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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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

Fingerprint

Transforming Growth Factors
Growth
Skin
Fibrosis
Fibroblasts
Immunity
Genes
Myofibroblasts
Dermis
Wound Healing

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Fang, Feng ; Shangguan, Anna J. ; Kelly, Kathleen ; Wei, Jun ; Gruner, Katherine ; Ye, Boping ; Wang, Wenxia ; Bhattacharyya, Swati ; Hinchcliff, Monique E. ; Tourtellotte, Warren G. ; Varga, John. / Early growth response 3 (Egr-3) is induced by transforming growth factor-β and regulates fibrogenic responses. In: American Journal of Pathology. 2013 ; Vol. 183, No. 4. pp. 1197-1208.
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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.",
author = "Feng Fang and Shangguan, {Anna J.} and Kathleen Kelly and Jun Wei and Katherine Gruner and Boping Ye and Wenxia Wang and Swati Bhattacharyya and Hinchcliff, {Monique E.} and Tourtellotte, {Warren G.} and John Varga",
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Fang, F, Shangguan, AJ, Kelly, K, Wei, J, Gruner, K, Ye, B, Wang, W, Bhattacharyya, S, Hinchcliff, ME, Tourtellotte, WG & Varga, J 2013, 'Early growth response 3 (Egr-3) is induced by transforming growth factor-β and regulates fibrogenic responses', American Journal of Pathology, vol. 183, no. 4, pp. 1197-1208. https://doi.org/10.1016/j.ajpath.2013.06.016

Early growth response 3 (Egr-3) is induced by transforming growth factor-β and regulates fibrogenic responses. / Fang, Feng; Shangguan, Anna J.; Kelly, Kathleen; Wei, Jun; Gruner, Katherine; Ye, Boping; Wang, Wenxia; Bhattacharyya, Swati; Hinchcliff, Monique E.; Tourtellotte, Warren G.; Varga, John.

In: American Journal of Pathology, Vol. 183, No. 4, 01.10.2013, p. 1197-1208.

Research output: Contribution to journalArticle

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AU - Fang, Feng

AU - Shangguan, Anna J.

AU - Kelly, Kathleen

AU - Wei, Jun

AU - Gruner, Katherine

AU - Ye, Boping

AU - Wang, Wenxia

AU - Bhattacharyya, Swati

AU - Hinchcliff, Monique E.

AU - Tourtellotte, Warren G.

AU - Varga, John

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N2 - 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.

AB - 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.

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