Portal de Periódicos da CAPES

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

2012; Nature Portfolio; Volume: 3; Issue: 1 Linguagem: Inglês

10.1038/ncomms1734

2041-1723

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,

Dupuytren's Contracture and Treatments

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. Aberrant activation of the TGF-β pathway leads to fibrotic disease. Distler and colleagues show that TGF-β-mediated fibrosis requires the decrease of Dickkopf-1, an antagonist of canonical Wnt signalling, suggesting that the two pathways interact for the manifestation of this disease.