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Thromb Haemost 2004; 92(02): 253-261
DOI: 10.1160/TH04-05-0324
Theme Issue Article
Schattauer GmbH

Extracellular regulation of TGF-β activity in wound repair: growth factor latency as a sensor mechanism for injury

Georg Brunner
1   Department of Cancer Research, Fachklinik Hornheide, Münster, Germany
,
Robert Blakytny
1   Department of Cancer Research, Fachklinik Hornheide, Münster, Germany
› Author AffiliationsFinancial support: This work was supported by grants from the Deutsche Forschungsgemeinschaft (BR 1125/2-1 and BR 1125/2-2).
Further Information

Publication History

Received 27 May 2004

Accepted after revision 08 June 2004

Publication Date:
30 November 2017 (online)

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Summary

The transforming growth factor-β (TGF-β) family of growth factors are major regulators of wound repair, scar formation, and fibrosis. One of the prominent features of TGF-β biology is the fact that this growth factor is secreted as a latent precursor, which may be directed to and stored at specific sites in the cellular microenvironment. Targeting and mobilization, and particularly extracellular activation of latent TGF-β control the biological action of this growth factor. This review will focus on mechanisms of extracellular TGF-β regulation relevant to and potentially operating in wound repair and scarring.

Keywords

TGF-β - TGF-β regulation - latent TGF-β activation - wound repair - scarring
 

  • References

  • 1 Singer AJ, Clark RAF. Mechanism of disease: Cutaneous wound healing. N Engl J Med 1999; 341: 738-746.
    CrossrefPubMedGoogle Scholar
  • 2 Roberts AB. Transforming growth factor-β: Activity and efficacy in animal models of wound healing. Wound Rep Reg 1995; 03: 408-418.
    CrossrefPubMedGoogle Scholar
  • 3 O’Kane S, Ferguson MWJ. Transforming growth factor βs and wound healing. Int J Biochem Cell Biol 1997; 29: 63-78.
    CrossrefPubMedGoogle Scholar
  • 4 Munz B, Hübner G, Tretter Y. et al. A novel role of activin in inflammation and repair. J Endocrinol 1999; 161: 187-193.
    CrossrefPubMedGoogle Scholar
  • 5 Assoian RK, Komoriya A, Meyers CA. et al. Transforming growth factor-β in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem 1983; 258: 7155-7160.
    CrossrefPubMedGoogle Scholar
  • 6 Assoian RK, Sporn MB. Type beta transforming growth factor in human platelets: Release during degranulation and action on vascular smooth muscle cells. J Cell Biol 1986; 102: 1712-1733.
    PubMedGoogle Scholar
  • 7 Wahl SM, Wong H, McCartney-Fancis N. Role of growth factors in inflammation and repair. J Cell Biochem 1989; 40: 193-199.
    CrossrefPubMedGoogle Scholar
  • 8 Yang EY, Moses HL. Transforming growth factor β1-induced changes in migration, proliferation, and angiogenesis in the chicken chorioallantoic membrane. J Cell Biol 1990; 111: 731-741.
    CrossrefPubMedGoogle Scholar
  • 9 Garlick JA, Taichman LB. Effect of TGF-β1 on re-epithelialization of human keratinocytes in vitro: An organotypic model. J Invest Dermatol 1994; 103: 554-559.
    CrossrefPubMedGoogle Scholar
  • 10 Chan T, Ghahary A, Demare J. et al. Development, characterization, and wound healing of the keratin 14 promoted transforming growth factor-β1 transgenic mouse. Wound Rep Reg 2002; 10: 177-187.
    CrossrefPubMedGoogle Scholar
  • 11 Koch RM, Roche NS, Parks WT. et al. Incisional wound healing in transforming growth factor-β1 null mice. Wound Rep Reg 2000; 08: 179-191.
    CrossrefPubMedGoogle Scholar
  • 12 Amendt C, Mann A, Schirmacher P. et al. Resistance of keratinocytes to TGFβ-mediated growth restriction and apoptosis induction accelerates re-epithelialization in skin wounds. J Cell Sci 2002; 115: 2189-2198.
    PubMedGoogle Scholar
  • 13 Ashcroft GS, Yang X, Glick AB. et al. Mice lacking Smad 3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1999; 01: 260-266.
    CrossrefPubMedGoogle Scholar
  • 14 Mustoe TA, Pierce GF, Thomason A. et al. Accelerated healing of incisional wounds in rats induced by transforming growth factor-β. Science 1987; 237: 1333-1336.
    CrossrefPubMedGoogle Scholar
  • 15 Shah M, Foreman DM, Ferguson MW. Control of scarring in adult wounds by neutralising antibody to transforming growth factor β. Lancet 1992; 339: 213-214.
    CrossrefPubMedGoogle Scholar
  • 16 Border WA, Noble NA. Transforming growth factor β in tissue fibrosis. N Engl J Med 1994; 331: 1286-1292.
    CrossrefPubMedGoogle Scholar
  • 17 Cowin AJ, Hatzirodos N, Holding CA. et al. Effect of healing on the expression of transforming growth factor β(s) and their receptors in chronic venous leg ulcers. J Invest Dermatol 2001; 117: 1282-1289.
    CrossrefPubMedGoogle Scholar
  • 18 Jude EB, Blakytny R, Bulmer J. et al. Transforming growth factor-beta 1, 2, 3 and receptor type I and II in diabetic foot ulcers. Diabet Med 2002; 19: 440-447.
    CrossrefPubMedGoogle Scholar
  • 19 Frank S, Madlener M, Werner S. Transforming growth factors β1, β2, and β3 and their receptors are differentially regulated during normal and impaired wound healing. J Biol Chem 1996; 271: 10188-93.
    CrossrefPubMedGoogle Scholar
  • 20 Beck LS, DeGuzman L, Wyne PL. et al. One systemic administration of transforming growth factor-β1 reverses ageor glucocorticoid-impaired wound healing. J Clin Invest 1993; 92: 2841-2849.
    CrossrefPubMedGoogle Scholar
  • 21 Pierce GF, Mustoe TA, Lingelbach J. et al. Transforming growth factor β reverses the glucocorticoid-induced wound-healing deficits in rats: Possible regulation in macrophages by platelet-derived growth factor. Proc Natl Acad Sci USA 1989; 86: 2229-2233.
    CrossrefPubMedGoogle Scholar
  • 22 Shah M, Foreman DM, Ferguson MWJ. Neutralisation of TGF-β1 and TGF-β2 or exogenous addition of TGF-β3 to cutaneous rat wounds reduces scarring. J Cell Sci 1995; 108: 985-1002.
    PubMedGoogle Scholar
  • 23 Hübner G, Hu Q, Smola H. et al. Strong induction of activin expression after injury suggests an important role of activin in wound repair. Dev Biol 1996; 173: 490-498.
    CrossrefPubMedGoogle Scholar
  • 24 Munz B, Smola H, Engelhardt F. et al. Overexpression of activin A in the skin of transgenic mice reveals new activities of activin in epidermal morphogenesis, dermal fibrosis and wound repair. EMBO J 1999; 18: 5205-5215.
    CrossrefPubMedGoogle Scholar
  • 25 Wankell M, Munz B, Hübner G. et al. Impaired wound healing in transgenic mice overexpressing the activin antagonist follistatin in the epidermis. EMBO J 2001; 20: 5361-5372.
    CrossrefPubMedGoogle Scholar
  • 26 Munger JS, Harpel JG, Gleizes PE. et al. Latent transforming growth factor-β: Structural features and mechanisms of activation. Kidney Int 1997; 51: 1376-1382.
    CrossrefPubMedGoogle Scholar
  • 27 Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFβ activation. Cell Sci 2003; 116: 217-224.
    CrossrefPubMedGoogle Scholar
  • 28 Gentry LE, Nash BW. The pro domain of prepro-transforming growth factor β1 when independently expressed is a functional binding protein for the mature growth factor. Biochemistry 1990; 29: 6851-6857.
    CrossrefPubMedGoogle Scholar
  • 29 Koli K, Saharinen J, Hyytiäinen M. et al. Latency, activation, and binding proteins of TGF-β. Microsc Res Tech 2001; 52: 354-362.
    CrossrefPubMedGoogle Scholar
  • 30 Taipale J, Miyazono K, Heldin CH. et al. Latent transforming growth factor-β1 associates to fibroblast extracellular matrix via latent TGF-β binding protein. J Cell Biol 1994; 124: 171-181.
    CrossrefPubMedGoogle Scholar
  • 31 Yang L, Qiu CX, Ludlow A. et al. Active transforming growth factor-β in wound repair: Determination using a new assay. Am J Pathol 1999; 154: 105-111.
    CrossrefPubMedGoogle Scholar
  • 32 Blakytny R, Ludlow A, Martin GEM. et al. Latent TGF-β1 activation by platelets. J Cell Physiol 2004; 199: 67-76.
    CrossrefPubMedGoogle Scholar
  • 33 Slivka SR, Loskutoff DJ. Platelets stimulate endothelial cells to synthesize type 1 plasminogen activator inhibitor. Evaluation of the role of transforming growth factor β. Blood 1991; 77: 1013-1019.
    PubMedGoogle Scholar
  • 34 Murphy-Ullrich JE, Schultz-Cherry S, Höök M. Transforming growth factor-β complexes with thrombospondin. Mol Biol Cell 1992; 03: 181-188.
    CrossrefPubMedGoogle Scholar
  • 35 Ribeirio SMF, Poczatek M, Schultz-Cherry S. et al. The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-β. J Biol Chem 1999; 274: 13586-93.
    CrossrefPubMedGoogle Scholar
  • 36 Crawford SE, Stellmach V, Murphy-Ullrich JE. et al. Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 1998; 93: 1159-1170.
    CrossrefPubMedGoogle Scholar
  • 37 Murphy-Ullrich JE, Poczatek M. Activation of latent TGF-β by thrombospondin-1: Mechanisms and physiology. Cyt Growth Factor Rev 2000; 11: 59-69.
    PubMedGoogle Scholar
  • 38 Grainger DJ, Frow EK. Thrombospondin 1 does not activate transforming growth factor β1 in a chemically defined system or in smooth-muscle-cell cultures. Biochem J 2000; 350: 291-298.
    CrossrefPubMedGoogle Scholar
  • 39 Abdelouahed M, Ludlow A, Brunner G, Lawler J. Activation of platelet-transforming growth factor β-1 in the absence of thrombospondin-1. J Biol Chem 2000; 275: 17933-6.
    CrossrefPubMedGoogle Scholar
  • 40 Grainger DJ, Wakefield L, Bethell HW. et al. Release and activation of platelet latent TGF-β in blood clots during dissolution with plasmin. Nature Med 1995; 01: 932-937.
    CrossrefPubMedGoogle Scholar
  • 41 Nunes I, Gleizes PE, Metz CN. et al. Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol 1997; 136: 1151-1163.
    CrossrefPubMedGoogle Scholar
  • 42 Unsöld C, Hyytiäinen M, Bruckner-Tuderman L. et al. Latent TGF-β binding protein LTBP-1 contains three potential extracellular matrix interacting domains. J Cell Sci 2001; 114: 187-197.
    PubMedGoogle Scholar
  • 43 Isogai Z, Ono RN, Ushiro S. et al. Latent transforming growth factor β–binding protein 1 interacts with fibrillin and is a microfibrilassociated protein. J Biol Chem 2003; 278: 2750-2757.
    CrossrefPubMedGoogle Scholar
  • 44 Flaumenhaft R, Abe M, Sato Y. et al. Role of the latent TGF-β binding protein in the activation of latent TGF-β by co-cultures of endothelial and smooth muscle cells. J Cell Biol 1993; 120: 995-1002.
    CrossrefPubMedGoogle Scholar
  • 45 Sato Y, Rifkin DB. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: Activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture. J Cell Biol 1989; 109: 309-315.
    CrossrefPubMedGoogle Scholar
  • 46 Taipale J, Koli K, Keski-Oja J. Release of transforming growth factor-β1 from the pericellular matrix of cultured fibroblasts and fibrosarcoma cells by plasmin and thrombin. J Biol Chem 1992; 267: 25378-84.
    PubMedGoogle Scholar
  • 47 Taipale J, Lohi J, Saarinen J. et al. Human mast cell chymase and leukocyte elastase release latent transforming growth factor-β1 from the extracellular matrix of cultured human epithelial and endothelial cells. J Biol Chem 1995; 270: 4689-4696.
    CrossrefPubMedGoogle Scholar
  • 48 Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000; 14: 163-176.
    PubMedGoogle Scholar
  • 49 Mu D, Cambier S, Fjellbirkeland L. et al. The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1. J Cell Biol 2002; 157: 493-507.
    CrossrefPubMedGoogle Scholar
  • 50 Maeda S, Dean DD, Gomez R. et al. The first stage of transforming growth factor beta1 activation is release of the large latent complex from the extracellular matrix of growth plate chondrocytes by matrix vesicle stromelysin-1 (MMP-3). Calcif Tissue Int 2002; 70: 54-65.
    CrossrefPubMedGoogle Scholar
  • 51 Nunes I, Shapiro RL, Rifkin DB. Characterization of latent TGF-β activation by murine peritoneal macrophages. J Immunol 1995; 155: 1450-1459.
    PubMedGoogle Scholar
  • 52 Godar S, Horejsi V, Weidle UH. et al. M6P/ IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-β1. Eur J Immunol 1999; 29: 1004-1013.
    CrossrefPubMedGoogle Scholar
  • 53 Yehualaeshet T, O’Connor R, Green-Johnson J. et al. Activation of rat alveolar macrophagederived latent transforming growth factor β-1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am J Pathol 1999; 155: 841-851.
    CrossrefPubMedGoogle Scholar
  • 54 Antonelli-Orlidge A, Saunders KB, Smith SR. et al. An activated form of transforming growth factor β is produced by cocultures of endothelial cells and pericytes. Proc Natl Acad Sci USA 1989; 86: 4544-4548.
    CrossrefPubMedGoogle Scholar
  • 55 Sato Y, Rifkin DB. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: Activation of a latent transforming growth factor-β1-like molecule by plasmin during co-culture. J Cell Biol 1989; 109: 309-15.
    CrossrefPubMedGoogle Scholar
  • 56 Bugge TH, Kombrinck KW, Flick MJ. et al. Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 1996; 87: 709-719.
    CrossrefPubMedGoogle Scholar
  • 57 Lee CG, Homer RJ, Zhu Z. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor-β1. J Exp Med 2001; 194: 809-821.
    CrossrefPubMedGoogle Scholar
  • 58 Shephard P, Martin GEM, Smola-Hess S. et al. Myofibroblast differentiation is induced in keratinocyte-fibroblast co-cultures and is antagonistically regulated by endogenous TGF-β and interleukin-1. Am J Pathol 2004; 164: 2055-2066.
    CrossrefPubMedGoogle Scholar
  • 59 Munger S, Huang X, Kawakatsu H. et al. The integrin αvβ6 binds and activates latent TGFβ1: A mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999; 96: 319-328.
    CrossrefPubMedGoogle Scholar
  • 60 Annes JP, Rifkin DB, Munger JS. The integrin αvβ6 binds and activates latent TGFβ3. FEBS Lett 2002; 511: 65-68.
    CrossrefPubMedGoogle Scholar
  • 61 Clark RA, Ashcroft GS, Spencer MJ. et al. Re-epithelialization of normal human excisional wounds is associated with a switch from αvβ5 to αvβ6 integrins. Br J Dermatol 1996; 135: 46-51.
    PubMedGoogle Scholar
  • 62 Haapasalmi K, Zhang K, Tonnesen M. et al. Keratinocytes in human wounds express αvβ6 integrin. J Invest Dermatol 1996; 106: 42-48.
    CrossrefPubMedGoogle Scholar
  • 63 Romer J, Bugge TH, Pyke C. et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 1996; 02: 287-292.
    CrossrefPubMedGoogle Scholar
  • 64 DiPietro LA, Nissen NN, Gamelli RL. et al. Thrombospondin 1 synthesis and function in wound repair. Am J Pathol 1996; 148: 1851-1860.
    PubMedGoogle Scholar
  • 65 Streit M, Velasco P, Riccardi L. et al. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J 2000; 19: 3272-3282.
    CrossrefPubMedGoogle Scholar
  • 66 Agah A, Kyriakides TR, Lawler J. et al. The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/ TSP2-null mice. Am J Pathol 2002; 161: 831-839.
    CrossrefPubMedGoogle Scholar
  • 67 Häkkinen L, Koivisto L, Gardner H. et al. Increased expression of β6-integrin in skin leads to spontaneous development of chronic wounds. Am J Pathol 2004; 164: 229-242.
    CrossrefPubMedGoogle Scholar
  • 68 Bugge TH, Kombrinck KW, Flick MJ. et al. Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 1996; 87: 709-719.
    CrossrefPubMedGoogle Scholar
  • 69 Lopez-Casillas F, Wrana JL, Massague J. Betaglycan presents ligand to the TGFβ signaling receptor. Cell 1993; 73: 1435-1444.
    CrossrefPubMedGoogle Scholar
  • 70 Eickelberg O, Centrella M, Reiss M. et al. Betaglycan inhibits TGF-β signaling by preventing type I-type II receptor complex formation. Glycosaminoglycan modifications alter betaglycan function. J Biol Chem 2002; 277: 823-829.
    CrossrefPubMedGoogle Scholar
  • 71 Letamendia A, Lastres P, Botella LM. et al. Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. J Biol Chem 1998; 273: 33011-9.
    CrossrefPubMedGoogle Scholar
  • 72 Hildebrand A, Romaris M, Rasmussen LM. et al. Interaction of the small interstitial proteoglycans biglycan, decorin, and fibromodulin with transforming growth factor β. Biochem J 1994; 302: 527-534.
    CrossrefPubMedGoogle Scholar
  • 73 Soo C, Hu F-Y, Zhang X. et al. Differential expression of fibromodulin, a transforming growth factor-β modulator, in fetal skin development and scarless repair. Am J Pathol 2000; 157: 423-433.
    CrossrefPubMedGoogle Scholar
  • 74 Webb DJ, Wen J, Lysiak JJ. et al. Murine α-macroglobulins demonstrate divergent activities as neutralizers of transforming growth factor-β and as inducers of nitric oxide synthesis. J Biol Chem 1996; 271: 24982-8.
    CrossrefPubMedGoogle Scholar
  • 75 Borth W. α2-Macroglobulin, a multifunctional binding protein with targeting characteristics. FASEB J 1992; 06: 3345-3353.
    CrossrefPubMedGoogle Scholar
  • 76 Umans L, Serneels L, Overbergh L. et al. Targeted inactivation of the mouse α2-macroglobulin gene. J Biol Chem 1995; 270: 19778-85.
    CrossrefPubMedGoogle Scholar
  • 77 Umans L, Serneels L, Overbergh L. et al. α2-Macroglobulinand murinoglobulin-1deficient mice: A mouse model for acute pancreatitis. Am J Pathol 1999; 155: 983-993.
    CrossrefPubMedGoogle Scholar
  • 78 Schaefer L, Raslik I, Gröne H-J. et al. Small proteoglycans in human diabetic nephropathy: Discrepancy between glomerular expression and protein accumulation of decorin, biglycan, lumican, and fibromodulin. FASEB J 2001; 15: 559-561.
    CrossrefPubMedGoogle Scholar
  • 79 Schoppet M, Chavakis T, Al-Fakhri N. et al. Molecular interactions and functional interference between vitronectin and transforming growth factor-β. Lab Invest 2002; 82: 37-46.
    CrossrefPubMedGoogle Scholar
  • 80 Mooradian DL, Lucas RC, Weatherbee JA. et al. Transforming growth factor-β1 binds to immobilized fibronectin. J Cell Biochem 1989; 41: 189-200.
    CrossrefPubMedGoogle Scholar
  • 81 Annes J, Vassallo M, Munger JS. et al. A genetic screen to identify latent transforming growth factor β activators. Anal Biochem 2004; 327: 45-54.
    CrossrefPubMedGoogle Scholar