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

Nat Commun. 2012 Mar 13:3:735. doi: 10.1038/ncomms1734.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cells, Cultured
  • Extracellular Matrix / metabolism
  • Female
  • Fibrosis / metabolism
  • Fibrosis / pathology*
  • Humans
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • RNA, Small Interfering
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Wnt Proteins
  • p38 Mitogen-Activated Protein Kinases