Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing.
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-ss 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-ss-dependent physiological and pathological matrix remodeling.
Wu
Minghua
M
Division of Rheumatology, Feinberg School of Medicine, Northwestern University, 240 E Huron St., Chicago, IL 60611, USA.
Melichian
Denisa S
DS
de la Garza
Mauricio
M
Gruner
Katherine
K
Bhattacharyya
Swati
S
Barr
Luke
L
Nair
Aisha
A
Shahrara
Shiva
S
Sporn
Peter H S
PH
Mustoe
Thomas A
TA
Tourtellotte
Warren G
WG
Varga
John
J
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D003094:Collagen; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008171:Lung Diseases / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012871:Skin Diseases / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D014945:Wound Healing / Q000235:genetics*
D051766:Early Growth Response Protein 1; D001761:Bleomycin; D003094:Collagen
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