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Tytuł:
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Increased expression of the transforming growth factor β-inducible gene HIC-5 in systemic sclerosis skin and fibroblasts: a novel antifibrotic therapeutic target.
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Autorzy:
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Piera-Velazquez S; Jefferson Institute of Molecular Medicine and Scleroderma Center.
Fertala J; Jefferson Institute of Molecular Medicine and Scleroderma Center.; Department of Orthopedic Surgery Research, Thomas Jefferson University, Philadelphia.
Huaman-Vargas G; Jefferson Institute of Molecular Medicine and Scleroderma Center.
Louneva N; Jefferson Institute of Molecular Medicine and Scleroderma Center.; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jiménez SA; Jefferson Institute of Molecular Medicine and Scleroderma Center.
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Źródło:
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Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2020 Oct 01; Vol. 59 (10), pp. 3092-3098.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: Oxford, UK : Avenel, N.J. : Oxford University Press ; Distributed by Mercury International, c1999-
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MeSH Terms:
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Collagen Type I/*metabolism
Fibroblasts/*metabolism
Intracellular Signaling Peptides and Proteins/*metabolism
LIM Domain Proteins/*metabolism
Scleroderma, Systemic/*metabolism
Actins/metabolism ; Collagen/metabolism ; Collagen Type I/genetics ; Collagen Type I, alpha 1 Chain ; Gene Expression ; Gene Knockdown Techniques ; Humans ; Intracellular Signaling Peptides and Proteins/drug effects ; Intracellular Signaling Peptides and Proteins/genetics ; LIM Domain Proteins/drug effects ; LIM Domain Proteins/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Scleroderma, Systemic/genetics ; Skin/metabolism ; Transforming Growth Factor beta/pharmacology
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Contributed Indexing:
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Keywords: HIC-5 gene; Hic-5 protein; TGF-β; antifibrotic therapy; collagen; fibrosis; systemic sclerosis
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Substance Nomenclature:
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0 (ACTA2 protein, human)
0 (Actins)
0 (Collagen Type I)
0 (Collagen Type I, alpha 1 Chain)
0 (Intracellular Signaling Peptides and Proteins)
0 (LIM Domain Proteins)
0 (TGFB1I1 protein, human)
0 (Transforming Growth Factor beta)
9007-34-5 (Collagen)
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Entry Date(s):
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Date Created: 20200523 Date Completed: 20210122 Latest Revision: 20211204
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Update Code:
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20240105
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DOI:
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10.1093/rheumatology/keaa200
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PMID:
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32442272
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Objective: SSc is a systemic fibrotic disease affecting skin, numerous internal organs and the microvasculature. The molecular pathogenesis of SSc tissue fibrosis has not been fully elucidated, although TGF-β1 plays a crucial role. The Hic-5 protein encoded by the TGF-β1-inducible HIC-5 gene participates in numerous TGF-β-mediated pathways, however, the role of Hic-5 in SSc fibrosis has not been investigated. The aim of this study was to examine HIC-5 involvement in SSc tissue fibrosis.
Methods: Affected skin from three patients with diffuse SSc and dermal fibroblasts cultured from affected and non-affected SSc skin were examined for HIC-5 and COL1A1 gene expression. Real-time PCR, IF microscopy, western blotting and small interfering RNA-mediated HIC-5 were performed.
Results: HIC-5 and COL1A1 transcripts and Hic-5, type 1 collagen (COL1) and α-smooth muscle actin (α-SMA) protein levels were increased in clinically affected SSc skin compared with normal skin and in cultured dermal fibroblasts from affected SSc skin compared with non-affected skin fibroblasts from the same patients. HIC-5 knockdown caused a marked reduction of COL1 production in SSc dermal fibroblasts.
Conclusion: HIC-5 expression is increased in affected SSc skin compared with skin from normal individuals. Affected SSc skin fibroblasts display increased HIC-5 and COL1A1 expression compared with non-affected skin fibroblasts from the same patients. Hic-5 protein was significantly increased in cultured SSc dermal fibroblasts. HIC-5 mRNA knockdown in SSc fibroblasts caused >50% reduction of COL1 production. Although these are preliminary results owing to the small number of skin samples studied, they indicate that Hic-5 plays a role in the profibrotic activation of SSc dermal fibroblasts and may represent a novel molecular target for antifibrotic therapy in SSc.
(© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
