Induktion von Hitzeschockprotein 90 durch Transforming Growth Factor ß als neuer pro-fibrotischer Signalweg in der systemischen Sklerose

• Applicant: Professor Dr. Georg Schett
• Subject Area: Rheumatology
• Term: from 2010 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 167610658

• Final Report Year: 2015

Final Report Abstract

Wir zeigen im geförderten Projekt, dass Hsp90β in SSc-Fibroblasten TGF-β abhängig überexprimiert wird. Eine Hemmung von Hsp90 hemmt die TGF-β abhängige Aktivierung von Smad3 und von JAK2/STAT3. Inaktivierung von Hsp90 reduziert die TGF-β-induzierte Aktivierung von Fibroblasten in vitro und hat potente anti-fibrotische Effekte in verschiedenen Tiermodellen der SSc. Hsp90- und Jak2 Hemmer haben synergistische anti-fibrotische Effekte. Diese Daten könnten direkte translationale Relevanz haben, da eine Vielzahl verschiedener Hsp90 Inhibitoren derzeit in onkologischen Erkrankungen erprobt wird.

Publications

• Inactivation of the transcription factor STAT4 prevents inflammation-driven fibrosis in systemic sclerosis animal models. Arthritis & Rheumatism, Vol. 63. 2011, Issue 3, pp. 800–809.
  Avouac, Jérôme; Fürnrohr, Barbara G.; Tomcik, Michal; Palumbo, Katrin; Zerr, Pawel; Horn, Angelika; Dees, Clara; Akhmetshina, Alfiya; Beyer, Christian; Distler, Oliver; Schett, Georg; Allanore, Yannick & Distler, Jörg H. W.
  
• Inhibition of glycogen synthase kinase 3{beta} induces dermal fibrosis by activation of the canonical Wnt pathway. Annals of the Rheumatic Diseases, Vol. 70. 2011, Issue 12 , pp. 2191-2198.
  Bergmann, Christina; Akhmetshina, Alfiya; Dees, Clara; Palumbo, Katrin; Zerr, Pawel; Beyer, Christian; Zwerina, Jochen; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Platelet-derived serotonin links vascular disease and tissue fibrosis. Journal of Experimental Medicine, Vol. 208. 2011, pp. 961-972.
  Dees, Clara; Akhmetshina, Alfiya; Zerr, Pawel; Reich, Nicole; Palumbo, Katrin; Horn, Angelika; Jüngel, Astrid; Beyer, Christian; Krönke, Gerhard; Zwerina, Jochen; Reiter, Rudolf; Alenina, Natalia; Maroteaux, Luc; Gay, Steffen; Schett, Georg; Distler, Oliver & Distler, Jörg H.W.
  
• The transcription factor JunD mediates transforming growth factor {beta}-induced fibroblast activation and fibrosis in systemic sclerosis. Annals of the Rheumatic Diseases, Vol. 70.2011, Issue 7, pp. 1320-1326.
  Palumbo, Katrin; Zerr, Pawel; Tomcik, Michal; Vollath, Stefan; Dees, Clara; Akhmetshina, Alfiya; Avouac, Jerome; Yaniv, Moshe; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Activation of canonical Wnt signalling is required for TGF-β mediated fibrosis. Nature Communications, Vol. 3. 2012, Article number: 735.
  Akhmetshina, Alfiya; Palumbo, Katrin; Dees, Clara; Bergmann, Christina; Venalis, Paulius; Zerr, Pawel; Horn, Angelika; Kireva, Trayana; Beyer, Christian; Zwerina, Jochen; Schneider, Holm; Sadowski, Anika; Riener, Marc-Oliver; MacDougald, Ormond A.; Distler, Oliver; Schett, Georg & Distler, Jörg H.W.
  
• Combined inhibition of c-Abl and PDGF receptors for prevention and treatment of murine sclerodermatous chronic graft-versus-host disease. The American Journal of Pathology, Vol. 181. 2012, Issue 5, pp. 1672–1680.
  Zerr, Pawel; Distler, Alfiya; Palumbo-Zerr, Katrin; Tomcik, Michal; Vollath, Stefan; Dees, Clara; Egberts, Friederike; Tinazzi, Ilaria; Del Galdo, Francesco; Distler, Oliver; Schett, Georg; Spriewald, Bernd M. & Distler, Jörg H.W.
  
• Inhibition of AP-1 signaling abrogates TGF-ß mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis & Rheumatism, Vol. 64. 2012, Issue 5, pp. 1642–1652.
  Avouac, Jérôme; Palumbo, Katrin; Tomcik, Michal; Zerr, Pawel; Dees, Clara; Horn, Angelika; Maurer, Britta; Akhmetshina, Alfiya; Beyer, Christian; Sadowski, Anika; Schneider, Holm; Shiozawa, Shunichi; Distler, Oliver; Schett, Georg; Allanore, Yannick & Distler, Jörg H. W.
  
• Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood, Vol. 120. 2012, Issue 14, pp. 2909-2917.
  Zerr, Pawel; Palumbo-Zerr, Katrin; Distler, Alfiya; Tomcik, Michal; Vollath, Stefan; Munoz, Luis E.; Beyer, Christian; Dees, Clara; Egberts, Friederike; Tinazzi, Ilaria; Del Galdo, Francesco; Distler, Oliver; Schett, Georg; Spriewald, Bernd M. & Distler, Jörg H. W.
  
• JAK2 as a novel mediator of the pro-fibrotic effects of TGFβ in systemic sclerosis. Arthritis & Rheumatism, Vol. 64. 2012, Issue 9, pp. 3006–3015.
  Dees, Clara; Tomcik, Michal; Palumbo‐Zerr, Katrin; Distler, Alfiya; Beyer, Christian; Lang, Veronika; Horn, Angelika; Zerr, Pawel; Zwerina, Jochen; Gelse, Kolja; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Annals of the Rheumatic Diseases, Vol. 71. 2012, Issue 6, pp. 1019-1026.
  Beyer, Christian; Reich, Nicole; Schindler, Sonia C.; Akhmetshina, Alfiya; Dees, Clara; Tomcik, Michal; Hirth-Dietrich, Claudia; von Degenfeld, Georges; Sandner, Peter; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Activation of pregnane X receptor inhibits experimental dermal fibrosis. Annals of the Rheumatic Diseases, Vol. 72. 2013, Issue 4, pp. 621-625.
  Beyer, Christian; Skapenko, Alla; Distler, Alfiya; Dees, Clara; Reichert, Helena; Munoz, Louis; Leipe, Jan; Schulze-Koops, Hendrik; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Autophagy regulates TNFα-mediated joint destruction in experimental arthritis. Annals of the Rheumatic Diseases, Vol. 72. 2013, Issue 5, pp. 761-768.
  Lin, Neng-Yu; Beyer, Christian; Gießl, Andreas; Kireva, Trayana; Scholtysek, Carina; Uderhardt, Stefan; Munoz, Luis Enrique; Dees, Clara; Distler, Alfiya; Wirtz, Stefan; Krönke, Gerhard; Spencer, Brian; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling. Annals of the Rheumatic Diseases, Vol. 72. 2013, Issue 9, pp. 1575-1580.
  Distler, Alfiya; Deloch, Lisa; Huang, Jingang; Dees, Clara; Lin, Neng-Yu; Palumbo-Zerr, Katrin; Beyer, Christian; Weidemann, Alexander; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Combined inhibition of morphogen pathways demonstrates additive antifibrotic effects and improved tolerability. Annals of the Rheumatic Diseases, Vol. 73.2014, Issue 6, pp. 1264-1268.
  Distler, Alfiya; Lang, Veronika; Del Vecchio, Tina; Huang, Jingang; Zhang, Yun; Beyer, Christian; Lin, Neng-Yu; Palumbo-Zerr, Katrin; Distler, Oliver; Schett, Georg & Distler, Jörg HW
  
• Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-β signalling to prevent fibrosis. Annals of the Rheumatic Diseases, Vol. 73. 2014, Issue 6, pp. 1215-1222.
  Tomcik, Michal; Zerr, Pawel; Pitkowski, Jana; Palumbo-Zerr, Katrin; Avouac, Jérôme; Distler, Oliver; Becvar, Radim; Senolt, Ladislav; Schett, Georg & Distler, Jörg H.
  
• Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling. Annals of the Rheumatic Diseases, Vol. 73. 2014, Issue 3, pp. 624-627.
  Distler, Alfiya; Ziemer, Clara; Beyer, Christian; Lin, Neng-Yu; Chen, Chih-Wei; Palumbo-Zerr, Katrin; Dees, Clara; Weidemann, Alexander; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Inhibition of casein kinase II reduces TGFβ induced fibroblast activation and ameliorates experimental fibrosis. Annals of the Rheumatic Diseases, Vol. 74. 2015, Issue 5, pp. 936-943.
  Zhang, Yun; Dees, Clara; Beyer, Christian; Lin, Neng-Yu; Distler, Alfiya; Zerr, Pawel; Palumbo, Katrin; Susok, Laura; Kreuter, Alexander; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.
  
• Vitamin D receptor regulates TGF-β signalling in systemic sclerosis. Annals of the Rheumatic Diseases, Vol. 74. 2015, Issue 3, e20.
  Zerr, Pawel; Vollath, Stefan; Palumbo-Zerr, Katrin; Tomcik, Michal; Huang, Jingang; Distler, Alfiya; Beyer, Christian; Dees, Clara; Gela, Kolja; Distler, Oliver; Schett, Georg & Distler, Jörg H. W.