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

Author

Listed:
  • Alfiya Akhmetshina

    (University of Erlangen-Nuremberg
    Erlangen)

  • Katrin Palumbo

    (University of Erlangen-Nuremberg
    Erlangen)

  • Clara Dees

    (University of Erlangen-Nuremberg
    Erlangen)

  • Christina Bergmann

    (University of Erlangen-Nuremberg
    Erlangen)

  • Paulius Venalis

    (University of Erlangen-Nuremberg
    Erlangen)

  • Pawel Zerr

    (University of Erlangen-Nuremberg
    Erlangen)

  • Angelika Horn

    (University of Erlangen-Nuremberg
    Erlangen)

  • Trayana Kireva

    (University of Erlangen-Nuremberg
    Erlangen)

  • Christian Beyer

    (University of Erlangen-Nuremberg
    Erlangen)

  • Jochen Zwerina

    (University of Erlangen-Nuremberg
    Erlangen)

  • Holm Schneider

    (University of Erlangen-Nuremberg
    Erlangen)

  • Anika Sadowski

    (University of Erlangen-Nuremberg
    Erlangen)

  • Marc-Oliver Riener

    (University of Erlangen-Nuremberg
    Erlangen)

  • Ormond A. MacDougald

    (University of Michigan)

  • Oliver Distler

    (Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich)

  • Georg Schett

    (University of Erlangen-Nuremberg
    Erlangen)

  • Jörg H.W. Distler

    (University of Erlangen-Nuremberg
    Erlangen)

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.

Suggested Citation

  • Alfiya Akhmetshina & Katrin Palumbo & Clara Dees & Christina Bergmann & Paulius Venalis & Pawel Zerr & Angelika Horn & Trayana Kireva & Christian Beyer & Jochen Zwerina & Holm Schneider & Anika Sadows, 2012. "Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1734
    DOI: 10.1038/ncomms1734
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    Cited by:

    1. Hermann Agis & Amy Collins & Andrei D Taut & Qiming Jin & Laura Kruger & Christoph Görlach & William V Giannobile, 2014. "Cell Population Kinetics of Collagen Scaffolds in Ex Vivo Oral Wound Repair," PLOS ONE, Public Library of Science, vol. 9(11), pages 1-10, November.
    2. Wenxia Wang & Swarna Bale & Jun Wei & Bharath Yalavarthi & Dibyendu Bhattacharyya & Jing Jing Yan & Hiam Abdala-Valencia & Dan Xu & Hanshi Sun & Roberta G. Marangoni & Erica Herzog & Sergejs Berdnikov, 2022. "Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Han-Yi Chen & Wan-Chen Hsieh & Yu-Chieh Liu & Huei-Ying Li & Po-Yo Liu & Yu-Ting Hsu & Shao-Chun Hsu & An-Chi Luo & Wei-Chen Kuo & Yi-Jhen Huang & Gan-Guang Liou & Meng-Yun Lin & Chun-Jung Ko & Hsing-, 2024. "Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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