title: Early growth response 3 (Egr-3) is induced by transforming growth factor-β and regulates fibrogenic responses.
abstract: Members of the early growth response (Egr) gene family of transcription factors have nonredundant biological functions. Although Egr-3 is implicated primarily in neuromuscular development and immunity, its regulation and role in tissue repair and fibrosis has not been studied. We now show that in normal skin fibroblasts, Egr-3 was potently induced by transforming growth factor-β via canonical Smad3. Moreover, transient Egr-3 overexpression was sufficient to stimulate fibrotic gene expression, whereas deletion of Egr-3 resulted in substantially attenuated transforming growth factor-β responses. Genome-wide expression profiling in fibroblasts showed that genes associated with tissue remodeling and wound healing were prominently up-regulated by Egr-3. Notably, <5% of fibroblast genes regulated by Egr-1 or Egr-2 were found to be coregulated by Egr-3, revealing substantial functional divergence among these Egr family members. In a mouse model of scleroderma, development of dermal fibrosis was accompanied by accumulation of Egr-3-positive myofibroblasts in the lesional tissue. Moreover, skin biopsy samples from patients with scleroderma showed elevated Egr-3 levels in the dermis, and Egr-3 mRNA levels correlated with the extent of skin involvement. These results provide the first evidence that Egr-3, a functionally distinct member of the Egr family with potent effects on inflammation and immunity, is up-regulated in scleroderma and is necessary and sufficient for profibrotic responses, suggesting important and distinct roles in the pathogenesis of fibrosis.
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Feng
authors.initials: F
authors.lastname: Fang
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Shangguan
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kelly
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Pathology and Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Katherine
authors.initials: K
authors.lastname: Gruner
authors.affiliation: College of Life and Science, China Pharmaceutical University, Nanjing, China.
authors.forename: Boping
authors.initials: B
authors.lastname: Ye
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Monique E
authors.initials: ME
authors.lastname: Hinchcliff
authors.affiliation: Department of Pathology and Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Warren G
authors.initials: WG
authors.lastname: Tourtellotte
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address: j-varga@northwestern.edu.
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D051776:Early Growth Response Protein 3 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: C079945:EGR3 protein, human; D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; C486109:Egr1 protein, mouse; C497327:Egr2 protein, mouse; C497369:Egr3 protein, mouse; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D051776:Early Growth Response Protein 3
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