title: Therapeutic effects of NK-HDAC-1, a novel histone deacetylase inhibitor, on collagen-induced arthritis through the induction of apoptosis of fibroblast-like synoviocytes.
abstract: The purpose of this study is to investigate the therapeutic effects of a novel histone deacetylase inhibitor (HDACi), NK-HDAC-1, on collagen-induced arthritis (CIA) and pathogenic fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). The proliferation and apoptosis of FLSs treated with NK-HDAC-1 were evaluated by flow cytometry and fluorescence staining. The effect of NK-HDAC-1 treatment on pro-inflammatory cytokine production was determined by ELISA. CIA was established in DBA/1 mice, and NK-HDAC-1 or vehicle was administered daily after the onset of arthritis. Clinical and histological scores were calculated to assess the therapeutic efficacy of NK-HDAC-1. NK-HDAC-1 significantly inhibited the proliferation of FLSs through cell cycle arrest at the G2/M checkpoint and enhanced apoptosis of FLSs. The activity of caspases was increased during NK-HDAC-1 treatment. IL-6 production by FLSs was also suppressed by NK-HDAC-1. Furthermore, the oral administration of NK-HDAC-1 significantly enhanced synoviocyte apoptosis in vivo and inhibited CIA progression. Compared with subcroylanilide hydroxamic acid which exhibited moderate prophylactic efficacy, NK-HDAC-1 demonstrated therapeutic efficacy in CIA. NK-HDAC-1 is a novel HDACi that may ameliorate inflammatory arthritis by regulating the activation, apoptosis, and inflammatory responses of FLSs. This is the first study to support that NK-HDAC-1 may be a potential therapeutic agent for RA.
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Sun
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wang
authors.forename: Weikang
authors.initials: W
authors.lastname: Guo
authors.forename: Fanlei
authors.initials: F
authors.lastname: Hu
authors.forename: Haihong
authors.initials: H
authors.lastname: Yao
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Cao
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.forename: Peng G
authors.initials: PG
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001583:Benzoxazoles / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D016207:Cytokines / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*
chemical_list: C574634:3-(1-(1-(benzo(d)oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide; D001583:Benzoxazoles; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D003094:Collagen; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9
references.citation: Immunol Rev. 2010 Jan;233(1):233-55
references.pmid: 20193003
references.citation: Arthritis Rheum. 2009 Aug;60(8):2232-41
references.pmid: 19644872
references.citation: Lancet. 2010 Sep 25;376(9746):1094-108
references.pmid: 20870100
references.citation: Cell. 1996 May 3;85(3):307-10
references.pmid: 8616886
references.citation: J Med Chem. 2012 Apr 12;55(7):3066-75
references.pmid: 22435669
references.citation: Arthritis Rheum. 2003 Sep;48(9):2670-81
references.pmid: 13130488
references.citation: Curr Pharm Des. 2008;14(8):803-20
references.pmid: 18393882
references.citation: Ann Rheum Dis. 2012 Apr;71 Suppl 2:i46-54
references.pmid: 22460138
references.citation: Arthritis Res Ther. 2008;10(3):R60
references.pmid: 18507845
references.citation: Br J Pharmacol. 2007 Apr;150(7):862-72
references.pmid: 17325656
references.citation: Arthritis Rheum. 1988 Mar;31(3):315-24
references.pmid: 3358796
references.citation: Expert Opin Ther Pat. 2013 Jan;23(1):1-17
references.pmid: 23094822
references.citation: Arthritis Res Ther. 2008;10(5):226
references.pmid: 18983693
references.citation: Cancer Res. 2003 Apr 1;63(7):1712-21
references.pmid: 12670926
references.citation: Arthritis Rheum. 2002 Apr;46(4):1109-20
references.pmid: 11953991
references.citation: Nat Med. 2009 Dec;15(12):1414-20
references.pmid: 19898488
references.citation: Exp Mol Pathol. 2009 Oct;87(2):99-104
references.pmid: 19577564