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| Description
| - 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)-beta 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-beta receptor I (T beta RI). Results Expression of Hsp90 beta was increased in SSc skin and in murine models of SSc in a TGF-beta-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-beta signalling and completely prevented the stimulatory effects of TGF-beta on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-beta 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 beta 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. Conclusions Hsp90 is upregulated in SSc and is critical for TGF-beta signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-beta 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.
- 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)-beta 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-beta receptor I (T beta RI). Results Expression of Hsp90 beta was increased in SSc skin and in murine models of SSc in a TGF-beta-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-beta signalling and completely prevented the stimulatory effects of TGF-beta on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-beta 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 beta 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. Conclusions Hsp90 is upregulated in SSc and is critical for TGF-beta signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-beta 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. (en)
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| Title
| - Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis
- Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis (en)
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| skos:prefLabel
| - Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis
- Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis (en)
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| skos:notation
| - RIV/00216208:11110/14:10284362!RIV15-MSM-11110___
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| http://linked.open...avai/riv/aktivita
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| http://linked.open...avai/riv/aktivity
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| http://linked.open...iv/cisloPeriodika
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| http://linked.open...vai/riv/dodaniDat
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| http://linked.open...aciTvurceVysledku
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| http://linked.open.../riv/druhVysledku
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| http://linked.open...iv/duvernostUdaju
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| http://linked.open...titaPredkladatele
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| http://linked.open...dnocenehoVysledku
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| http://linked.open...ai/riv/idVysledku
| - RIV/00216208:11110/14:10284362
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| http://linked.open...riv/jazykVysledku
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| http://linked.open.../riv/klicovaSlova
| - Hsp90; fibrosis; systemic sclerosis (en)
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| http://linked.open.../riv/klicoveSlovo
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| http://linked.open...odStatuVydavatele
| - GB - Spojené království Velké Británie a Severního Irska
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| http://linked.open...ontrolniKodProRIV
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| http://linked.open...i/riv/nazevZdroje
| - Annals of the Rheumatic Diseases
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| http://linked.open...in/vavai/riv/obor
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| http://linked.open...ichTvurcuVysledku
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| http://linked.open...cetTvurcuVysledku
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| http://linked.open...UplatneniVysledku
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| http://linked.open...v/svazekPeriodika
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| http://linked.open...iv/tvurceVysledku
| - Šenolt, Ladislav
- Schett, G.
- Tomčík, Michal
- Zerr, P.
- Bečvář, Radim
- Palumbo-Zerr, K.
- Avouac, J.
- Distler, J.
- Distler, J. H.
- Pitkowski, J.
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| http://linked.open...ain/vavai/riv/wos
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| issn
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| number of pages
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| http://bibframe.org/vocab/doi
| - 10.1136/annrheumdis-2012-203095
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| http://localhost/t...ganizacniJednotka
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