Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds

Abstract Similar to the hypertrophic scar and keloids, the efficacy of glucorticoids (GC) for vocal fold injury is highly variable. We previously reported dexamethasone enhanced the pro-fibrotic effects of transforming growth factor (TGF)-β as a potential mechanism for inconsistent clinical outcomes...

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Autores principales:	Ryosuke Nakamura, Shigeyuki Mukudai, Renjie Bing, Michael J. Garabedian, Ryan C. Branski
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c74949bf7687426e93e1fbbc5bb29eb1
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spelling	oai:doaj.org-article:c74949bf7687426e93e1fbbc5bb29eb12021-12-02T12:33:44ZComplex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds10.1038/s41598-020-77445-92045-2322https://doaj.org/article/c74949bf7687426e93e1fbbc5bb29eb12020-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-77445-9https://doaj.org/toc/2045-2322Abstract Similar to the hypertrophic scar and keloids, the efficacy of glucorticoids (GC) for vocal fold injury is highly variable. We previously reported dexamethasone enhanced the pro-fibrotic effects of transforming growth factor (TGF)-β as a potential mechanism for inconsistent clinical outcomes. In the current study, we sought to determine the mechanism(s) whereby GCs influence the fibrotic response and mechanisms underlying these effects with an emphasis on TGF-β and nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling. Human VF fibroblasts (HVOX) were treated with three commonly-employed GCs+ /-TGF-β1. Phosphorylation of the glucocorticoid receptor (GR:NR3C1) and activation of NR4A1 was analyzed by western blotting. Genes involved in the fibrotic response, including ACTA2, TGFBR1, and TGFBR2 were analyzed by qPCR. RNA-seq was performed to identify global changes in gene expression induced by dexamethasone. GCs enhanced phosphorylation of GR at Ser211 and TGF-β-induced ACTA2 expression. Dexamethasone upregulated TGFBR1, and TGFBR2 in the presence of TGF-β1 and increased active NR4A1. RNA-seq results confirmed numerous pathways, including TGF-β signaling, affected by dexamethasone. Synergistic pro-fibrotic effects of TGF-β were observed across GCs and appeared to be mediated, at least partially, via upregulation of TGF-β receptors. Dexamethasone exhibited diverse regulation of gene expression including NR4A1 upregulation consistent with the anti-fibrotic potential of GCs.Ryosuke NakamuraShigeyuki MukudaiRenjie BingMichael J. GarabedianRyan C. BranskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ryosuke Nakamura Shigeyuki Mukudai Renjie Bing Michael J. Garabedian Ryan C. Branski Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds
description	Abstract Similar to the hypertrophic scar and keloids, the efficacy of glucorticoids (GC) for vocal fold injury is highly variable. We previously reported dexamethasone enhanced the pro-fibrotic effects of transforming growth factor (TGF)-β as a potential mechanism for inconsistent clinical outcomes. In the current study, we sought to determine the mechanism(s) whereby GCs influence the fibrotic response and mechanisms underlying these effects with an emphasis on TGF-β and nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling. Human VF fibroblasts (HVOX) were treated with three commonly-employed GCs+ /-TGF-β1. Phosphorylation of the glucocorticoid receptor (GR:NR3C1) and activation of NR4A1 was analyzed by western blotting. Genes involved in the fibrotic response, including ACTA2, TGFBR1, and TGFBR2 were analyzed by qPCR. RNA-seq was performed to identify global changes in gene expression induced by dexamethasone. GCs enhanced phosphorylation of GR at Ser211 and TGF-β-induced ACTA2 expression. Dexamethasone upregulated TGFBR1, and TGFBR2 in the presence of TGF-β1 and increased active NR4A1. RNA-seq results confirmed numerous pathways, including TGF-β signaling, affected by dexamethasone. Synergistic pro-fibrotic effects of TGF-β were observed across GCs and appeared to be mediated, at least partially, via upregulation of TGF-β receptors. Dexamethasone exhibited diverse regulation of gene expression including NR4A1 upregulation consistent with the anti-fibrotic potential of GCs.
format	article
author	Ryosuke Nakamura Shigeyuki Mukudai Renjie Bing Michael J. Garabedian Ryan C. Branski
author_facet	Ryosuke Nakamura Shigeyuki Mukudai Renjie Bing Michael J. Garabedian Ryan C. Branski
author_sort	Ryosuke Nakamura
title	Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds
title_short	Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds
title_full	Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds
title_fullStr	Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds
title_full_unstemmed	Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds
title_sort	complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/c74949bf7687426e93e1fbbc5bb29eb1
work_keys_str_mv	AT ryosukenakamura complexfibroblastresponsetoglucocorticoidsmayunderlievariabilityofclinicalefficacyinthevocalfolds AT shigeyukimukudai complexfibroblastresponsetoglucocorticoidsmayunderlievariabilityofclinicalefficacyinthevocalfolds AT renjiebing complexfibroblastresponsetoglucocorticoidsmayunderlievariabilityofclinicalefficacyinthevocalfolds AT michaeljgarabedian complexfibroblastresponsetoglucocorticoidsmayunderlievariabilityofclinicalefficacyinthevocalfolds AT ryancbranski complexfibroblastresponsetoglucocorticoidsmayunderlievariabilityofclinicalefficacyinthevocalfolds
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Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds

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