Systemic sclerosis is a complex disease with widespread skin
fibrosis and variable visceral organ involvement. Since
transforming growth factor-beta (
TGFbeta) has been implicated in driving
fibrosis in
systemic sclerosis, a mechanism-derived gene expression signature was used to assay
TGFbeta-responsive gene expression in the skin of patients with
systemic sclerosis (SSc). Primary dermal fibroblasts from patients with diffuse SSc (dSSc) and healthy controls were treated with
TGFbeta, and the genome-wide gene expression was measured on
DNA microarrays over a time course of 24 hours. Eight hundred and ninety-four probes representing 674 uniquely annotated genes were identified as
TGFbeta responsive. Expression of the
TGFbeta-responsive signature was examined in skin biopsies from 17 dSSc, seven limited SSc (lSSc), three
morphea patients, and six healthy controls. The
TGFbeta-responsive signature was expressed in 10 out of 17 dSSc skin biopsies, but was not found in lSSc,
morphea, or healthy control biopsies. Expression of dSSC the
TGFbeta-responsive signature stratifies patients into two major groups, one of which corresponds to the "diffuse-proliferation" intrinsic subset that showed higher modified Rodnan skin score and a higher likelihood of scleroderma
lung disease. The
TGFbeta-responsive signature is found in only a subset of dSSc patients who could be targeted by specific
therapies.