Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing

Minghua Wu, Denisa S. Melichian, Mauricio De La Garza, Katherine Gruner, Swati Bhattacharyya, Luke Barr, Aisha Nair, Shiva Shahrara, Peter H S Sporn, Thomas A. Mustoe, Warren G. Tourtellotte, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

The early growth response gene (Egr-1) codes for a zinc finger transcription factor that has important roles in the regulation of cell growth, differentiation, and survival. Aberrant Egr-1 expression is implicated in carcinogenesis, inflammation, atherosclerosis, and ischemic injury. We reported previously that normal fibroblasts stimulated by transforming growth factor-β showed rapid and transient induction of Egr-1. Moreover, we observed that tissue expression of Egr-1 was elevated in patients with scleroderma, which suggests that Egr-1 may be involved in tissue repair and fibrosis. Here, we investigated matrix remodeling and wound healing in mice harboring gain of function or loss of function mutations of Egr-1. Using the model of bleomycin-induced scleroderma, we found that the early influx of inflammatory cells into the skin and lungs, and the subsequent development of fibrosis in these organs, were markedly attenuated in Egr-1 null mice. Furthermore, full-thickness incisional skin wound healing was impaired, and skin fibroblasts lacking Egr-1 showed reduced migration and myofibroblast transdifferentiation in vitro. In contrast, transgenic mice with fibroblast-specific Egr-1 overexpression showed exuberant tissue repair, with enhanced collagen accumulation and increased tensile strength of incisional wounds. Together, these results point to the fundamental role that Egr-1 plays in the regulation of transforming growth factor-β-dependent physiological and pathological matrix remodeling.

Original languageEnglish (US)
Pages (from-to)1041-1055
Number of pages15
JournalAmerican Journal of Pathology
Volume175
Issue number3
DOIs
StatePublished - Jan 1 2009

Fingerprint

Early Growth Response Protein 1
Wound Healing
Fibrosis
Fibroblasts
Transforming Growth Factors
Skin
Myofibroblasts
Tensile Strength
Zinc Fingers
Bleomycin
Wounds and Injuries
Growth
Transgenic Mice
Cell Differentiation
Cell Survival
Atherosclerosis
Carcinogenesis
Transcription Factors
Collagen
Inflammation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Wu, Minghua ; Melichian, Denisa S. ; De La Garza, Mauricio ; Gruner, Katherine ; Bhattacharyya, Swati ; Barr, Luke ; Nair, Aisha ; Shahrara, Shiva ; Sporn, Peter H S ; Mustoe, Thomas A. ; Tourtellotte, Warren G. ; Varga, John. / Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing. In: American Journal of Pathology. 2009 ; Vol. 175, No. 3. pp. 1041-1055.
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abstract = "The early growth response gene (Egr-1) codes for a zinc finger transcription factor that has important roles in the regulation of cell growth, differentiation, and survival. Aberrant Egr-1 expression is implicated in carcinogenesis, inflammation, atherosclerosis, and ischemic injury. We reported previously that normal fibroblasts stimulated by transforming growth factor-β showed rapid and transient induction of Egr-1. Moreover, we observed that tissue expression of Egr-1 was elevated in patients with scleroderma, which suggests that Egr-1 may be involved in tissue repair and fibrosis. Here, we investigated matrix remodeling and wound healing in mice harboring gain of function or loss of function mutations of Egr-1. Using the model of bleomycin-induced scleroderma, we found that the early influx of inflammatory cells into the skin and lungs, and the subsequent development of fibrosis in these organs, were markedly attenuated in Egr-1 null mice. Furthermore, full-thickness incisional skin wound healing was impaired, and skin fibroblasts lacking Egr-1 showed reduced migration and myofibroblast transdifferentiation in vitro. In contrast, transgenic mice with fibroblast-specific Egr-1 overexpression showed exuberant tissue repair, with enhanced collagen accumulation and increased tensile strength of incisional wounds. Together, these results point to the fundamental role that Egr-1 plays in the regulation of transforming growth factor-β-dependent physiological and pathological matrix remodeling.",
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Wu, M, Melichian, DS, De La Garza, M, Gruner, K, Bhattacharyya, S, Barr, L, Nair, A, Shahrara, S, Sporn, PHS, Mustoe, TA, Tourtellotte, WG & Varga, J 2009, 'Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing', American Journal of Pathology, vol. 175, no. 3, pp. 1041-1055. https://doi.org/10.2353/ajpath.2009.090241

Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing. / Wu, Minghua; Melichian, Denisa S.; De La Garza, Mauricio; Gruner, Katherine; Bhattacharyya, Swati; Barr, Luke; Nair, Aisha; Shahrara, Shiva; Sporn, Peter H S; Mustoe, Thomas A.; Tourtellotte, Warren G.; Varga, John.

In: American Journal of Pathology, Vol. 175, No. 3, 01.01.2009, p. 1041-1055.

Research output: Contribution to journalArticle

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T1 - Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing

AU - Wu, Minghua

AU - Melichian, Denisa S.

AU - De La Garza, Mauricio

AU - Gruner, Katherine

AU - Bhattacharyya, Swati

AU - Barr, Luke

AU - Nair, Aisha

AU - Shahrara, Shiva

AU - Sporn, Peter H S

AU - Mustoe, Thomas A.

AU - Tourtellotte, Warren G.

AU - Varga, John

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Y1 - 2009/1/1

N2 - The early growth response gene (Egr-1) codes for a zinc finger transcription factor that has important roles in the regulation of cell growth, differentiation, and survival. Aberrant Egr-1 expression is implicated in carcinogenesis, inflammation, atherosclerosis, and ischemic injury. We reported previously that normal fibroblasts stimulated by transforming growth factor-β showed rapid and transient induction of Egr-1. Moreover, we observed that tissue expression of Egr-1 was elevated in patients with scleroderma, which suggests that Egr-1 may be involved in tissue repair and fibrosis. Here, we investigated matrix remodeling and wound healing in mice harboring gain of function or loss of function mutations of Egr-1. Using the model of bleomycin-induced scleroderma, we found that the early influx of inflammatory cells into the skin and lungs, and the subsequent development of fibrosis in these organs, were markedly attenuated in Egr-1 null mice. Furthermore, full-thickness incisional skin wound healing was impaired, and skin fibroblasts lacking Egr-1 showed reduced migration and myofibroblast transdifferentiation in vitro. In contrast, transgenic mice with fibroblast-specific Egr-1 overexpression showed exuberant tissue repair, with enhanced collagen accumulation and increased tensile strength of incisional wounds. Together, these results point to the fundamental role that Egr-1 plays in the regulation of transforming growth factor-β-dependent physiological and pathological matrix remodeling.

AB - The early growth response gene (Egr-1) codes for a zinc finger transcription factor that has important roles in the regulation of cell growth, differentiation, and survival. Aberrant Egr-1 expression is implicated in carcinogenesis, inflammation, atherosclerosis, and ischemic injury. We reported previously that normal fibroblasts stimulated by transforming growth factor-β showed rapid and transient induction of Egr-1. Moreover, we observed that tissue expression of Egr-1 was elevated in patients with scleroderma, which suggests that Egr-1 may be involved in tissue repair and fibrosis. Here, we investigated matrix remodeling and wound healing in mice harboring gain of function or loss of function mutations of Egr-1. Using the model of bleomycin-induced scleroderma, we found that the early influx of inflammatory cells into the skin and lungs, and the subsequent development of fibrosis in these organs, were markedly attenuated in Egr-1 null mice. Furthermore, full-thickness incisional skin wound healing was impaired, and skin fibroblasts lacking Egr-1 showed reduced migration and myofibroblast transdifferentiation in vitro. In contrast, transgenic mice with fibroblast-specific Egr-1 overexpression showed exuberant tissue repair, with enhanced collagen accumulation and increased tensile strength of incisional wounds. Together, these results point to the fundamental role that Egr-1 plays in the regulation of transforming growth factor-β-dependent physiological and pathological matrix remodeling.

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