Early growth response 3 (Egr-3) is induced by transforming growth factor-β and regulates fibrogenic responses

Feng Fang, Anna J. Shangguan, Kathleen Kelly, Jun Wei, Katherine Gruner, Boping Ye, Wenxia Wang, Swati Bhattacharyya, Monique E. Hinchcliff, Warren G. Tourtellotte, John Varga*

*Corresponding author for this work

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28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1197-1208
Number of pages12
JournalAmerican Journal of Pathology
Volume183
Issue number4
DOIs
StatePublished - Oct 1 2013

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Fang, F., Shangguan, A. J., Kelly, K., Wei, J., Gruner, K., Ye, B., Wang, W., Bhattacharyya, S., Hinchcliff, M. E., Tourtellotte, W. G., & Varga, J. (2013). Early growth response 3 (Egr-3) is induced by transforming growth factor-β and regulates fibrogenic responses. American Journal of Pathology, 183(4), 1197-1208. https://doi.org/10.1016/j.ajpath.2013.06.016