Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling
Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling
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DOI：
10.1136/annrheumdis-2013-203995
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发表时间：
2014-03-01
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：
Distler, Alfiya;Ziemer, Clara;Distler, Joerg H. W.
目的经典和非经典Wnt信号通路已成为纤维化的核心通路。它们的促纤维化作用通过彼此独立的不同细胞内级联介导。因此，抑制这两种途径可能具有相加的抗纤维化作用。在这里，我们敲低了均匀性中断（EVI），首次同时靶向实验性纤维化中的经典和非经典Wnt信号传导。方法在博莱霉素诱导的皮肤纤维化小鼠模型和腺病毒过表达组成型活性TGF-受体I（AdTBRI）诱导的纤维化小鼠模型中评价siRNA介导的EVI敲低的抗纤维化作用。结果敲低EVI可减少成纤维细胞经典和非经典Wnt配体的释放，降低经典和非经典Wnt级联的激活，减少β-catenin和磷酸化JNK和cJun的积累。灭活EVI产生有效的抗纤维化作用，减少皮肤增厚，肌成纤维细胞分化和胶原蛋白的积累在博莱霉素诱导的小鼠模型和AdTBR-induced fibrosis.Conclusions抑制Wnt分泌敲低EVI抑制经典和非经典Wnt信号转导，并有效地减少实验性纤维化在不同的临床前模型。因此，抑制Wnt分泌可能是治疗纤维化的令人感兴趣的方法。
Objectives Canonical as well as non-canonical Wnt signalling pathways have emerged as core pathways of fibrosis. Their profibrotic effects are mediated via distinct intracellular cascades independently of each other. Thus, inhibition of both pathways may have additive antifibrotic effects. Here, we knocked down evenness interrupted (EVI) to simultaneously target for the first time canonical and non-canonical Wnt signalling in experimental fibrosis.Methods The antifibrotic effects of siRNA-mediated knockdown of EVI were evaluated in the mouse models of bleomycin-induced skin fibrosis and in fibrosis induced by adenoviral overexpression of a constitutively active TGF- receptor I (AdTBRI).Results Knockdown of EVI decreased the release of canonical and non-canonical Wnt ligands by fibroblasts and reduced the activation of canonical and non-canonical Wnt cascades in experimental fibrosis with decreased accumulation of -catenin and phosphorylated JNK and cJun. Inactivation of EVI exerted potent antifibrotic effects and reduced dermal thickening, myofibroblast differentiation and accumulation of collagen in the mouse models of bleomycin-induced and AdTBR-induced fibrosis.Conclusions Inhibition of Wnt secretion by knockdown of EVI inhibits canonical and non-canonical Wnt signalling and effectively reduces experimental fibrosis in different preclinical models. Inhibition of Wnt secretion may thus be an interesting approach for the treatment of fibrosis.