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 language | English |
|---|---|
| Pages (from-to) | 723-732 |
| Number of pages | 10 |
| Journal | Osteoarthritis and Cartilage |
| Volume | 16 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2008 |
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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
- Orthopedics and Sports Medicine
Cite this
Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. / Nasu, Yoshihisa; Nishida, Keiichiro; Miyazawa, Shinichi; Komiyama, T.; Kadota, Y.; Abe, N.; Yoshida, A.; Hirohata, Satoshi; Ohtsuka, Aiji; Ozaki, Toshihumi.
In: Osteoarthritis and Cartilage, Vol. 16, No. 6, 06.2008, p. 723-732.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model
AU - Nasu, Yoshihisa
AU - Nishida, Keiichiro
AU - Miyazawa, Shinichi
AU - Komiyama, T.
AU - Kadota, Y.
AU - Abe, N.
AU - Yoshida, A.
AU - Hirohata, Satoshi
AU - Ohtsuka, Aiji
AU - Ozaki, Toshihumi
PY - 2008/6
Y1 - 2008/6
N2 - 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.
AB - 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.
KW - Cartilage destruction
KW - Collagen antibody-induced arthritis
KW - Histone deacetylase inhibitor
KW - Matrix metalloproteinase
KW - Rheumatoid arthritis
KW - Tissue inhibitor of matrix metalloproteinase
KW - Trichostatin A
UR - http://www.scopus.com/inward/record.url?scp=44549083450&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44549083450&partnerID=8YFLogxK
U2 - 10.1016/j.joca.2007.10.014
DO - 10.1016/j.joca.2007.10.014
M3 - Article
C2 - 18226559
AN - SCOPUS:44549083450
VL - 16
SP - 723
EP - 732
JO - Osteoarthritis and Cartilage
JF - Osteoarthritis and Cartilage
SN - 1063-4584
IS - 6
ER -