Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen anti body-induced arthritis mouse model
Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen anti body-induced arthritis mouse model
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DOI：
10.1016/j.joca.2007.10.014
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发表时间：
2008-06-01
影响因子：
7
通讯作者：
Ozaki, T.
中科院分区：
文献类型：
--
作者：
Nasu, Y.;Nishida, K.;Ozaki, T.
目的：为探讨组蛋白去乙酰化酶（HDAC）抑制剂--在第15天，对后爪进行组织学检查。为了研究TSA对软骨细胞表达基质金属蛋白酶（MMP）-3、MMP-13、MMP-1的组织抑制剂（TIMP-1）和乙酰基-H4的影响，在第6天处死另一组小鼠。通过实时PCR检测促炎细胞因子刺激后小鼠软骨形成ATDC 5细胞中II型胶原、聚集蛋白聚糖、MMP-3和MMP-13 mRNA的体外直接作用。结果：在TSA治疗组中，临床关节炎明显改善，且呈剂量依赖性。TSA 2.0 mg/kg组的滑膜炎症严重程度和软骨破坏评分显著低于其他TSA给药组。在免疫组织化学上，TSA 2.0 mg/kg组中MMP-3和MMP-13阳性软骨细胞的数量显著低于对照组。相比之下，TSA 2.0 mg/kg组中TIMP-II阳性细胞和乙酰组蛋白H4阳性细胞的数量显著高于对照组。TSA可抑制ATDC 5诱导的IL-1-β和TNF-α诱导的MMP-3 mRNA表达上调，但对MMP-13 mRNA表达无明显影响。结论：TSA可减轻CAIA小鼠滑膜炎症。随后，软骨破坏也被TSA抑制，至少部分是通过调节软骨细胞基因表达。(C)2007年国际骨关节炎研究学会。由爱思唯尔有限公司出版。保留所有权利。
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 metal lop roteinase (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-II-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-beta and tumor necrosis factor-a-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. (C) 2007 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.