Egr-1 Induces a Profibrotic Injury/Repair Gene Program Associated with Systemic Sclerosis

Transforming growth factor-beta (TGF-beta) signaling is implicated in the pathogenesis of fibrosis in scleroderma or systemic sclerosis (SSc), but the precise mechanisms are poorly understood. The immediate-early gene Egr-1 is an inducible transcription factor with key roles in mediating fibrotic TGF-beta responses. To elucidate Egr-1 function in SSc-associated fibrosis, we examined change in gene expression induced by Egr-1 in human fibroblasts at the genome-wide level. Using microarray expression analysis, we derived a fibroblast "Egr-1-responsive gene signature'' comprising over 600 genes involved in cell proliferation, TGF-beta signaling, wound healing, extracellular matrix synthesis and vascular development. The experimentally derived "Egr-1-responsiv gene signature'' was then evaluated in an expression microarray dataset comprising skin biopsies from 27 patients with localized and systemic forms of scleroderma and six healthy controls. We found that the "Egr-1 responsive gene signature'' was substantially enriched in the "diffuse-proliferation'' subset comprising exclusively of patients with diffuse cutaneous SSc (dcSSc) of skin biopsies. A number of Egr-1-regulated genes was also associated with the "inflammatory'' intrinsic subset. Only a minority of Egr-1-regulated genes was concordantly regulated by TGF-beta. These results indicate that Egr-1 induces a distinct profibrotic/wound healing gene expression program in fibroblasts that is associated with skin biopsies from SSc patients with diffuse cutaneous disease. These observations suggest that targeting Egr-1 expression or activity might be a novel therapeutic strategy to control fibrosis in specific SSc subsets.