Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis
Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis
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DOI：
10.1136/annrheumdis-2012-202544
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发表时间：
2013-07-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
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作者：
Beyer, Christian;Reichert, Helena;Distler, Joerg H. W.
背景和目的纤维化是一个主要的社会经济负担，但有效的抗纤维化治疗在临床常规。越来越多的证据表明Wnt信号在纤维化疾病如系统性硬化症中起着重要作用，因此我们评估了药理学Wnt抑制在实验性皮肤纤维化中的转化潜力。方法我们研究了PKF 118 -310和ICG-001的抗纤维化作用，这两种新型的下游经典Wnt信号抑制剂，在预防和治疗博来霉素诱导的皮肤纤维化的模型中，以及在由组成性活性转化生长因子（TGF）-β受体I的腺病毒过表达诱导的实验性皮肤纤维化中。001在所有实验中耐受良好。通过皮肤厚度、羟脯氨酸含量和肌成纤维细胞计数测定，两种治疗方法均显示出预防和逆转博莱霉素诱导的真皮纤维化的抗纤维化作用。PKF 118 -310和ICG-001是有效的抑制TGF-β受体I驱动的纤维化作为评估由相同的结果measurement.Conclusions阻断经典Wnt信号传导PKF 118 -310和ICG-001在不同的皮肤纤维化模型显示抗纤维化作用。两种疗法均耐受良好。尽管需要进一步的实验证据来证明疗效和耐受性，但抑制经典Wnt信号传导是一种有希望的纤维化治疗方法。
Background and objectives Fibrosis is a major socioeconomic burden, but effective antifibrotic therapies are not available in the clinical routine. There is growing evidence for a central role of Wnt signalling in fibrotic diseases such as systemic sclerosis, and we therefore evaluated the translational potential of pharmacological Wnt inhibition in experimental dermal fibrosis.Methods We examined the antifibrotic effects of PKF118-310 and ICG-001, two novel inhibitors of downstream canonical Wnt signalling, in the models of prevention and treatment of bleomycin-induced dermal fibrosis as well as in experimental dermal fibrosis induced by adenoviral overexpression of a constitutively active transforming growth factor (TGF)-beta receptor I.Results PKF118-310 and ICG-001 were well tolerated throughout all experiments. Both therapeutic approaches showed antifibrotic effects in preventing and reversing bleomycin-induced dermal fibrosis as measured by skin thickness, hydroxyproline content and myofibroblast counts. PKF118-310 and ICG-001 were effective in inhibiting TGF-beta receptor I-driven fibrosis as assessed by the same outcome measures.Conclusions Blockade of canonical Wnt signalling by PKF118-310 and ICG-001 showed antifibrotic effects in different models of skin fibrosis. Both therapies were well tolerated. Although further experimental evidence for efficacy and tolerability is necessary, inhibition of canonical Wnt signalling is a promising treatment approach for fibrosis.