TY - JOUR T1 - Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-β signalling to prevent fibrosis JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 1215 LP - 1222 DO - 10.1136/annrheumdis-2012-203095 VL - 73 IS - 6 AU - Michal Tomcik AU - Pawel Zerr AU - Jana Pitkowski AU - Katrin Palumbo-Zerr AU - Jérôme Avouac AU - Oliver Distler AU - Radim Becvar AU - Ladislav Senolt AU - Georg Schett AU - Jörg H Distler Y1 - 2014/06/01 UR - http://ard.bmj.com/content/73/6/1215.abstract N2 - Objectives 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)-β signalling and for the treatment of fibrosis in preclinical models of SSc. Methods 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-β receptor I (TβRI). Results Expression of Hsp90β was increased in SSc skin and in murine models of SSc in a TGF-β-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-β signalling and completely prevented the stimulatory effects of TGF-β on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-β 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 TβRI. 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. Conclusions Hsp90 is upregulated in SSc and is critical for TGF-β signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-β 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. ER -