Profibrotic Role of Inducible Heat Shock Protein 90 α Isoform in Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-beta, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform (Hsp90 alpha). Available evidence supports overexpression and secretion of Hsp90 alpha as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90 alpha in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90 alpha mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90 alpha-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90 alpha levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90 alpha levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90 alpha isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.

Automated summary

This study investigated the expression and function of Hsp90 alpha in skin fibrosis. The results showed that Hsp90 alpha is overexpressed in fibrotic conditions and is associated with disease severity in SSc patients.