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S.6.1 β-catenin is a central mediator in SSc

Beyer, C. ; Schramm, A. ; Distler, A. ; Dees, C. ; Taketo, M. M. ; de Crombrugghe, B. ; Distler, O. ; Schett, G. ; Distler, J. H. W. ; Dees, C. ; Tomcik, M. ; Palumbo, K. ; Akhmetshina, A. ; Horn, A. ; Zerr, P. ; Distler, O. ; Schett, G. ; Distler, J. H. W. ; Distler, A. ; Palumbo, K. ; Dees, C. ; Bergmann, C. ; Venalis, P. ; Zerr, P. ; Horn, A. ; Beyer, C. ; MacDougald, O. A. ; Distler, O. ; Schett, G. ; Distler, J. H. W. ; Lagares, D. ; Busnadiego, O. ; Garcia-Fernandez, R. ; Kapoor, M. ; Liu, S. ; Carter, D. ; Abraham, D. ; Shi-Wen, X. ; Carreira, P. ; Fontaine, B. ; Shea, B. ; Tager, A. ; Leask, A. ; Lamas, S. ; Rodriguez-Pascual, F.

In: Rheumatology, 2012, vol. 51, p. ii12-ii14

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    Title
    • S.6.1 β-catenin is a central mediator in SSc
    Author
    • Beyer, C.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Kyoto, Japan, Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, USA and Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
    • Schramm, A.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Kyoto, Japan, Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, USA and Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
    • Distler, A.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Kyoto, Japan, Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, USA and Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
    • Dees, C.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Kyoto, Japan, Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, USA and Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
    • Taketo, M. M.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Kyoto, Japan, Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, USA and Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
    • de Crombrugghe, B.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Kyoto, Japan, Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, USA and Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
    • Distler, O.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Kyoto, Japan, Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, USA and Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
    • Schett, G.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Kyoto, Japan, Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, USA and Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
    • Distler, J. H. W.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Kyoto, Japan, Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, USA and Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
    • Dees, C.. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Rheumatology of the First Faculty of Medicine, Charles University Prague, Prague, Czech Republic and Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland.
    • Tomcik, M.. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Rheumatology of the First Faculty of Medicine, Charles University Prague, Prague, Czech Republic and Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland.
    • Palumbo, K.. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Rheumatology of the First Faculty of Medicine, Charles University Prague, Prague, Czech Republic and Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland.
    • Akhmetshina, A.. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Rheumatology of the First Faculty of Medicine, Charles University Prague, Prague, Czech Republic and Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland.
    • Horn, A.. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Rheumatology of the First Faculty of Medicine, Charles University Prague, Prague, Czech Republic and Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland.
    • Zerr, P.. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Rheumatology of the First Faculty of Medicine, Charles University Prague, Prague, Czech Republic and Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland.
    • Distler, O.. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Rheumatology of the First Faculty of Medicine, Charles University Prague, Prague, Czech Republic and Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland.
    • Schett, G.. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Rheumatology of the First Faculty of Medicine, Charles University Prague, Prague, Czech Republic and Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland.
    • Distler, J. H. W.. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Rheumatology of the First Faculty of Medicine, Charles University Prague, Prague, Czech Republic and Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland.
    • Distler, A.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Palumbo, K.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Dees, C.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Bergmann, C.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Venalis, P.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Zerr, P.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Horn, A.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Beyer, C.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • MacDougald, O. A.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Distler, O.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Schett, G.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Distler, J. H. W.. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, USA and Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
    • Lagares, D.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Busnadiego, O.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Garcia-Fernandez, R.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Kapoor, M.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Liu, S.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Carter, D.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Abraham, D.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Shi-Wen, X.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Carreira, P.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Fontaine, B.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Shea, B.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Tager, A.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Leask, A.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Lamas, S.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    • Rodriguez-Pascual, F.. Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid (UCM), Madrid, Spain, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Genomics Centre, London, Canada, University College London, London, UK, Hospital Universitario 12 de Octubre, Madrid, Spain and Massachusetts General Hospital, Boston, USA.
    Document Type
    • Postprint
    OAI-PMH Identifier
    • oai:doc.rero.ch:298289
    Summary
    Background. β-catenin is the central integrator of canonical Wnt signalling. Since recent evidence suggests a central role of Wnts in fibrosis, we examined the β-catenin/Wnt pathway in SSc and focused on the role of β-catenin in fibroblast activation. Methods. We performed qPCR for several Wnt ligands and axin-2 to examine Wnt expression in SSc skin. We further studied protein levels of Wnt-1, -4, -10b and β-catenin by IHC. To establish the effects of β-catenin/Wnt signalling on collagen release, we created mice with fibroblast-specific stabilization of β-catenin (dEx3 β-catenin (wt/fl) × Col1a2; Cre-ER) as well as mice carrying fibroblast-specific deletion of β-catenin [Ctnnb1(fl/fl) × Col1a2; Cre-ER]. Summary of the results. We could demonstrate mRNA overexpression of Wnt-1, -2, -9a, -9b, -10a, -10b and -16 in SSc skin. Wnt-1, -4 and -10b consistently showed strong expression in SSc skin when compared with healthy skin. On protein level, however, Wnt-4 was indistinguishable between SSc patients and healthy controls, whereas Wnt-1 and Wnt-10b protein levels were increased in SSc skin. The overexpression of Wnt-1 and Wnt-10b resulted in a prominent nuclear accumulation of β-catenin in fibroblasts. Finally, increased mRNA levels of the target gene axin-2 confirmed the activation of canonical Wnt signalling. In dEx3 β-catenin (wt/ex) mice, we addressed the consequences of enhanced Wnt signalling and increased accumulation of β-catenin in SSc. We selectively targeted β-catenin in fibroblasts. Cre-activated dEx3 β-catenin (wt/fl) × Col1a2; Cre-ER mice showed massive and spontaneous dermal thickening even 2 weeks after Cre activation. Eight weeks after Cre-activation, skin thickening cumulated at 102.6% (P < 0.001). In line with the dermal thickening, hydroxyproline content and myofibroblast counts showed strong increases. To test the therapeutic potential of targeting β-catenin/Wnt signaling, we created Ctnnb1(fl/fl) x Col1a2;Cre-ER mice to specifically delete β-catenin in fibroblasts. After Cre activation and β-catenin deletion in fibroblasts, mice were challenged with bleomycin subcutaneously for 4 weeks. We found that Cre-activated Ctnnb1(fl/fl) × Col1a2; Cre-ER mice were protected from bleomycin-induced dermal with a reduction of skin thickening by 71% (P < 0.05). Conclusions. We demonstrated a prominent activation of canonical Wnt signalling in SSc with nuclear accumulation of β-catenin in fibroblasts and activation of the target gene axin-2. Our results showed that fibroblast-specific stabilization of β-catenin resulted in enhanced collagen release, whereas deletion of β-catenin potently reduced collagen production. Together, our findings highlight a key role of β-catenin in fibroblast activation and fibrosis. Thus, β-catenin may be promising molecular target for anti-fibrotic therapies