title: Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model.
abstract: OBJECTIVE
  To investigate the effect of the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), on joint inflammation and cartilage degeneration in a collagen antibody-induced arthritis (CAIA) mouse model.
  
  
  METHODS
  CAIA mice were given daily subcutaneous injections of various concentrations of TSA (0, 0.5, 1.0, and 2.0 mg/kg) and various parameters were monitored for 14 days. On Day 15, the hind paws were examined histologically. To investigate the effects of TSA on the expressions of matrix metalloproteinase (MMP)-3, MMP-13, tissue inhibitor of MMP-1 (TIMP-1), and acetyl-H4 by chondrocytes, another group of mice was sacrificed on Day 6. In vitro direct effect of TSA was examined by real-time PCR for mRNA of type II collagen, aggrecan, MMP-3, and MMP-13 in murine chondrogenic ATDC5 cells after pro-inflammatory cytokine stimulation.
  
  
  RESULTS
  In the TSA-treated group, clinical arthritis was significantly ameliorated in a dose-dependent manner. The severity of synovial inflammation and the cartilage destruction score were significantly lower in the TSA 2.0 mg/kg group compared to the other TSA-treated groups. On immunohistochemistry, the number of MMP-3 and MMP-13-positive chondrocytes was significantly lower in the TSA 2.0 mg/kg group than in the control group. In contrast, the number of TIMP-1-positive cells and acetyl-histone H4-positive cells was significantly higher in the TSA 2.0mg/kg group than in the control group. TSA suppressed interleukin 1-beta and tumor necrosis factor-alpha-stimulated up-regulation of MMP-3, but not MMP-13 mRNA expression by ATDC5.
  
  
  CONCLUSIONS
  The systemic administration of TSA ameliorated synovial inflammation in CAIA mice. Subsequently cartilage destruction was also suppressed by TSA, at least in part, by modulating chondrocyte gene expression.
authors.affiliation: Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nasu
authors.forename: K
authors.initials: K
authors.lastname: Nishida
authors.forename: S
authors.initials: S
authors.lastname: Miyazawa
authors.forename: T
authors.initials: T
authors.lastname: Komiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Kadota
authors.forename: N
authors.initials: N
authors.lastname: Abe
authors.forename: A
authors.initials: A
authors.lastname: Yoshida
authors.forename: S
authors.initials: S
authors.lastname: Hirohata
authors.forename: A
authors.initials: A
authors.lastname: Ohtsuka
authors.forename: T
authors.initials: T
authors.lastname: Ozaki
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000235:genetics; D012720:Severity of Illness Index; D013585:Synovitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; C012589:trichostatin A; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3