P035 Pharmacological inhibition of the canonical WNT signalling pathway represents a potential novel therapy for fibrosis in Crohn’s disease
A. Lewis*1, A. Nijhuis1, G. Berti1, C. L. Bishop2, R. Feakins3, J. O. Lindsay4, A. Silver1
1Blizard Institute, Barts and The London School of Medicine and Dentistry, Centre for Genomics and Child Health, London, UK, 2Blizard Institute, Barts and The London School of Medicine and Dentistry, Centre for Cell Biology and Cutaneous Research, London, UK, 3Department of Histopathology, The Royal London Hospital, London, UK, 4Blizard Institute, Barts and The London School of Medicine and Dentistry, Centre for Immunobiology, London, UK
Intestinal fibrosis and subsequent stricturing does not respond to current therapies and is the main indication for surgery in Crohn’s disease (CD). Complete understanding of the underlying molecular mechanisms of fibrosis is required to uncover novel therapies. Transforming Growth Factor (TGF-β) signalling promotes intestinal fibrosis in CD and cross-talk between TGF-β and the Wingless (WNT) signalling pathway contributes to fibrosis in other organs. However, the role of the WNT pathway in CD fibrosis is not well characterised. In this study, we evaluate markers of WNT signalling in stricturing CD patients and assess the ability of ICG-001, a potent WNT inhibitor that disrupts β-catenin transcriptional complexes, to inhibit TGF-β/ WNT signalling and limit fibrosis
TGF-β/WNT cross-talk was analysed in intestinal fibroblasts (CCD-18Co cells) stimulated with TGF-β (10 ng/ml) for 48 h in the presence or absence of ICG-001 (10 μM). β-Catenin and collagen I protein levels were assessed using immunofluorescence. Molecules within the WNT pathway modulated by TGF-β were identified using a targeted qRT-PCR array containing 92 WNT genes (TaqMan Array Human WNT Pathway). The mRNA levels of TGF-β / WNT markers were analysed by qPCR in the mucosa-overlying strictured intestine in CD patients.
TGF-β increased nuclear β-catenin levels (1.94 fold,
Increased WNT signalling in fibrotic strictures contributes to the development of TGF-β-induced fibrosis in CD patients. Treatment with ICG-001 can limit WNT signalling