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(The FASEB Journal. 2004;18:816-827.)
© 2004 FASEB

TGF-ß signaling and the fibrotic response

ANDREW LEASK1, and DAVID J. ABRAHAM

Centre for Rheumatology, Department of Medicine, Royal Free & University College Medical School, Rowland Hill Street, London, UK NW3 2PF

1Correspondence: Centre for Rheumatology, Department of Medicine, Royal Free & University College Medical School, Rowland Hill St., London, UK NW3 2PF. E-mail: a.leask{at}rfc.ucl.ac.uk

The cause of fibrotic diseases, pathologies characterized by excessive production, deposition, and contraction of extracellular matrix, is unknown. To understand the molecular basis of fibrotic disease, it is essential to appreciate how matrix deposition is normally controlled and how this process is dysregulated in fibrogenesis. This review discusses the current state of knowledge concerning interactions among the profibrotic proteins transforming growth factor-ß (TGF-ß), connective tissue growth factor (CTGF, CCN2), and ED-A fibronectin (ED-A FN) and the antifibrotic proteins tumor necrosis factor-{alpha} (TNF-{alpha}) and {gamma}-interferon (IFN-{gamma}).—Leask, A., Abraham, D. J. TGF-ß signaling and the fibrotic response.


Key Words: Smad • MAP kinase • CTGF • prostacyclin • TNF-{alpha} • scleroderma • ED-A fibronectin




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M. Pescatori, A. Broccolini, C. Minetti, E. Bertini, C. Bruno, A. D'amico, C. Bernardini, M. Mirabella, G. Silvestri, V. Giglio, et al.
Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression
FASEB J, April 1, 2007; 21(4): 1210 - 1226.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
P.-P. Kuang, X.-H. Zhang, C. B. Rich, J. A. Foster, M. Subramanian, and R. H. Goldstein
Activation of elastin transcription by transforming growth factor-beta in human lung fibroblasts
Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L944 - L952.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
H.-R. Kang, S. J. Cho, C. G. Lee, R. J. Homer, and J. A. Elias
Transforming Growth Factor (TGF)-beta1 Stimulates Pulmonary Fibrosis and Inflammation via a Bax-dependent, Bid-activated Pathway That Involves Matrix Metalloproteinase-12
J. Biol. Chem., March 9, 2007; 282(10): 7723 - 7732.
[Abstract] [Full Text] [PDF]

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 J. Clin. Pathol.Home page
H. Higashiyama, D. Yoshimoto, Y. Okamoto, H. Kikkawa, S. Asano, and M. Kinoshita
Receptor-activated Smad localisation in Bleomycin-induced pulmonary fibrosis
J. Clin. Pathol., March 1, 2007; 60(3): 283 - 289.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
R. Fuchshofer, A. H. L. Yu, U. Welge-Lussen, and E. R. Tamm
Bone Morphogenetic Protein-7 Is an Antagonist of Transforming Growth Factor-{beta}2 in Human Trabecular Meshwork Cells
Invest. Ophthalmol. Vis. Sci., February 1, 2007; 48(2): 715 - 726.
[Abstract] [Full Text] [PDF]

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 Int ImmunolHome page
M. Sakuma, K. Hatsushika, K. Koyama, R. Katoh, T. Ando, Y. Watanabe, M. Wako, M. Kanzaki, S. Takano, H. Sugiyama, et al.
TGF-{beta} type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody
Int. Immunol., February 1, 2007; 19(2): 117 - 126.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
C. D. Keller, P. Rivera Gil, M. Tolle, M. van der Giet, J. Chun, H. H. Radeke, M. Schafer-Korting, and B. Kleuser
Immunomodulator FTY720 Induces Myofibroblast Differentiation via the Lysophospholipid Receptor S1P3 and Smad3 Signaling
Am. J. Pathol., January 1, 2007; 170(1): 281 - 292.
[Abstract] [Full Text] [PDF]

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 J. Cell Sci.Home page
A. Leask and D. J. Abraham
All in the CCN family: essential matricellular signaling modulators emerge from the bunker
J. Cell Sci., December 1, 2006; 119(23): 4803 - 4810.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
X. Liu, S. Q. Sun, A. Hassid, and R. S. Ostrom
cAMP Inhibits Transforming Growth Factor-beta-Stimulated Collagen Synthesis via Inhibition of Extracellular Signal-Regulated Kinase 1/2 and Smad Signaling in Cardiac Fibroblasts
Mol. Pharmacol., December 1, 2006; 70(6): 1992 - 2003.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
F. Milliat, A. Francois, M. Isoir, E. Deutsch, R. Tamarat, G. Tarlet, A. Atfi, P. Validire, J. Bourhis, J.-C. Sabourin, et al.
Influence of Endothelial Cells on Vascular Smooth Muscle Cells Phenotype after Irradiation: Implication in Radiation-Induced Vascular Damages
Am. J. Pathol., October 1, 2006; 169(4): 1484 - 1495.
[Abstract] [Full Text] [PDF]

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 Mol. Biol. CellHome page
B. M. Zhao and F. M. Hoffmann
Inhibition of Transforming Growth Factor-beta1-induced Signaling and Epithelial-to-Mesenchymal Transition by the Smad-binding Peptide Aptamer Trx-SARA
Mol. Biol. Cell, September 1, 2006; 17(9): 3819 - 3831.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
K. Hayashida, D. R. Johnston, O. Goldberger, and P. W. Park
Syndecan-1 Expression in Epithelial Cells Is Induced by Transforming Growth Factor beta through a PKA-dependent Pathway
J. Biol. Chem., August 25, 2006; 281(34): 24365 - 24374.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
C. Neurohr, S. L. Nishimura, and D. Sheppard
Activation of Transforming Growth Factor-beta by the Integrin {alpha}vbeta8 Delays Epithelial Wound Closure
Am. J. Respir. Cell Mol. Biol., August 1, 2006; 35(2): 252 - 259.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
J. K. Crean, F. Furlong, D. Mitchell, E. McArdle, C. Godson, and F. Martin
Connective tissue growth factor/CCN2 stimulates actin disassembly through Akt/protein kinase B-mediated phosphorylation and cytoplasmic translocation of p27Kip-1
FASEB J, August 1, 2006; 20(10): 1712 - 1714.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
X. Shi-Wen, F. Rodriguez-Pascual, S. Lamas, A. Holmes, S. Howat, J. D. Pearson, M. R. Dashwood, R. M. du Bois, C. P. Denton, C. M. Black, et al.
Constitutive ALK5-Independent c-Jun N-Terminal Kinase Activation Contributes to Endothelin-1 Overexpression in Pulmonary Fibrosis: Evidence of an Autocrine Endothelin Loop Operating through the Endothelin A and B Receptors.
Mol. Cell. Biol., July 1, 2006; 26(14): 5518 - 5527.
[Abstract] [Full Text] [PDF]

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 Arterioscler. Thromb. Vasc. Bio.Home page
M. Wang, D. Zhao, G. Spinetti, J. Zhang, L.-Q. Jiang, G. Pintus, R. Monticone, and E. G. Lakatta
Matrix Metalloproteinase 2 Activation of Transforming Growth Factor-{beta}1 (TGF-{beta}1) and TGF-{beta}1-Type II Receptor Signaling Within the Aged Arterial Wall
Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1503 - 1509.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
J. M. McClung, J. M. Davis, M. A. Wilson, E. C. Goldsmith, and J. A. Carson
Estrogen status and skeletal muscle recovery from disuse atrophy
J Appl Physiol, June 1, 2006; 100(6): 2012 - 2023.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
S. Saika, K. Ikeda, O. Yamanaka, K. C. Flanders, Y. Okada, T. Miyamoto, A. Kitano, A. Ooshima, Y. Nakajima, Y. Ohnishi, et al.
Loss of Tumor Necrosis Factor {alpha} Potentiates Transforming Growth Factor {beta}-mediated Pathogenic Tissue Response during Wound Healing
Am. J. Pathol., June 1, 2006; 168(6): 1848 - 1860.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
Y.-M. Zhang, J. Bo, G. E. Taffet, J. Chang, J. Shi, A. K. Reddy, L. H. Michael, M. D. Schneider, M. L. Entman, R. J. Schwartz, et al.
Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis
FASEB J, May 1, 2006; 20(7): 916 - 925.
[Abstract] [Full Text] [PDF]

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 ChestHome page
C. Karagiannidis, V. Velehorschi, B. Obertrifter, H.-N. Macha, A. Linder, and L. Freitag
High-Level Expression of Matrix-Associated Transforming Growth Factor-{beta}1 in Benign Airway Stenosis
Chest, May 1, 2006; 129(5): 1298 - 1304.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
X. Shi-wen, L. A. Stanton, L. Kennedy, D. Pala, Y. Chen, S. L. Howat, E. A. Renzoni, D. E. Carter, G. Bou-Gharios, R. J. Stratton, et al.
CCN2 Is Necessary for Adhesive Responses to Transforming Growth Factor-beta1 in Embryonic Fibroblasts
J. Biol. Chem., April 21, 2006; 281(16): 10715 - 10726.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
T. Meyer-ter-Vehn, S. Gebhardt, W. Sebald, M. Buttmann, F. Grehn, G. Schlunck, and P. Knaus
p38 Inhibitors Prevent TGF-{beta}-Induced Myofibroblast Transdifferentiation in Human Tenon Fibroblasts.
Invest. Ophthalmol. Vis. Sci., April 1, 2006; 47(4): 1500 - 1509.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. S. Augustus, J. Buchanan, T.-S. Park, K. Hirata, H.-l. Noh, J. Sun, S. Homma, J. D'armiento, E. D. Abel, and I. J. Goldberg
Loss of Lipoprotein Lipase-derived Fatty Acids Leads to Increased Cardiac Glucose Metabolism and Heart Dysfunction
J. Biol. Chem., March 31, 2006; 281(13): 8716 - 8723.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
N. C. Henderson, A. C. Mackinnon, S. L. Farnworth, F. Poirier, F. P. Russo, J. P. Iredale, C. Haslett, K. J. Simpson, and T. Sethi
Galectin-3 regulates myofibroblast activation and hepatic fibrosis
PNAS, March 28, 2006; 103(13): 5060 - 5065.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Renal Physiol.Home page
W. Qi, X. Chen, T. S. Polhill, S. Sumual, S. Twigg, R. E. Gilbert, and C. A. Pollock
TGF-beta1 induces IL-8 and MCP-1 through a connective tissue growth factor-independent pathway
Am J Physiol Renal Physiol, March 1, 2006; 290(3): F703 - F709.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
B. Wang, S. Li, P. J. Southern, and P. P. Cleary
Streptococcal modulation of cellular invasion via TGF-beta1 signaling
PNAS, February 14, 2006; 103(7): 2380 - 2385.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
Y. Chen, X. Shi-wen, J. van Beek, L. Kennedy, M. McLeod, E. A. Renzoni, G. Bou-Gharios, S. Wilcox-Adelman, P. F. Goetinck, M. Eastwood, et al.
Matrix Contraction by Dermal Fibroblasts Requires Transforming Growth Factor-{beta}/Activin-Linked Kinase 5, Heparan Sulfate-Containing Proteoglycans, and MEK/ERK: Insights into Pathological Scarring in Chronic Fibrotic Disease
Am. J. Pathol., December 1, 2005; 167(6): 1699 - 1711.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
E.-S. Akool, A. Doller, R. Muller, P. Gutwein, C. Xin, A. Huwiler, J. Pfeilschifter, and W. Eberhardt
Nitric Oxide Induces TIMP-1 Expression by Activating the Transforming Growth Factor {beta}-Smad Signaling Pathway
J. Biol. Chem., November 25, 2005; 280(47): 39403 - 39416.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
G. E. Davis and D. R. Senger
Endothelial Extracellular Matrix: Biosynthesis, Remodeling, and Functions During Vascular Morphogenesis and Neovessel Stabilization
Circ. Res., November 25, 2005; 97(11): 1093 - 1107.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
A. Sakthianandeswaren, C. M. Elso, K. Simpson, J. M. Curtis, B. Kumar, T. P. Speed, E. Handman, and S. J. Foote
The wound repair response controls outcome to cutaneous leishmaniasis
PNAS, October 25, 2005; 102(43): 15551 - 15556.
[Abstract] [Full Text] [PDF]


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