Canonical Wnt signalling as a key regulator of fibrogenesis - implications for targeted therapies?
Canonical Wnt signalling as a key regulator of fibrogenesis - implications for targeted therapies?
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DOI：
10.1111/exd.12255
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发表时间：
2013-11-01
影响因子：
3.6
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Dees, Clara;Distler, Joerg H. W.
经典Wnt信号属于所谓的形态发生途径，在发育和组织稳态中起着重要作用。Wnt信号通路是一个重要的调控途径，在不同的水平上受到严格的控制。然而，经典Wnt信号传导的不受控制的激活已经涉及各种人类疾病的发病机制。在过去的几年中，异常的Wnt信号转导已被证明在纤维化疾病，包括系统性硬化症（SSc）。在这篇综述中，我们将讨论目前的研究状态典型的Wnt信号在SSc。经典Wnt信号传导的活化诱导成纤维细胞活化，随后肌成纤维细胞分化和过度胶原蛋白释放导致组织纤维化。遗传或药理学阻断Wnt激活可改善不同临床前模型中的实验性纤维化。这些发现具有直接的翻译意义，因为目前在临床试验中评估了几种Wnt信号传导的小分子抑制剂，其中一些已经显示出初步的有希望的结果。
Canonical Wnt signalling belongs to the so-called morphogen pathways and plays essential roles in development and tissue homeostasis. Being such a crucial regulatory pathway, Wnt signalling is tightly controlled at different levels. However, uncontrolled activation of canonical Wnt signalling has been implicated into the pathogenesis of various human disorders. In the last years, aberrant Wnt signalling has been demonstrated in fibrotic diseases including systemic sclerosis (SSc). In this review, we will discuss the current state of research on canonical Wnt signalling in SSc. Activation of canonical Wnt signalling induces fibroblast activation with subsequent myofibroblast differentiation and excessive collagen release resulting in tissue fibrosis. Genetic or pharmacological blockade of Wnt activation ameliorates experimental fibrosis in different preclinical models. These findings have direct translational implications because several small molecule inhibitors of Wnt signalling are currently evaluated in clinical trials and some already showed first promising results.