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

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          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.

          Abstract

          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.

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          Most cited references 40

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          Wnt signaling in disease and in development.

           Roel Nusse (2004)
          The highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how Wnt signals work. The catalogue of Wnt signaling components has exploded. We now realize that multiple extracellular, cytoplasmic, and nuclear components modulate Wnt signaling. Moreover, receptor-ligand specificity and multiple feedback loops determine Wnt signaling outputs. It is also clear that Wnt signals are required for adult tissue maintenance. Perturbations in Wnt signaling cause human degenerative diseases as well as cancer.
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            Criteria for the classification of early systemic sclerosis.

            We propose criteria for the early diagnosis and classification of systemic sclerosis that reflect the vascular and serological advances of the last 2 decades.
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              Wnt/beta-catenin signaling promotes renal interstitial fibrosis.

              Wnts compose a family of signaling proteins that play an essential role in kidney development, but their expression in adult kidney is thought to be silenced. Here, we analyzed the expression and regulation of Wnts and their receptors and antagonists in normal and fibrotic kidneys after obstructive injury. In the normal mouse kidney, the vast majority of 19 different Wnts and 10 frizzled receptor genes was expressed at various levels. After unilateral ureteral obstruction, all members of the Wnt family except Wnt5b, Wnt8b, and Wnt9b were upregulated in the fibrotic kidney with distinct dynamics. In addition, the expression of most Fzd receptors and Wnt antagonists was also induced. Obstructive injury led to a dramatic accumulation of beta-catenin in the cytoplasm and nuclei of renal tubular epithelial cells, indicating activation of the canonical pathway of Wnt signaling. Numerous Wnt/beta-catenin target genes (c-Myc, Twist, lymphoid enhancer-binding factor 1, and fibronectin) were induced, and their expression was closely correlated with renal beta-catenin abundance. Delivery of the Wnt antagonist Dickkopf-1 gene significantly reduced renal beta-catenin accumulation and inhibited the expression of Wnt/beta-catenin target genes. Furthermore, gene therapy with Dickkopf-1 inhibited myofibroblast activation; suppressed expression of fibroblast-specific protein 1, type I collagen, and fibronectin; and reduced total collagen content in the model of obstructive nephropathy. In summary, these results establish a role for Wnt/beta-catenin signaling in the pathogenesis of renal fibrosis and identify this pathway as a potential therapeutic target.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                13 March 2012
                : 3
                : 735
                Affiliations
                [1 ]Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg , 91054 Erlangen , Germany.
                [2 ]Department of Pediatrics, University of Erlangen-Nuremberg , 91054 Erlangen , Germany.
                [3 ]Department of Pathology, University of Erlangen-Nuremberg , 91054 Erlangen , Germany.
                [4 ]Department of Molecular & Integrative Physiology, University of Michigan , Ann Arbor, 48105, USA.
                [5 ]Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich , 8091, Switzerland.
                Author notes
                Article
                ncomms1734
                10.1038/ncomms1734
                3316881
                22415826
                Copyright © 2012, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

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