Histone Deacetylase 7, a Potential Target for the Antifibrotic Treatment of Systemic Sclerosis
Histone Deacetylase 7, a Potential Target for the Antifibrotic Treatment of Systemic Sclerosis
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DOI：
10.1002/art.24494
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发表时间：
2009-05-01
影响因子：
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通讯作者：
Juengel, Astrid
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文献类型：
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作者：
Hemmatazad, Hossein;Rodrigues, Hanna Maciejewska;Juengel, Astrid
目标。我们最近发现，在使用曲古抑素a （TSA）治疗系统性硬化症（SSc）皮肤成纤维细胞后，细胞因子诱导的I型胶原和纤维连接蛋白转录显著减少。此外，在小鼠纤维化模型中，TSA可阻止细胞外基质的真皮积聚。本研究的目的是分析组蛋白去乙酰化酶7 （HDAC-7）的沉默作为TSA发挥其抗纤维化作用的可能机制。用TSA和/或转化生长因子p处理SSc患者的皮肤成纤维细胞，通过实时聚合酶链反应、Western blotting和Sircol胶原蛋白检测分析hdac 1-11、细胞外基质蛋白、结缔组织生长因子（CTGF）和细胞间粘附分子1 （ICAM-1）的表达。使用小干扰rna使HDAC-7沉默。SSc成纤维细胞未显示hdac的特定表达模式。TSA显著抑制HDAC-7的表达，上调HDAC-3的表达。HDAC-7的沉默减少了I型和III型胶原的组成和细胞因子诱导的产生，但没有纤维连接蛋白，正如TSA所做的那样。最有趣的是，TSA诱导了CTGF和ICAM-1的表达，而沉默HDAC-7对它们的表达没有影响。沉默HDAC-7似乎不仅与TSA一样有效，而且是治疗SSc的更特异性靶点，因为它不会上调ICAM-I和CTGF等促纤维化分子的表达。这一观察结果可能会导致针对SSc的更特异性和毒性更小的靶向治疗的发展。
Objective. We have recently shown a significant reduction in cytokine-induced transcription of type I collagen and fibronectin in systemic sclerosis (SSc) skin fibroblasts upon treatment with trichostatin A (TSA). Moreover, in a mouse model of fibrosis, TSA prevented the dermal accumulation of extracellular matrix. The purpose of this study was to analyze the silencing of histone deacetylase 7 (HDAC-7) as a possible mechanism by which TSA exerts its antifibrotic function.Methods. Skin fibroblasts from patients with SSc were treated with TSA and/or transforming growth factor P. Expression of HDACs 1-11, extracellular matrix proteins, connective tissue growth factor (CTGF), and intercellular adhesion molecule 1 (ICAM-1) was analyzed by real-time polymerase chain reaction, Western blotting, and the Sircol collagen assay. HDAC-7 was silenced using small interfering RNA.Results. SSc fibroblasts did not show a specific pattern of expression of HDACs. TSA significantly inhibited the expression of HDAC-7, whereas HDAC-3 was up-regulated. Silencing of HDAC-7 decreased the constitutive and cytokine-induced production of type I and type III collagen, but not fibronectin, as TSA had done. Most interestingly, TSA induced the expression of CTGF and ICAM-1, while silencing of HDAC-7 had no effect on their expression.Conclusion. Silencing of HDAC-7 appears to be not only as effective as TSA, but also a more specific target for the treatment of SSc, because it does not up-regulate the expression of profibrotic molecules such as ICAM-I and CTGF. This observation may lead to the development of more specific and less toxic targeted therapies for SSc.