RRC ID 43250
Author Nasu Y, Nishida K, Miyazawa S, Komiyama T, Kadota Y, Abe N, Yoshida A, Hirohata S, Ohtsuka A, Ozaki T.
Title Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model.
Journal Osteoarthritis Cartilage
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.
CONCLUSION: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.
Volume 16(6)
Pages 723-32
Published 2008-6-1
DOI 10.1016/j.joca.2007.10.014
PII S1063-4584(07)00345-7
PMID 18226559
MeSH Animals Antirheumatic Agents / therapeutic use Arthritis, Experimental / metabolism Arthritis, Experimental / pathology Arthritis, Experimental / prevention & control* Cartilage, Articular / metabolism Cartilage, Articular / pathology Disease Models, Animal Enzyme Inhibitors / therapeutic use* Gene Expression Regulation / drug effects Histone Deacetylase Inhibitors* Hydroxamic Acids / therapeutic use* Male Matrix Metalloproteinase 13 / biosynthesis Matrix Metalloproteinase 13 / genetics Matrix Metalloproteinase 3 / biosynthesis Matrix Metalloproteinase 3 / genetics Mice Mice, Inbred DBA RNA, Messenger / genetics Severity of Illness Index Synovitis / metabolism Synovitis / pathology Synovitis / prevention & control* Tissue Inhibitor of Metalloproteinase-1 / biosynthesis Tissue Inhibitor of Metalloproteinase-1 / genetics
IF 4.793
Times Cited 106
Human and Animal Cells ATDC5(RCB0565)