title: Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-β signalling to prevent fibrosis.
abstract: OBJECTIVE
  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.
authors: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, , Erlangen, Germany.
authors: Michal
authors: M
authors: Tomcik
authors: Pawel
authors: P
authors: Zerr
authors: Jana
authors: J
authors: Pitkowski
authors: Katrin
authors: K
authors: Palumbo-Zerr
authors: Jérôme
authors: J
authors: Avouac
authors: Oliver
authors: O
authors: Distler
authors: Radim
authors: R
authors: Becvar
authors: Ladislav
authors: L
authors: Senolt
authors: Georg
authors: G
authors: Schett
authors: Jörg H
authors: JH
authors: Distler
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C475219:Tsk1 protein, mouse; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Fibroblasts; Systemic Sclerosis; Treatment