Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-β signalling to prevent fibrosis

Abstract

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 bleomycininduced 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 bleomycininduced 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.

Heat shock protein 90 inhibition: A potential double- or triple-edged sword in the treatment of mucous membrane pemphigoid

“…These future investigations could yield some relevant information about the role of Hsp90 in MMP and, together with already existing knowledge on the powerful anti-inflammatory and anti-scarring effects of anti-Hsp90 treatment [14][15][16][17][18][19][20][21]25,[28][29][30], possibly support the introduction of nontoxic Hsp90 inhibitors for future medical management of patients with this potentially devastating disease that may otherwise cause permanent damage when therapy is delayed or ineffective.…”

“…Based on the above, we hypothesize that pharmacological Hsp90 blockade could represent a double-edged sword in the treatment of MMP by pleiotropic targeting of the mentioned Hsp90 inhibitor-prone pathophysiological factors involved in both inflammatory subepidermal blister formation and cicatricial processes [19][20][21]25,[28][29][30]. Due to their additional anti-cancer activity, Hsp90 inhibitors could even be proclaimed as a triple-edged sword against the malignancy-associated anti-laminin 332 subtype of MMP [12].…”

“…Recently, it has been shown that Hsp90 inhibition effectively targets canonical TGF-b signaling to prevent fibrosis in cultured fibroblasts and in preclinical murine models of different stages of systemic sclerosis (i.e., in bleomycin-induced dermal fibrosis, tight skin-1 mice, and mice overexpressing the constitutively active TGF-b receptor I). The potent antifibrotic effects of the Hsp90 inhibitor 17-DMAG in all these various models indicate that this treatment may be effective not only in inflammation-related but also in inflammation-independent fibrotic conditions [29].…”

Expression of TGF-beta receptor 1 and Smads in the tissues of primary spontaneous pneumothorax

“…Moreover, it is reported by Sibinska and some other researchers that activation of interstitial lung fibroblast and presence of extracellular matrix production are pathological features of pulmonary fibrosis, and the effect of TGF-β1 on the pathological changes is mainly mediated through the TGF-β/Smads signaling pathway. Moreover, the anti-fibrosis effect of heat shock protein HSP90 is related to TGF-β receptor destruction and inhibition of Smad2/3 activation (7,8). So, it is thought that the role of TGF-β and its downstream cytokines in PSP bullae might induce pulmonary fibrosis.…”

Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

“…Our recent findings (26) as well as those of other groups have indicated that Hsp90 is a critical modulator of fibrosis via alteration of the TGF␤ signaling pathway (27)(28)(29)(30). To further develop this line of research, the present study was designed to look into the possible role of Hsp90 in STAT-3-mediated fibrotic signaling during cardiac hypertrophy and associated fibrosis.…”