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

Osteoarthritis Cartilage. 2008 Jun;16(6):723-32. doi: 10.1016/j.joca.2007.10.014. Epub 2008 Jan 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Antirheumatic Agents
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • trichostatin A
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3