Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling
Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling
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DOI：
10.1136/annrheumdis-2016-210294
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发表时间：
2017-04-01
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：
Chen, Chih-Wei;Beyer, Christian;Distler, Joerg H. W.
目的在系统性硬化症(SSC)的成纤维细胞中，Wnt信号与纤维形成程序的激活有关。豪猪是哺乳动物分泌Wnt蛋白所必需的一种O-酰基转移酶。方法在博莱霉素性皮肤纤维化小鼠模型、皮肤紧张型小鼠模型、硬皮病型慢性移植物抗宿主病(CGVHD)小鼠模型和转化生长因子受体I活性诱导的纤维化小鼠模型中评价豪猪平抑物的抗纤维化作用。结果药物相关且耐受性良好的GNF6231可抑制纤维化小鼠皮肤Wnt信号的激活。GNF6231可改善所有四种模型的皮肤纤维化。GNF6231治疗也减少了与小鼠cGVHD相关的肺纤维化。最重要的是，GNF6231阻止了纤维化的进展，并显示出逆转已建立的纤维化的证据。结论这些数据表明，通过抑制豪猪碱来靶向Wnt通路为SSC的纤维化提供了一种潜在的治疗方法。这一点特别令人感兴趣，因为一种与GNF6231非常接近的类似物已经在人类身上显示出强大的途径抑制作用，并可能用于临床试验。
Objectives Wnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc.Methods The porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-a-receptor I.Results Treatment with pharmacologically relevant and well-tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis.Conclusions These data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.