Our previous study demonstrated that heat shock protein 90 (Hsp90) is overexpressed in the involved skin of patients with systemic sclerosis (SSc) and in experimental dermal fibrosis. Pharmacological inhibition of Hsp90 prevented the stimulatory effects of transforming growth factor-beta on collagen synthesis and the development of dermal fibrosis in three preclinical models of SSc. In the next step of the preclinical analysis, herein, we aimed to evaluate the efficacy of an Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in the treatment of established experimental dermal fibrosis induced by bleomycin. Treatment with 17-DMAG demonstrated potent antifibrotic and anti-inflammatory properties: it decreased dermal thickening, collagen content, myofibroblast count, expression of transforming growth factor beta receptors, and pSmad3-positive cell counts, as well as leukocyte infiltration and systemic levels of crucial cytokines/chemokines involved in the pathogenesis of SSc, compared to vehicle-treated mice. 17-DMAG effectively prevented further progression and may induce regression of established bleomycin-induced dermal fibrosis to an extent comparable to nintedanib. These findings provide further evidence of the vital role of Hsp90 in the pathophysiology of SSc and characterize it as a potential target for the treatment of fibrosis with translational implications due to the availability of several Hsp90 inhibitors in clinical trials for other indications.

Department of Internal Medicine 3 and Institute for Clinical Immunology University of Erlangen Nuremberg 91054 Erlangen Germany

Department of Physiotherapy Faculty of Physical Education and Sport Charles University 16252 Prague Czech Republic

Department of Rheumatology 1st Faculty of Medicine Charles University 12800 Prague Czech Republic

Institute of Rheumatology 12800 Prague Czech Republic

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Biomedicines. 2023 Oct 09;11(10):2736. doi: 10.3390/biomedicines11102736. PubMed

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S100A4-neutralizing monoclonal antibody 6B12 counteracts the established experimental skin fibrosis induced by bleomycin

Correction: Štorkánová et al. Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin. Biomedicines 2021, 9, 650

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