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Journal of Cell Science, Vol 108, Issue 3 985-1002, Copyright © 1995 by Company of Biologists
JOURNAL ARTICLES |
M Shah, DM Foreman and MW Ferguson
Cells, Immunology and Development Division, School of Biological Sciences, University of Manchester, UK.
Exogenous addition of neutralising antibody to transforming growth factor-beta 1,2 to cutaneous wounds in adult rodents reduces scarring. Three isoforms of transforming growth factor-beta (1, 2 and 3) have been identified in mammals. We investigated the isoform/isoforms of TGF-beta responsible for cutaneous scarring by: (i) reducing specific endogenous TGF-beta isoforms by exogenous injection of isoform specific neutralising antibodies; and (ii) increasing the level of specific TGF-beta isoforms by exogenous infiltration into the wound margins. Exogenous addition of neutralising antibody to TGF-beta 1 plus neutralising antibody to TGF-beta 2 reduced the monocyte and macrophage profile, neovascularisation, fibronectin, collagen III and collagen I deposition in the early stages of wound healing compared to control wounds. Treatment with neutralising antibodies to TGF-betas 1 and 2 markedly improved the architecture of the neodermis to resemble that of normal dermis and reduced scarring while the control wounds healed with scar formation. Exogenous addition of neutralising antibody to TGF-beta 1 alone also reduced the monocyte and macrophage profile, fibronectin, collagen III and collagen I deposition compared to control wounds. However, treatment with neutralising antibody to TGF-beta 1 alone only marginally reduced scarring. By contrast, wounds treated with neutralising antibody to TGF-beta 2 alone did not differ from control wounds. Interestingly, exogenous addition of the TGF-beta 3 peptide also reduced the monocyte and macrophage profile, fibronectin, collagen I and collagen III deposition in the early stages of wound healing and markedly improved the architecture of the neodermis and reduced scarring. By contrast, wounds treated with either TGF-beta 1 or with TGF-beta 2 had more extracellular matrix deposition in the early stages of wound healing but did not differ from control wounds in the final quality of scarring. This study clearly demonstrates isoform specific differences in the role of TGF-betas in wound healing and cutaneous scarring. TGF-beta 1 and TGF-beta 2 are implicated in cutaneous scarring. This study also suggests a novel therapeutic use of exogenous recombinant, TGF-beta 3 as an anti-scarring agent.
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M. F. Cordeiro, M. B. Reichel, J. A. Gay, F. D’Esposita, R. A. Alexander, and P. T. Khaw Transforming Growth Factor-{beta}1, -{beta}2, and -{beta}3 In Vivo: Effects on Normal and Mitomycin C-Modulated Conjunctival Scarring Invest. Ophthalmol. Vis. Sci., August 1, 1999; 40(9): 1975 - 1982. [Abstract] [Full Text] [PDF]
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 B. C. McKaig, S. S. Makh, C. J. Hawkey, D. K. Podolsky, and Y. R. Mahida Normal human colonic subepithelial myofibroblasts enhance epithelial migration (restitution) via TGF-beta 3 Am J Physiol Gastrointest Liver Physiol, May 1, 1999; 276(5): G1087 - G1093. [Abstract] [Full Text] [PDF]
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J. Li, K. Foitzik, E. Calautti, H. Baden, T. Doetschman, and G. P. Dotto TGF-beta 3, but Not TGF-beta 1, Protects Keratinocytes against 12-O-Tetradecanoylphorbol-13-acetate-induced Cell Death in Vitro and in Vivo J. Biol. Chem., February 12, 1999; 274(7): 4213 - 4219. [Abstract] [Full Text] [PDF]
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 M F CORDEIRO and P T KHAW The healing optic nerve in glaucoma: transforming growth factor beta and optic nerve head remodelling Br J Ophthalmol, February 1, 1999; 83(2): 132 - 133. [Full Text]
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Y Taya, S O'Kane, and M. Ferguson Pathogenesis of cleft palate in TGF-beta3 knockout mice Development, January 9, 1999; 126(17): 3869 - 3879. [Abstract] [PDF]
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L. Yang, C. X. Qiu, A. Ludlow, M. W. J. Ferguson, and G. Brunner Active Transforming Growth Factor-ß in Wound Repair : Determination Using a New Assay Am. J. Pathol., January 1, 1999; 154(1): 105 - 111. [Abstract] [Full Text] [PDF]
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J. Wang, H. Zheng, C.-C. Sung, K. K. Richter, and M. Hauer-Jensen Cellular Sources of Transforming Growth Factor-ß Isoforms in Early and Chronic Radiation Enteropathy Am. J. Pathol., November 1, 1998; 153(5): 1531 - 1540. [Abstract] [Full Text] [PDF]
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M. B Reichel, M F. Cordeiro, R. A Alexander, I. A Cree, S. S Bhattacharya, and P. T Khaw New model of conjunctival scarring in the mouse eye Br J Ophthalmol, September 1, 1998; 82(9): 1072 - 1077. [Abstract] [Full Text]
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Y. KAJI, T. MITA, H. OBATA, T. TSURU, K. SOYA, E. SHIRASAWA, H. SAKAI, A. HANYU, M. KATO, and H. YAMASHITA Expression of transforming growth factor beta superfamily and their receptors in the corneal stromal wound healing process after excimer laser keratectomy Br J Ophthalmol, April 1, 1998; 82(4): 456g - 456. [Full Text]
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 M. R. Ward, A. Agrotis, P. Kanellakis, R. Dilley, G. Jennings, and A. Bobik Inhibition of Protein Tyrosine Kinases Attenuates Increases in Expression of Transforming Growth Factor-ß Isoforms and Their Receptors Following Arterial Injury Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 2461 - 2470. [Abstract] [Full Text]
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S. S. Huang, Q. Liu, F. E. Johnson, Y. Konish, and J. S. Huang Transforming Growth Factor beta Peptide Antagonists and Their Conversion to Partial Agonists J. Biol. Chem., October 24, 1997; 272(43): 27155 - 27159. [Abstract] [Full Text] [PDF]
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Q. Liu, S. S. Huang, and J. S. Huang Function of the Type V Transforming Growth Factor beta Receptor in Transforming Growth Factor beta -induced Growth Inhibition of Mink Lung Epithelial Cells J. Biol. Chem., July 25, 1997; 272(30): 18891 - 18895. [Abstract] [Full Text] [PDF]
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M. Lyon, G. Rushton, and J. T. Gallagher The Interaction of the Transforming Growth Factor-beta s with Heparin/Heparan Sulfate Is Isoform-specific J. Biol. Chem., July 18, 1997; 272(29): 18000 - 18006. [Abstract] [Full Text] [PDF]
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 L. Wu, A. Siddiqui, D. E. Morris, D. A. Cox, S. I. Roth, and T. A. Mustoe Transforming Growth Factor {beta}3 (TGF{beta}3) Accelerates Wound Healing Without Alteration of Scar Prominence: Histologic and Competitive Reverse-Transcription-Polymerase Chain Reaction Studies Arch Surg, July 1, 1997; 132(7): 753 - 760. [Abstract] [PDF]
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S. Frank, M. Madlener, and S. Werner Transforming Growth Factors beta1, beta2, and beta3 and Their Receptors Are Differentially Regulated during Normal and Impaired Wound Healing J. Biol. Chem., April 26, 1996; 271(17): 10188 - 10193. [Abstract] [Full Text] [PDF]
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 B. C. McKaig, K. Hughes, P. J. Tighe, and Y. R. Mahida Differential expression of TGF-beta isoforms by normal and inflammatory bowel disease intestinal myofibroblasts Am J Physiol Cell Physiol, January 1, 2002; 282(1): C172 - C182. [Abstract] [Full Text] [PDF]
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