Interrogation of the Pathogenesis of Stiff Skin Syndrome: A Congenital Form of Scleroderma

Hal Dietz, MD
Johns Hopkins University School of Medicine
Howard Hughes Medical Institute

Project Summary:

The goal of this research project is to better understand the basic mechanisms that initiate and sustain pro-fibrotic programs in individuals with scleroderma and in that manner, to develop and test novel and rational treatment strategies. It is the hope and intention of the Dietz lab that interrogation of the etiology and pathogenesis of a rare Mendelian form of scleroderma, called stiff skin syndrome (SSS), will reveal mechanisms relevant to more common but complex presentations of disease, prominently including systemic sclerosis (SSc). Their immediate goal is to create targeted mouse models of SSS and to use this rare but tractable form of disease to develop hypotheses regarding SSc.

Research Update:

Insights regarding initiating events derived from their demonstration that SSS is caused by mutations in fibrillin-1 that specifically impair integrin binding to its amino acid Arg-Gly-Asp (RGD) sequence. Two mouse models have been created; one harbors a naturally-occurring mutation in the RGD domain that had previously been observed in two families with SSS. The other harbors a RGD to RGE mutation in fibrillin-1 (causing an obligate loss of integrin binding) that will allow the Dietz lab to test the hypothesis that impaired interaction between integrins and fibrillin-1 is indeed the critical initiating event. Informatively, both models show fully penetrant dense dermal fibrosis by three months of age in association with increased surface expression of integrin subtypes known to activate TGFbeta (TGFβ), an important pro-fibrotic cytokine. The lab reasoned that treatment of SSS mice with a β1-integrin activating antibody (β1AAb) might "trick" dermal cells into believing that they could sense their matrix ligands (e.g. fibrillin-1), and that this might have a therapeutic effect. Remarkably, treatment with β1AAb fully prevented skin fibrosis in both SSS mouse models. Furthermore, they showed that use of a TGFβ inhibitor could reverse established fibrosis in SSS mice. Upregulation of surface integrins and phenotypic rescue with β1AAb or TGFβ antagonists was also observed in cultured dermal fibroblasts from patients with SSc. Both SSS mice and SSc fibroblasts show low expression of miR29, a small regulatory RNA molecule, that inhibits expression of many matrix elements including fibrillar collagens; treatment effects seen with either β1AAb or TGFβ antagonists correlate with normalization of miR29 expression. When stimulated with TGFβ, SSc fibroblasts show unique and marked activation of the noncanonical ERK TGFβ signaling cascade, as compared to the canonical Smad TGFb signaling cascade when compared to control cells. This effect is prevented by treatment with β1AAb. These data suggest that β3 integrin not only augments TGFβ signaling, but also specifically influences the choice between the Smad and ERK cascades (favoring ERK), perhaps through a direct potentiating interaction between αvβ3 and TGFβ receptors. In keeping with an active role for βvβ3 integrin and ERK in disease progression, fibrotic programs are abrogated after introduction of β3 integrin haplo insufficiency or treatment with an ERK antagonist in SSS mice and SSc cells, respectively.

What this project means for people with scleroderma:

This study provides a refined understanding of the mechanism of multiple forms of scleroderma and offers new treatment strategies, including β1 integrin agonists or antagonists to β3 integrin, TGFβ and ERK, that can be efficiently tested and refined using validated mouse models of human disease.

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