  - 0 (Benzamides)
RN  - 0 (Chemokines)
RN  - 0 (Cytokines)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NW-21 compound)
RN  - 0 (Pyridines)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 1ZNY4FKK9H (entinostat)
RN  - EC 3.5.1.98 (Histone Deacetylase 1)
SB  - IM
MH  - Animals
MH  - Arthritis, Experimental/*complications/drug therapy
MH  - Benzamides/*pharmacology/therapeutic use
MH  - Bone Resorption/*prevention & control
MH  - Cells, Cultured
MH  - Chemokines/metabolism
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Histone Deacetylase 1/*antagonists & inhibitors
MH  - Histone Deacetylase Inhibitors/*pharmacology/therapeutic use
MH  - Humans
MH  - Hydroxamic Acids/pharmacology/therapeutic use
MH  - In Vitro Techniques
MH  - Inflammation/*prevention & control
MH  - Lipopolysaccharides/pharmacology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Monocytes/drug effects/metabolism/pathology
MH  - Osteoclasts/drug effects/metabolism/pathology
MH  - Pyridines/*pharmacology/therapeutic use
MH  - Tumor Necrosis Factor-alpha/pharmacology
OTO - NOTNLM
OT  - bone loss
OT  - collagen antibody-induced arthritis
OT  - histone deacetylase 1
OT  - inflammation
OT  - osteoclasts
EDAT- 2015/04/03 06:00
MHDA- 2015/12/15 06:00
CRDT- 2015/04/03 06:00
PHST- 2014/05/05 00:00 [received]
PHST- 2015/04/03 06:00 [entrez]
PHST- 2015/04/03 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
AID - kev022 [pii]
AID - 10.1093/rheumatology/kev022 [doi]
PST - ppublish
SO  - Rheumatology (Oxford). 2015 Sep;54(9):1713-23. doi: 10.1093/rheumatology/kev022. 
      Epub 2015 Mar 31.