The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses
Feng Fang,Kohtaro Ooka,Swati Bhattachyya,Jun Wei,Minghua Wu,Pan Du,Simon Lin,Francesco Del Galdo,Carol Feghali-Bostwick,John Varga +9 more
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TLDR
It is shown that transforming growth factor (TGF)-β induced a Smad3-dependent sustained stimulation of Egr2 gene expression in normal fibroblasts, and this results provide the first evidence that Egr-2 is a functionally distinct transcription factor that is both necessary and sufficient for TGF-β-induced profibrotic responses.Abstract:
Although the early growth response-2 (Egr-2, alias Krox20) protein shows structural and functional similarities to Egr-1, these two related early-immediate transcription factors are nonredundant. Egr-2 plays essential roles in peripheral nerve myelination, adipogenesis, and immune tolerance; however, its regulation and role in tissue repair and fibrosis remain poorly understood. We show herein that transforming growth factor (TGF)-β induced a Smad3-dependent sustained stimulation of Egr2 gene expression in normal fibroblasts. Overexpression of Egr-2 was sufficient to stimulate collagen gene expression and myofibroblast differentiation, whereas these profibrotic TGF-β responses were attenuated in Egr-2–depleted fibroblasts. Genomewide transcriptional profiling revealed that multiple genes associated with tissue remodeling and wound healing were up-regulated by Egr-2, but the Egr-2–regulated gene expression profile overlapped only partially with the Egr-1–regulated gene profile. Levels of Egr-2 were elevated in lesional tissue from mice with bleomycin-induced scleroderma. Moreover, elevated Egr-2 was noted in biopsy specimens of skin and lung from patients with systemic sclerosis. These results provide the first evidence that Egr-2 is a functionally distinct transcription factor that is both necessary and sufficient for TGF-β–induced profibrotic responses and is aberrantly expressed in lesional tissue in systemic sclerosis and in a murine model of scleroderma. Together, these findings suggest that Egr-2 plays an important nonredundant role in the pathogenesis of fibrosis. Targeting Egr-2 might represent a novel therapeutic strategy to control fibrosis.read more
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Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities
TL;DR: Precise characterization of the deregulated extracellular and intracellular signaling pathways, mediators and cellular differentiation programs that contribute to fibrosis in SSc will facilitate the development of selective, targeted therapeutic strategies.
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Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma.
Swati Bhattacharyya,Kathleen Kelley,Denisa S. Melichian,Zenshiro Tamaki,Feng Fang,Yunyun Su,Gilbert Feng,Richard M. Pope,G. R. Scott Budinger,Gökhan M. Mutlu,Robert Lafyatis,Timothy R D J Radstake,Carol Feghali-Bostwick,John Varga +13 more
TL;DR: A novel model to account for persistent fibrogenesis in scleroderma is suggested, in which activation of fibroblast TLR4 signaling results in augmented transforming growth factor-β1 sensitivity with increased matrix production and progressive connective tissue remodeling.
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Cellular interactions in the pathogenesis of interstitial lung diseases
Gianluca Bagnato,Sergio Harari +1 more
TL;DR: The pathogenic mechanisms by cell of interest are analyzed, comparing the role of cell subsets in the pathogenesis of IPF and systemic sclerosis and new insights into the complex cellular contributions and interactions will be provided.
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Review: Interstitial Lung Disease Associated With Systemic Sclerosis and Idiopathic Pulmonary Fibrosis: How Similar and Distinct?
Erica L. Herzog,Aditi Mathur,Andrew M. Tager,Carol Feghali-Bostwick,Frank Schneider,John Varga +5 more
TL;DR: This review compares and contrasts salient features of SSc-associated interstitial lung disease and idiopathic pulmonary fibrosis, focusing on clinical manifestations, lung imaging, and pathology, along with current concepts of pathogenesis, including animal models, translational studies, genetic factors, and predictive biomarkers.
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Egr-1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis)
TL;DR: Observations highlight a previously unsuspected fundamental physiological function for the Egr‐1–Nab2 signalling axis in regulating fibrogenesis, and suggest that EGr‐1 may be a potential novel therapeutic target in human diseases complicated by fibrosis.
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