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Nintedanib inhibits TGF-β-induced myofibroblast transdifferentiation in human Tenon’s fibroblasts

PURPOSE: This study aimed to investigate the effect of nintedanib on the conversion of human Tenon’s fibroblasts (HTFs) into myofibroblasts and reveal the molecular mechanisms involved. METHODS: Primary cultured HTFs were incubated with transforming growth factor β1 (TGF-β1) alone or combined with n...

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Autores principales: Lin, Xianchai, Wen, Jiamin, Liu, Rongjiao, Gao, Wuyou, Qu, Bo, Yu, Minbin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Molecular Vision 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300612/
https://www.ncbi.nlm.nih.gov/pubmed/30636861
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author Lin, Xianchai
Wen, Jiamin
Liu, Rongjiao
Gao, Wuyou
Qu, Bo
Yu, Minbin
author_facet Lin, Xianchai
Wen, Jiamin
Liu, Rongjiao
Gao, Wuyou
Qu, Bo
Yu, Minbin
author_sort Lin, Xianchai
collection PubMed
description PURPOSE: This study aimed to investigate the effect of nintedanib on the conversion of human Tenon’s fibroblasts (HTFs) into myofibroblasts and reveal the molecular mechanisms involved. METHODS: Primary cultured HTFs were incubated with transforming growth factor β1 (TGF-β1) alone or combined with nintedanib, and cell proliferation and migration were measured by cell counting kit-8 (CCK8) and the scratch wound assay, respectively. HTF contractility was evaluated with a 3D collagen contraction assay. The mRNA and protein levels of α smooth muscle actin (α-SMA) and Snail and the phosphorylation levels of Smad2/3, p38 mitogen-activated protein kinase (p38MAPK), and extracellular signal-regulated kinase ½ (ERK1/2) were determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunofluorescence staining. RESULTS: Nintedanib inhibited the proliferation and migration of HTFs in a dose-dependent manner. Furthermore, nintedanib prevented HTF myofibroblast differentiation via downregulation of mRNA and protein expression of α-SMA and Snail. A three-dimensional (3D) collagen gel contraction assay demonstrated that nintedanib effectively inhibits myofibroblast contraction induced by TGF-β1. Mechanistically, we revealed that nintedanib reduces the TGF-β1-induced phosphorylation of Smad2/3, p38MAPK, and ERK1/2, suggesting that nintedanib acts through both classic and nonclassic signaling pathways of TGF-β1 to prevent HTF activation. CONCLUSIONS: Our study provides new evidence that nintedanib has potent antifibrotic effects in HTFs and suggests that it may be used as a potential therapeutic agent for subconjunctival fibrosis.
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spelling pubmed-63006122019-01-11 Nintedanib inhibits TGF-β-induced myofibroblast transdifferentiation in human Tenon’s fibroblasts Lin, Xianchai Wen, Jiamin Liu, Rongjiao Gao, Wuyou Qu, Bo Yu, Minbin Mol Vis Research Article PURPOSE: This study aimed to investigate the effect of nintedanib on the conversion of human Tenon’s fibroblasts (HTFs) into myofibroblasts and reveal the molecular mechanisms involved. METHODS: Primary cultured HTFs were incubated with transforming growth factor β1 (TGF-β1) alone or combined with nintedanib, and cell proliferation and migration were measured by cell counting kit-8 (CCK8) and the scratch wound assay, respectively. HTF contractility was evaluated with a 3D collagen contraction assay. The mRNA and protein levels of α smooth muscle actin (α-SMA) and Snail and the phosphorylation levels of Smad2/3, p38 mitogen-activated protein kinase (p38MAPK), and extracellular signal-regulated kinase ½ (ERK1/2) were determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunofluorescence staining. RESULTS: Nintedanib inhibited the proliferation and migration of HTFs in a dose-dependent manner. Furthermore, nintedanib prevented HTF myofibroblast differentiation via downregulation of mRNA and protein expression of α-SMA and Snail. A three-dimensional (3D) collagen gel contraction assay demonstrated that nintedanib effectively inhibits myofibroblast contraction induced by TGF-β1. Mechanistically, we revealed that nintedanib reduces the TGF-β1-induced phosphorylation of Smad2/3, p38MAPK, and ERK1/2, suggesting that nintedanib acts through both classic and nonclassic signaling pathways of TGF-β1 to prevent HTF activation. CONCLUSIONS: Our study provides new evidence that nintedanib has potent antifibrotic effects in HTFs and suggests that it may be used as a potential therapeutic agent for subconjunctival fibrosis. Molecular Vision 2018-12-09 /pmc/articles/PMC6300612/ /pubmed/30636861 Text en Copyright © 2018 Molecular Vision. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited, used for non-commercial purposes, and is not altered or transformed.
spellingShingle Research Article
Lin, Xianchai
Wen, Jiamin
Liu, Rongjiao
Gao, Wuyou
Qu, Bo
Yu, Minbin
Nintedanib inhibits TGF-β-induced myofibroblast transdifferentiation in human Tenon’s fibroblasts
title Nintedanib inhibits TGF-β-induced myofibroblast transdifferentiation in human Tenon’s fibroblasts
title_full Nintedanib inhibits TGF-β-induced myofibroblast transdifferentiation in human Tenon’s fibroblasts
title_fullStr Nintedanib inhibits TGF-β-induced myofibroblast transdifferentiation in human Tenon’s fibroblasts
title_full_unstemmed Nintedanib inhibits TGF-β-induced myofibroblast transdifferentiation in human Tenon’s fibroblasts
title_short Nintedanib inhibits TGF-β-induced myofibroblast transdifferentiation in human Tenon’s fibroblasts
title_sort nintedanib inhibits tgf-β-induced myofibroblast transdifferentiation in human tenon’s fibroblasts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300612/
https://www.ncbi.nlm.nih.gov/pubmed/30636861
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