Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling
Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling
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DOI：
10.1136/annrheumdis-2012-202275
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发表时间：
2013-09-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Distler, Alfiya;Deloch, Lisa;Distler, Joerg H. W.
目的经典Wnt信号最近成为系统性硬化症成纤维细胞活化和组织纤维化的关键介质。在这里，我们研究了端锚聚合酶作为抑制纤维化疾病中经典Wnt信号传导的新分子靶点。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（Ad-TBRI）诱导的实验性纤维化中评价端锚聚合酶抑制剂XAV-939或siRNA介导的端锚聚合酶敲低的抗纤维化作用。结果端锚聚合酶的失活抑制了实验性纤维化中经典Wnt信号的激活，并降低了β-catenin在细胞核中的积聚和靶基因c-myc的mRNA水平。用XAV-939或siRNA介导的皮肤中端锚聚合酶敲低的处理有效地减少了博来霉素诱导的真皮增厚、静息成纤维细胞向肌成纤维细胞的分化和胶原蛋白的积累。在Ad-TBRI驱动的皮肤纤维化中也观察到有效的抗纤维化作用。抑制tankyrases是不受限制的局部或全身toxicity.ConclusionsInactivation的tankyrases有效地废除了典型的Wnt信号的激活，并表现出有效的抗纤维化作用，在耐受良好的剂量。因此，端锚聚合酶可能是纤维化疾病靶向治疗的候选者。
ObjectivesCanonical Wnt signalling has recently emerged as a key mediator of fibroblast activation and tissue fibrosis in systemic sclerosis. Here, we investigated tankyrases as novel molecular targets for inhibition of canonical Wnt signalling in fibrotic diseases.MethodsThe antifibrotic effects of the tankyrase inhibitor XAV-939 or of siRNA-mediated knockdown of tankyrases were evaluated in the mouse models of bleomycin-induced dermal fibrosis and in experimental fibrosis induced by adenoviral overexpression of a constitutively active TGF- receptor I (Ad-TBRI).ResultsInactivation of tankyrases prevented the activation of canonical Wnt signalling in experimental fibrosis and reduced the nuclear accumulation of -catenin and the mRNA levels of the target gene c-myc. Treatment with XAV-939 or siRNA-mediated knockdown of tankyrases in the skin effectively reduced bleomycin-induced dermal thickening, differentiation of resting fibroblasts into myofibroblasts and accumulation of collagen. Potent antifibrotic effects were also observed in Ad-TBRI driven skin fibrosis. Inhibition of tankyrases was not limited by local or systemic toxicity.ConclusionsInactivation of tankyrases effectively abrogated the activation of canonical Wnt signalling and demonstrated potent antifibrotic effects in well-tolerated doses. Thus, tankyrases might be candidates for targeted therapies in fibrotic diseases.