title: Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis.
abstract: The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases.
authors.affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Christina
authors.initials: C
authors.lastname: Bergmann
authors.forename: Paulius
authors.initials: P
authors.lastname: Venalis
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Angelika
authors.initials: A
authors.lastname: Horn
authors.forename: Trayana
authors.initials: T
authors.lastname: Kireva
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Holm
authors.initials: H
authors.lastname: Schneider
authors.forename: Anika
authors.initials: A
authors.lastname: Sadowski
authors.forename: Marc-Oliver
authors.initials: MO
authors.lastname: Riener
authors.forename: Ormond A
authors.initials: OA
authors.lastname: MacDougald
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D034622:RNA Interference; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D048051:p38 Mitogen-Activated Protein Kinases