title: 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.
abstract: 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.
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Fang
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Ooka
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattachyya
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Minghua
authors.initials: M
authors.lastname: Wu
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.forename: Simon
authors.initials: S
authors.lastname: Lin
authors.forename: Francesco
authors.initials: F
authors.lastname: Del Galdo
authors.forename: Carol A
authors.initials: CA
authors.lastname: Feghali-Bostwick
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D016212:Transforming Growth Factor beta