Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling

Chen CW, Beyer C, Liu J, Maier C, Li C, Thuong Trinh-Minh , Xu X, Cole SH, Hsieh MH, Ng N, Althage A, Meeusen S, Pan S, Svensson EC, Seidel HM, Schett G, Gergely P, Harris JL, Distler J (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

DOI: 10.1136/annrheumdis-2016-210294

Abstract

Wnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc.The porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-?-receptor I.Treatment with pharmacologically relevant and well-tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis.These data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.

Authors with CRIS profile

Christian Beyer Department of Medicine 3 – Rheumatology and Immunology Christiane Maier Professur für Molekulare und Experimentelle Chirurgie Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Novartis Institutes for BioMedical Research, Inc. US United States (USA) (US) Novartis AG CH Switzerland (CH)

How to cite

APA:

Chen, C.-W., Beyer, C., Liu, J., Maier, C., Li, C., Thuong Trinh-Minh, .,... Distler, J. (2017). Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling. Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2016-210294

MLA:

Chen, Chih-Wei, et al. "Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling." Annals of the Rheumatic Diseases (2017).

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