Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis

• DOI: 10.1038/ncomms1734
• Publication Date: 2012-03-13
• Authors: Alfiya Akhmetshina; Katrin Palumbo; Clara Dees; Christina Bergmann; Paulius Venalis; Pawel Zerr; Angelika Horn; Trayana Kireva; Christian Beyer; Jochen Zwerina; Holm Schneider; Anika Sadowski; Marc-Oliver Riener; Ormond A. MacDougald; Oliver Distler; Georg Schett; Jörg H.W. Distler
• Keywords: LRP5; LRP6

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.