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 journalArticlepeer-review

83 Scopus citations

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 - Sep 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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