Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-β signalling to prevent fibrosis
Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-β signalling to prevent fibrosis
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DOI：
10.1136/annrheumdis-2012-203095
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发表时间：
2013-05
影响因子：
27.4
通讯作者：
M. Tomčík;P. Zerr;J. Pitkowski;K. Palumbo-Zerr;J. Avouac;O. Distler;R. Bečvář;L. Šenolt;G. Schett;J. Distler
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文献类型：
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作者：
M. Tomčík;P. Zerr;J. Pitkowski;K. Palumbo-Zerr;J. Avouac;O. Distler;R. Bečvář;L. Šenolt;G. Schett;J. Distler
目的系统性硬化症（SSc）和其他纤维化疾病的靶向治疗尚不可用。我们评估了热休克蛋白90（Hsp 90）抑制作为抑制异常转化生长因子（TGF）-β信号传导和治疗SSc临床前模型纤维化的新方法的疗效。方法采用定量PCR、免疫印迹和免疫组化方法检测Hsp 90的表达。在培养的成纤维细胞、博来霉素诱导的皮肤纤维化、皮肤紧绷（Tsk-1）小鼠和过度表达组成型活性TGF-β受体I（TβRI）的小鼠中分析了Hsp 90抑制的作用。结果Hsp 90 β在SSc皮肤和小鼠模型中表达增加，且呈TGF-β依赖性。通过17-二甲氨基乙氨基-17-去甲氧基格尔德霉素（17-DMAG）抑制Hsp 90抑制典型的TGF-β信号传导，并完全阻止TGF-β对胶原合成和肌成纤维细胞分化的刺激作用。17-DMAG治疗可降低SSc小鼠模型中典型TGF-β信号传导的激活，并对博莱霉素诱导的皮肤纤维化、Tsk-1小鼠和过度表达组成性活性TβRI的小鼠发挥强效抗纤维化作用。真皮厚度、肌成纤维细胞数量和羟脯氨酸含量在17-DMAG处理后均显著降低。在抗纤维化剂量下，未观察到17-DMAG的毒性作用。结论Hsp 90在SSc中表达上调，并在TGF-β信号转导中起重要作用。Hsp 90的药理学抑制有效地阻断了TGF-β在培养的成纤维细胞和SSc的不同临床前模型中的促纤维化作用。这些结果具有翻译意义，因为几种Hsp 90抑制剂正在用于其他适应症的临床试验中。
Objectives Targeted therapies for systemic sclerosis (SSc) and other fibrotic diseases are not yet available. We evaluated the efficacy of heat shock protein 90 (Hsp90) inhibition as a novel approach to inhibition of aberrant transforming growth factor (TGF)-β signalling and for the treatment of fibrosis in preclinical models of SSc. Methods Expression of Hsp90 was quantified by quantitative PCR, western blot and immunohistochemistry. The effects of Hsp90 inhibition were analysed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, in tight-skin (Tsk-1) mice and in mice overexpressing a constitutively active TGF-β receptor I (TβRI). Results Expression of Hsp90β was increased in SSc skin and in murine models of SSc in a TGF-β-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-β signalling and completely prevented the stimulatory effects of TGF-β on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-β signalling in murine models of SSc and exerted potent antifibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice overexpressing a constitutively active TβRI. Dermal thickness, number of myofibroblasts and hydroxyproline content were all significantly reduced on treatment with 17-DMAG. No toxic effects were observed with 17-DMAG at antifibrotic doses. Conclusions Hsp90 is upregulated in SSc and is critical for TGF-β signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-β in cultured fibroblasts and in different preclinical models of SSc. These results have translational implications, as several Hsp90 inhibitors are in clinical trials for other indications.