| First Author | Fang F | Year | 2013 |
| Journal | Am J Pathol | Volume | 183 |
| Issue | 4 | Pages | 1197-208 |
| PubMed ID | 23906810 | Mgi Jnum | J:200920 |
| Mgi Id | MGI:5510271 | Doi | 10.1016/j.ajpath.2013.06.016 |
| Citation | Fang F, et al. (2013) Early Growth Response 3 (Egr-3) Is Induced by Transforming Growth Factor-beta and Regulates Fibrogenic Responses. Am J Pathol 183(4):1197-208 |
| abstractText | 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-beta 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-beta 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. |
