Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model

Y. Nasu, K. Nishida, S. Miyazawa, T. Komiyama, Y. Kadota, N. Abe, A. Yoshida, S. Hirohata, A. Ohtsuka, T. Ozaki

Research output: Contribution to journalArticle

114 Citations (Scopus)

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 2.0 mg/kg group than in the control group. TSA suppressed interleukin 1-β and tumor necrosis factor-α-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.

Original languageEnglish
Pages (from-to)723-732
Number of pages10
JournalOsteoarthritis and Cartilage
Volume16
Issue number6
DOIs
Publication statusPublished - Jun 1 2008

    Fingerprint

Keywords

  • Cartilage destruction
  • Collagen antibody-induced arthritis
  • Histone deacetylase inhibitor
  • Matrix metalloproteinase
  • Rheumatoid arthritis
  • Tissue inhibitor of matrix metalloproteinase
  • Trichostatin A

ASJC Scopus subject areas

  • Rheumatology
  • Biomedical Engineering
  • Orthopedics and Sports Medicine

Cite this