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 J., Fürnrohr B.G., Tomcik M., Palumbo K., Zerr P., Horn A., Dees C., Akhmetshina A., Beyer C., Distler O., Schett G., Allanore Y., Distler J.H.
  (See online at https://dx.doi.org/10.1002/art.30171)
• 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 C., Akhmetshina A., Dees C., Palumbo K., Zerr P., Beyer C., Zwerina J., Distler O., Schett G., Distler J.H.
  (See online at https://dx.doi.org/10.1136/ard.2010.147140)
• Platelet-derived serotonin links vascular disease and tissue fibrosis. Journal of Experimental Medicine, Vol. 208. 2011, pp. 961-972.
  Dees C, Akhmetshina A, Zerr P, Reich N, Palumbo K, Horn A, Jüngel A, Beyer C, Krönke G, Zwerina J, Reiter R, Alenina N, Maroteaux L, Gay S, Schett G, Distler O, Distler JH
  (See online at https://dx.doi.org/10.1084/jem.20101629)
• 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 K., Zerr P., Tomcik M., Vollath S., Dees C., Akhmetshina A., Avouac J., Yaniv M., Distler O., Schett G., Distler J.H.
  (See online at https://dx.doi.org/10.1136/ard.2010.148296)
• Activation of canonical Wnt signalling is required for TGF-β mediated fibrosis. Nature Communications, Vol. 3. 2012, Article number: 735.
  Akhmetshina A., Palumbo-Zerr K., Dees C., Bergmann C., Venalis P., Zerr P., Horn A., Kireva T., Beyer C., Zwerina J., Schneider H., Sadowski A., Riener M.O., MacDougald O.A., Distler O., Schett G., Distler J.H.
  (See online at https://doi.org/10.1038/ncomms1734)
• 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 P., Distler A., Palumbo-Zerr K., Tomcik M., Vollath S., Dees C., Egberts F., Tinazzi I., Del Galdo F., Distler O., Schett G., Spriewald B.M., Distler J.H.
  (See online at https://doi.org/10.1016/j.ajpath.2012.07.017)
• 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 J., Palumbo K., Tomcik M., Zerr P., Dees C., Horn A., Maurer B., Akhmetshina A., Beyer C., Sadowski A., Schneider H., Shiozawa S., Distler O., Schett G., Allanore Y., Distler J.H.
  (See online at https://doi.org/10.1002/art.33501)
• 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 P., Palumbo-Zerr K., Distler A., Tomcik M., Vollath S., Munoz L.E., Beyer C., Dees C., Egberts F., Tinazzi I., Del Galdo F., Distler O., Schett G., Spriewald B.M., Distler J.H.
  (See online at https://doi.org/10.1182/blood-2012-01-403428)
• 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 C, Tomcik M, Palumbo-Zerr K, Akhmetshina A, Beyer C, Lang V, Horn A, Zerr P, Zwerina J, Gelse K, Distler O, Schett G, Distler JH.
  (See online at https://doi.org/10.1002/art.34500)
• Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Annals of the Rheumatic Diseases, Vol. 71. 2012, Issue 6, pp. 1019-1026.
  Beyer C., Reich N., Schindler S.C., Akhmetshina A., Dees C., Tomcik M., Hirth-Dietrich C., von Degenfeld G., Sandner P., Distler O., Schett G., Distler J.H.
  (See online at https://doi.org/10.1136/annrheumdis-2011-200862)
• Activation of pregnane X receptor inhibits experimental dermal fibrosis. Annals of the Rheumatic Diseases, Vol. 72. 2013, Issue 4, pp. 621-625.
  Beyer C., Skapenko A., Distler A., Dees C., Reichert H., Munoz L., Leipe J., Schulze-Koops H., Distler O., Schett G., Distler J.H.
  (See online at https://doi.org/10.1136/annrheumdis-2012-202476)
• Autophagy regulates TNFα-mediated joint destruction in experimental arthritis. Annals of the Rheumatic Diseases, Vol. 72. 2013, Issue 5, pp. 761-768.
  Lin N.Y., Beyer C., Gießl A., Kireva T., Scholtysek C., Uderhardt S., Munoz L.E., Dees C., Distler A., Wirtz S., Krönke G., Spencer B., Distler O., Schett G., Distler J.H.
  (See online at https://doi.org/10.1136/annrheumdis-2012-201671)
• 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 A., Deloch L., Huang J., Dees C., Lin N.Y., Palumbo-Zerr K., Beyer C., Weidemann A., Distler O., Schett G., Distler J.H.
  (See online at https://doi.org/10.1136/annrheumdis-2012-202275)
• 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 A., Lang V., Del Vecchio T., Huang J., Zhang Y., Beyer C., Lin N.Y., Palumbo-Zerr K., Distler O., Schett G., Distler J.H.
  (See online at https://doi.org/10.1136/annrheumdis-2013-204221)
• 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 M., Zerr P., Pitkowski J., Palumbo-Zerr K., Avouac J., Distler O., Becvar R., Senolt L., Schett G., Distler J.H.
  (See online at https://doi.org/10.1136/annrheumdis-2012-203095)
• 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 A., Ziemer C., Beyer C., Lin N.Y., Chen C.W., Palumbo-Zerr K., Dees C., Weidemann A., Distler O., Schett G., Distler J.H.
  (See online at https://doi.org/10.1136/annrheumdis-2013-203995)
• 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 Y., Dees C., Beyer C., Lin N.Y., Distler A., Zerr P., Palumbo K., Susok L., Kreuter A., Distler O., Schett G., Distler J.H.
  (See online at https://doi.org/10.1136/annrheumdis-2013-204256)
• Vitamin D receptor regulates TGF-β signalling in systemic sclerosis. Annals of the Rheumatic Diseases, Vol. 74. 2015, Issue 3, e20.
  Zerr P., Vollath S., Palumbo-Zerr K., Tomcik M., Huang J., Distler A., Beyer C., Dees C., Gela K., Distler O., Schett G., Distler J.H.
  (See online at https://doi.org/10.1136/annrheumdis-2013-204378)