Essential role of connective tissue growth factor (CTGF) in transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from Graves' orbital fibroblasts

被引：70
作者：
Tsai, Chieh-Chih [1 ,2 ]
Wu, Shi-Bei [3 ]
Kau, Hui-Chuan [1 ,2 ,4 ]
Wei, Yau-Huei [5 ]
机构：
[1] Taipei Vet Gen Hosp, Dept Ophthalmol, Taipei, Taiwan
[2] Natl Yang Ming Univ, Taipei, Taiwan
[3] Taipei Med Univ, Biomed Commercializat Ctr, Taipei, Taiwan
[4] Koo Fdn Sun Yat Sen Canc Ctr, Dept Ophthalmol, Taipei, Taiwan
[5] Changhua Christian Hosp, Ctr Mitochondrial Med & Free Rad Res, Changhua, Taiwan
来源：
SCIENTIFIC REPORTS | 2018年 / 8卷
关键词：
EXTRACELLULAR-MATRIX; PROFIBROTIC ACTION; FIBROSIS; EXPRESSION; MECHANISMS; CELLS; DIFFERENTIATION; OPHTHALMOPATHY; PATHOGENESIS; CTGF/CCN2;
D O I：
10.1038/s41598-018-25370-3
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Connective tissue growth factor (CTGF) associated with transforming growth factor-beta (TGF-beta) play a pivotal role in the pathophysiology of many fibrotic disorders. However, it is not clear whether this interaction also takes place in GO. In this study, we investigated the role of CTGF in TGF-beta-induced extracellular matrix production and myofibroblast transdifferentiation in Graves' orbital fibroblasts. By Western blot analysis, we demonstrated that TGF-beta 1 induced the expression of CTGF, fibronectin, and alpha-smooth muscle actin (alpha-SMA) in Graves' orbital fibroblasts. In addition, the protein levels of fibronectin and alpha-SMA in Graves' orbital fibroblasts were also increased after treatment with a recombinant human protein CTGF (rhCTGF). Moreover, we transfected the orbital fibroblasts with a small hairpin RNA of CTGF gene (shCTGF) to knockdown the expression levels of CTGF, which showed that knockdown of CTGF significantly diminished TGF-beta 1-induced expression of CTGF, fibronectin and alpha-SMA proteins in Graves' orbital fibroblasts. Furthermore, the addition of rhCTGF to the shCTGF-transfected orbital fibroblasts could restore TGF-beta 1-induced expression of fibronectin and alpha-SMA proteins. Our findings demonstrate that CTGF is an essential downstream mediator for TGF-beta 1-induced extracellular matrix production and myofibroblast transdifferentiation in Graves' orbital fibroblasts and thus may provide with a potential therapeutic target for treatment of GO.
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页数：10
相关论文
共 46 条
[1]   Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β [J].
Abreu, JG ;
Ketpura, NI ;
Reversade, B ;
De Robertis, EM .
NATURE CELL BIOLOGY, 2002, 4 (08) :599-604
[2]   Connective tissue growth factor (CTGF/CCN2) is a downstream mediator for TGF-β1-induced extracellular matrix production in osteoblasts [J].
Arnott, J. A. ;
Nuglozeh, E. ;
Rico, M. C. ;
Arango-Hisijara, I. ;
Odgren, P. R. ;
Safadi, F. F. ;
Popoff, S. N. .
JOURNAL OF CELLULAR PHYSIOLOGY, 2007, 210 (03) :843-852
[3]   MECHANISMS OF DISEASE Graves' Ophthalmopathy [J].
Bahn, Rebecca S. .
NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (08) :726-738
[4]   Consensus statement of the European Group on Graves' Orbitopathy (EUGOGO) on management of Graves' Orbitopathy [J].
Bartalena, Luigi ;
Baldeschi, Lelio ;
Dickinson, Alison J. ;
Eckstein, Anja ;
Kendall-Taylor, Pat ;
Marcocci, Claudio ;
Mourits, Maarten P. ;
Perros, Petros ;
Boboridis, Kostas ;
Boschi, Antonella ;
Curro, Nicola ;
Daumerie, Chantal ;
Kahaly, George J. ;
Krassas, Gerasimos ;
Lane, Carol M. ;
Lazarus, John H. ;
Marino, Michele ;
Nardi, Marco ;
Neoh, Christopher ;
Orgiazzi, Jacques ;
Pearce, Simon ;
Pinchera, Aldo ;
Pitz, Susanne ;
Salvi, Mario ;
Sivelli, Paolo ;
Stahl, Matthias ;
von Arx, Georg ;
Wiersinga, Wilmar M. .
THYROID, 2008, 18 (03) :333-346
[5]   Fibroblasts and Myofibroblasts: What Are We Talking About? [J].
Baum, Jennifer ;
Duffy, Heather S. .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 2011, 57 (04) :376-379
[6]   Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis [J].
Bickelhaupt, Sebastian ;
Erbel, Christian ;
Timke, Carmen ;
Wirkner, Ute ;
Dadrich, Monika ;
Flechsig, Paul ;
Tietz, Alexandra ;
Pfoehler, Johanna ;
Gross, Wolfgang ;
Peschke, Peter ;
Hoeltgen, Line ;
Katus, Hugo A. ;
Groene, Hermann-Josef ;
Nicolay, Nils H. ;
Saffrich, Rainer ;
Debus, Juergen ;
Sternlicht, Mark D. ;
Seeley, Todd W. ;
Lipson, Kenneth E. ;
Huber, Peter E. .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2017, 109 (08)
[7]   Transforming Growth Factor β1-Induced NADPH Oxidase-4 Expression and Fibrotic Response in Conjunctival Fibroblasts [J].
Brown, Karl David ;
Shah, Manisha H. ;
Liu, Guei-Sheung ;
Chan, Elsa C. ;
Crowston, Jonathan G. ;
Peshavariya, Hitesh M. .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2017, 58 (07) :3011-3017
[8]   CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P3 signaling axis: Implications in the action mechanism of TGFβ [J].
Bruno, Gennaro ;
Cencetti, Francesca ;
Pertici, Irene ;
Japtok, Lukasz ;
Bernacchioni, Caterina ;
Donati, Chiara ;
Bruni, Paola .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2015, 1851 (02) :194-202
[9]   Tetramethylpyrazine Attenuates Transdifferentiation of TGF-β2-Treated Human Tenon's Fibroblasts [J].
Cai, Xiaoxiao ;
Yang, Yangfan ;
Chen, Pei ;
Ye, Yiming ;
Liu, Xiao'an ;
Wu, Kaili ;
Yu, Minbin .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2016, 57 (11) :4740-4748
[10]  
Choi K, 2012, MOL VIS, V18, P1010
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