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


METHODS
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-β-receptor I.


RESULTS
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.


CONCLUSIONS
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.
Department of Medicine 3 for Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Chih-Wei
CW
Chen
Department of Medicine 3 for Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Christian
C
Beyer
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
Jun
J
Liu
Department of Medicine 3 for Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Christiane
C
Maier
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
Chun
C
Li
Department of Medicine 3 for Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Thuong
T
Trinh-Minh
Department of Medicine 3 for Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Xiaohan
X
Xu
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
Stuart H
SH
Cole
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
Mindy H
MH
Hsieh
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
Nicholas
N
Ng
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
Alana
A
Althage
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
Shelly
S
Meeusen
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
Shifeng
S
Pan
Translational Medicine Autoimmunity Novartis Institutes for Biomedical Research, Basel, Switzerland.
Eric C
EC
Svensson
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
H Martin
HM
Seidel
Department of Medicine 3 for Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Georg
G
Schett
Translational Medicine Cardiovascular, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
Peter
P
Gergely
Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
Jennifer L
JL
Harris
Department of Medicine 3 for Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Jörg H W
JH
Distler
D000217:Acyltransferases; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001761:Bleomycin; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D006086:Graft vs Host Disease / Q000150:complications; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000517:prevention & control; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D012594:Scleroderma, Localized / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*
D000631:Aminopyridines; C000619955:GNF6231; D008565:Membrane Proteins; D010879:Piperazines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D000217:Acyltransferases; C491187:Porcn protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
Fibroblasts; Systemic Sclerosis; Treatment