The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

• DOI: 10.1016/j.ajpath.2011.01.035
• Publication Date: 2011-04-25T00:20:54Z
• Authors: Feng Fang; Kohtaro Ooka; Swati Bhattachyya; Jun Wei; Minghua Wu; Pan Du; Simon Lin; Francesco Del Galdo; Carol A. Feghali-...; John Varga
• Keywords: 0301 basic medicine; 0303 health sciences; Microscopy, Confocal; Scleroderma, Systemic; Transcription, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Transfection; Fibrosis; Immunohistochemistry; Up-Regulation; 3. Good health; Mice; 03 medical and health sciences; Transforming Growth Factor beta; Animals; Humans; Cells, Cultured; Early Growth Response Protein 2; Oligonucleotide Array Sequence Analysis

Although the early growth response-2 (Egr-2, alias Krox20) protein shows structural and functional similarities to Egr-1, these two related early-immediate transcription factors are nonredundant. Egr-2 plays essential roles in peripheral nerve myelination, adipogenesis, and immune tolerance; however, its regulation and role in tissue repair and fibrosis remain poorly understood. We show herein that transforming growth factor (TGF)-β induced a Smad3-dependent sustained stimulation of Egr2 gene expression in normal fibroblasts. Overexpression of Egr-2 was sufficient to stimulate collagen gene expression and myofibroblast differentiation, whereas these profibrotic TGF-β responses were attenuated in Egr-2-depleted fibroblasts. Genomewide transcriptional profiling revealed that multiple genes associated with tissue remodeling and wound healing were up-regulated by Egr-2, but the Egr-2-regulated gene expression profile overlapped only partially with the Egr-1-regulated gene profile. Levels of Egr-2 were elevated in lesional tissue from mice with bleomycin-induced scleroderma. Moreover, elevated Egr-2 was noted in biopsy specimens of skin and lung from patients with systemic sclerosis. These results provide the first evidence that Egr-2 is a functionally distinct transcription factor that is both necessary and sufficient for TGF-β-induced profibrotic responses and is aberrantly expressed in lesional tissue in systemic sclerosis and in a murine model of scleroderma. Together, these findings suggest that Egr-2 plays an important nonredundant role in the pathogenesis of fibrosis. Targeting Egr-2 might represent a novel therapeutic strategy to control fibrosis.