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

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

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Presentation transcript:

Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model Y. Nasu, M.D., K. Nishida, M.D., Ph.D., S. Miyazawa, M.D., Ph.D., T. Komiyama, M.D., Y. Kadota, M.D., N. Abe, M.D., Ph.D., A. Yoshida, S. Hirohata, M.D., Ph.D., A. Ohtsuka, M.D., Ph.D., T. Ozaki, M.D., Ph.D. Osteoarthritis and Cartilage Volume 16, Issue 6, Pages 723-732 (June 2008) DOI: 10.1016/j.joca.2007.10.014 Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Arthritis induction in mice and the effects of TSA. (A) The arthritis induction and TSA treatment protocol. Sampling 1: sections for immunohistochemistry. Sampling 2: histological evaluation of arthritis and cartilage destruction. (B) Severity of the clinical signs in untreated (CAIA) and TSA-treated mice (see Methods for scoring system). TSA treatment had a dose-dependent inhibitory effect against CAIA. (C) Body weight changes by group. After the onset of clinical arthritis, all mice lost a small amount of weight. No significant differences were observed among the groups. Data are expressed as the means (symbols)±s.e.m. (error bars) (*P<0.05 and **P<0.001 by Bonferroni/Dunn analysis). Osteoarthritis and Cartilage 2008 16, 723-732DOI: (10.1016/j.joca.2007.10.014) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Histological evaluation of arthritis. The severity of synovial inflammation was evaluated histologically in the specimens obtained on Day 15. Representative results showing the histological appearance of the hind paws are seen in the upper panel. The control group specimens showed synovial hyperplasia, inflammatory cells proliferation, pannus formation, and bone destruction. Joint pathology was less severe in TSA-treated mice. Arrows: synovial hyperplasia, asterisk: joint space. Original magnification: 100×. The mean synovial inflammation score was significantly lower in the TSA 1.0mg/kg and TSA 2.0mg/kg groups than in the control group (n=6). Error bars express ±s.e.m. (*P<0.01 and **P<0.001 by Bonferroni/Dunn analysis). Osteoarthritis and Cartilage 2008 16, 723-732DOI: (10.1016/j.joca.2007.10.014) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Inhibition of cartilage destruction by TSA treatment. Representative photographs of each grade of cartilage destruction, grade 4 in the control group, grade 3 in the TSA 0.5mg/kg group, grade 2 in the TSA 1.0mg/kg group, and grade 1 in the TSA 2.0mg/kg group. Original magnification: 400×. The total cartilage destruction score was significantly lower in the TSA 1.0mg/kg and TSA 2.0mg/kg groups than in the control group (n=6 each). Error bars express ±s.e.m. (*P<0.001 by Bonferroni/Dunn analysis). Osteoarthritis and Cartilage 2008 16, 723-732DOI: (10.1016/j.joca.2007.10.014) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 Immunohistochemical staining of MMP-3, MMP-13, and TIMP-1 in joint cartilage. The number of MMP-3 and MMP-13-positive chondrocytes was significantly lower in the TSA 2.0mg/kg group (n=5) than in the control group (n=5). In contrast, TIMP-1 was strongly expressed in the joint cartilage obtained from the TSA 2.0mg/kg group. The population of TIMP-1-positive chondrocytes was significantly higher in the TSA 2.0mg/kg group than in the control group. Representative immunohistochemistry results are shown in the upper panels. Error bars express ±SD (*P<0.01, **P<0.001 by Mann–Whitney U test). Osteoarthritis and Cartilage 2008 16, 723-732DOI: (10.1016/j.joca.2007.10.014) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 Immunohistochemical staining for acetyl-histone H4. Cartilage specimens obtained from the control and TSA 2.0mg/kg groups (n=5 each) were positive for acetyl-histone H4 (left panels). The number of acetyl-histone H4-positive cells was higher in the TSA 2.0mg/kg group than in the control group. Error bars express ±SD (*P<0.05 by Mann–Whitney U test). Osteoarthritis and Cartilage 2008 16, 723-732DOI: (10.1016/j.joca.2007.10.014) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 Effect of pro-inflammatory cytokine and TSA on the morphology and gene expression of murine ATDC5 chondrogenic cells. (A) Morphologic features of ATDC5 cells examined by phase-contrast microscopy. No differences were observed in the TSA-treated cells compared with non-stimulated or cytokine-stimulated cells. Original magnification: 200×. (B) The effect of cytokine stimulation and TSA treatment on the expression of type II collagen (Col2a1), aggrecan examined by RT-PCR. TSA did not show the significant catabolic effect on type II collagen and aggrecan expression. (C) The effect of cytokine stimulation and TSA treatment on the expression of MMP-3 and -13 mRNA by ATDC5 examined by real-time PCR. Cytokine-induced expression of MMP-3, but not MMP-13 was significantly suppressed by TSA treatment. All values are averages in triplicated tests. Error bars express ±SD (*P<0.05 by Mann–Whitney U test, n.s.: not significant). Osteoarthritis and Cartilage 2008 16, 723-732DOI: (10.1016/j.joca.2007.10.014) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions