title: A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritis.
abstract: OBJECTIVE
  Nuclear factor-kappaB (NF-kappaB) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universal inhibitor of NF-kappaB, might have antiarthritic effects.
  
  
  METHODS
  An adenovirus containing A20 complementary DNA (AdA20) was used to deliver A20 to human rheumatoid fibroblast-like synoviocytes (FLS) in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via intraarticular injection into the ankle joints bilaterally.
  
  
  RESULTS
  In vitro experiments demonstrated that AdA20 suppressed NF-kappaB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor alpha in FLS. Mice with CIA that were treated with AdA20 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels, than did control virus-injected mice. The protective effects of AdA20 were mediated by the inhibition of the NF-kappaB signaling pathway. The severity of arthritis was also significantly decreased in the untreated front paws, indicating a beneficial systemic effect of local suppression of NF-kappaB. Surprisingly, mice treated with AdA20 after the onset of CIA had significantly decreased arthritis severity from the onset of clinical signs to the end of the study.
  
  
  CONCLUSIONS
  These results suggest that using A20 to block the NF-kappaB pathway in rheumatoid joints reduces both the inflammatory response and the tissue destruction. The development of an immunoregulatory strategy based on A20 may therefore have therapeutic potential in the treatment of RA.
authors.affiliation: Gyeongsang National University Hospital and Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Young-Sool
authors.initials: YS
authors.lastname: Hah
authors.forename: Young-Rae
authors.initials: YR
authors.lastname: Lee
authors.forename: Jin-Su
authors.initials: JS
authors.lastname: Jun
authors.forename: Hye-Song
authors.initials: HS
authors.lastname: Lim
authors.forename: Hyun-Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Yong-Geun
authors.initials: YG
authors.lastname: Jeong
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Myoung Ja
authors.initials: MJ
authors.lastname: Chung
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Sang-Il
authors.initials: SI
authors.lastname: Lee
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3