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• W2315662504 abstract "Background Heat shock protein 90 (Hsp90) has a crucial role in folding and conformational stabilization of TGF-β receptors and also of Src kinases, which are intracellular mediators of the pro-fibrotic effects of TGF-β. Inhibition of Hsp90 accelerates ubiquitination and increases proteasomal degradation of TGF-β receptors and Src. Thus, inhibition of Hsp90 may become a novel approach to target TGF-β signaling. Objectives To evaluate the efficacy of Hsp90 inhibition as a novel approach for inhibition of aberrant TGF-β signaling and for the treatment of fibrosis in preclinical models of systemic sclerosis (SSc). Methods The expression of Hsp90 was quantified by qPCR, Western Blot and immunohistochemistry. Collagen content was quantified by qPCR, SirCol collagen and hydroxyproline assay. The effects of Hsp90 inhibition by 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) were analyzed 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). Mice were examined weekly for weight, activity and the texture of the fur. Results The 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-DMAG suppressed canonical TGF-β signaling and completely prevented the stimulatory effects of TGF-β on collagen synthesis and on myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-β signaling in murine models of SSc and exerted potent anti-fibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice over-expressing a constitutively active TβRI. In bleomycin-induced dermal fibrosis, treatment with 17-DMAG reduced dermal thickening by 56±6% (p Conclusions Hsp90 is upregulated in SSc and is critical for TGF-β signaling. Pharmacological inhibition of Hsp90 by 17-DMAG effectively blocks the pro-fibrotic effects of TGF-β in cultured fibroblasts and in three different preclinical models of SSc. These results have translational implications, because several Hsp90 inhibitors are already evaluated in clinical trials for other indications. Acknowledgements This study was performed with support of CMH Research Projects No 00000023728 Disclosure of Interest None Declared" @default.
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• W2315662504 date "2013-06-01" @default.
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• W2315662504 title "THU0057 Inhibition of Heat Shock Protein 90 (Hsp90) Prevents Fibrosis by Targeting Canonical TGF-B Signaling" @default.
• W2315662504 doi "https://doi.org/10.1136/annrheumdis-2013-eular.585" @default.
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