Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-? signalling to prevent fibrosis

Tomcik M, Zerr P, Pitkowski J, Palumbo-Zerr K, Avouac J, Distler O, Becvar R, Senolt L, Schett G, Distler J (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Book Volume: 73

Pages Range: 1215-22

Journal Issue: 6

DOI: 10.1136/annrheumdis-2012-203095

Abstract

Targeted therapies for systemic sclerosis (SSc) and other fibrotic diseases are not yet available. We evaluated the efficacy of heat shock protein 90 (Hsp90) inhibition as a novel approach to inhibition of aberrant transforming growth factor (TGF)-? signalling and for the treatment of fibrosis in preclinical models of SSc.Expression of Hsp90 was quantified by quantitative PCR, western blot and immunohistochemistry. The effects of Hsp90 inhibition were analysed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, in tight-skin (Tsk-1) mice and in mice overexpressing a constitutively active TGF-? receptor I (T?RI).Expression of Hsp90? was increased in SSc skin and in murine models of SSc in a TGF-?-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-? signalling and completely prevented the stimulatory effects of TGF-? on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-? signalling in murine models of SSc and exerted potent antifibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice overexpressing a constitutively active T?RI. Dermal thickness, number of myofibroblasts and hydroxyproline content were all significantly reduced on treatment with 17-DMAG. No toxic effects were observed with 17-DMAG at antifibrotic doses.Hsp90 is upregulated in SSc and is critical for TGF-? signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-? in cultured fibroblasts and in different preclinical models of SSc. These results have translational implications, as several Hsp90 inhibitors are in clinical trials for other indications.

Authors with CRIS profile

Involved external institutions

Univerzita Karlova v Praze / Charles University in Prague Czech Republic (CZ) Universitätsspital Zürich (USZ) Switzerland (CH)

How to cite

APA:

Tomcik, M., Zerr, P., Pitkowski, J., Palumbo-Zerr, K., Avouac, J., Distler, O.,... Distler, J. (2014). Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-? signalling to prevent fibrosis. Annals of the Rheumatic Diseases, 73(6), 1215-22. https://doi.org/10.1136/annrheumdis-2012-203095

MLA:

Tomcik, Michal, et al. "Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-? signalling to prevent fibrosis." Annals of the Rheumatic Diseases 73.6 (2014): 1215-22.

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