BACKGROUND AND AIMS Epithelial-mesenchymal transition [EMT] has been related to fibrosis and fistula formation, common complications associated with Crohn´s disease [CD]. The WNT signalling pathway mediates EMT, and specific WNT/FZD interactions have been related to the activation of this process in several diseases. We aim to analyse the relevance of EMT and WNT ligands and receptors in the penetrating behaviour of CD. METHODS Intestinal surgical resections were obtained from control and CD patients with a stenotic or penetrating behaviour. Fibrosis was determined by the histological analysis of collagen deposition and EMT by confocal microscopy. The expression of WNT ligands, inhibitors, and FZD receptors was analysed by RT-PCR, WB, IH, and IF studies. The effects of WNT2b and the role of FZD4 in EMT were analysed in HT29 epithelial cells. RESULTS Fibrosis and expression of EMT markers were detected in samples from CD patients irrespective of the clinical behaviour. However, an increased colocalisation of E-CADHERIN and VIMENTIN, an increased number of cells expressing WNT2b, and a higher expression of FZD4 and WNT2b/FZD4 interaction, were detected in intestinal tissue from the penetrating compared with the stenotic CD behaviour. WNT2b induced EMT in HT29 cells through FZD4 activation. CONCLUSIONS An increased EMT, associated with increased WNT2b/FZD4 interaction, was detected in intestinal tissue from CD patients with a penetrating behaviour. WNT2b, through FZD4 activation, induces EMT in vitro which points to a novel pharmacological target to prevent intestinal penetrating complications of CD.

中文翻译：

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WNT2b通过FZD4激活上皮-间充质转化：穿透性克罗恩病的相关性。

背景与目的上皮-间质转化[EMT]与纤维化和瘘管形成有关，这是与克罗恩病[CD]相关的常见并发症。WNT信号通路介导EMT，并且特定的WNT / FZD相互作用已与几种疾病中该过程的激活有关。我们旨在分析EMT和WNT配体和受体在CD穿透行为中的相关性。方法从具有狭窄或穿透性行为的对照和CD患者中进行肠外科手术切除。通过共聚焦显微镜通过胶原沉积和EMT的组织学分析确定纤维化。通过RT-PCR，WB，IH和IF研究分析了WNT配体，抑制剂和FZD受体的表达。在HT29上皮细胞中分析了WNT2b的作用和FZD4在EMT中的作用。结果在CD患者的样本中检测到纤维化和EMT标志物的表达，而与临床行为无关。但是，与狭窄的CD行为相比，在穿透的肠道组织中检测到E-CADHERIN和VIMENTIN的共定位增加，表达WNT2b的细胞数量增加以及FZD4和WNT2b / FZD4相互作用的表达更高。WNT2b通过FZD4激活在HT29细胞中诱导EMT。结论在具有穿透性行为的CD患者的肠道组织中检测到EMT增加，与WNT2b / FZD4相互作用增加有关。WNT2b通过FZD4激活，在体外诱导EMT，这是预防CD肠道穿透并发症的新药理学靶标。