Proteoglycans and Their Role in Wound Repair

  • Richard L. Gallo
  • Merton Bernfield


Proteoglycans are a heterogeneous group of protein-carbohydrate complexes that are distinguished from all other macromolecules by bearing glycosaminoglycan (GAG) chains. These linear polysaccharide chains are highly polyanionic (due to sulfate and carboxylate residues), bear the highest charge density of any vertebrate macro-molecule, and usually occupy a high proportion of the mass of the proteoglycans. The distinction is important because these properties differ from all other molecules in vertebrate tissues. Because of their chemical stability, the GAG chains have been known and well characterized for many years. Only relatively recently, with the identification of a large number of proteoglycan core proteins, have their roles in cellular behavior become apparent. The GAG chains play a primordial role in metazoans; they are produced by the simplest organisms and are synthesized very early during vertebrate development and by virtually every nucleated cell. While they have multiple potential functions, the explicit role of each GAG type depends both on its nature and on the core protein moiety to which the GAG chain is linked in a proteoglycan.


Heparan Sulfate Chondroitin Sulfate Core Protein Wound Repair Heparan Sulfate Proteoglycan 
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  1. Adzick, N. S., and Longaker, M. T., 1992, Fetal Wound Healing, Elsevier, New York.Google Scholar
  2. Aviezer, D., Hecht, D., Safran, M., Elsinger, M., David, G., and Yayon, A., 1994, Perlecan: Basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis, and angiogenesis, Cell 79:1005–1013.CrossRefPubMedGoogle Scholar
  3. Bassols, A., and Massagué, J., 1988, Transforming growth factor β regulates the expression and structure of extracellular matrix chondroitin/dermatan sulfate proteoglycans, J. Biol. Chem. 263:3039–3045.PubMedGoogle Scholar
  4. Bernfield, M., Kokenyesi, R., Kato, M., Hinkes, M. T., Spring, J., Gallo, R. L., and Lose, E. J., 1992, Biology of the syndecans: A family of transmembrane heparan sulfate proteoglycans, Annu. Rev. Cell Biol. 8:365–393.CrossRefPubMedGoogle Scholar
  5. Blochberger, T. C., Vergnes, J. P., Hempel, J., and Hassell, J. R., 1992, cDNA to chick lumican (corneal keratan sulfate proteoglycan) reveals homology to the small interstitital proteoglycan gene family and expression in muscle and intestine, J. Biol. Chem. 267:347–352.PubMedGoogle Scholar
  6. Brennan, M. J., Oldberg, A., Hayman, E. G., and Ruoslahti, E., 1983, Effect of a proteoglycan produced by rat tumor cells on their adhesion to fibronectin-collagen substrata, Cancer Res. 43:4302–4307.PubMedGoogle Scholar
  7. Brown, L. F., Kiang-Tech, Y., Berse, B., Tet-Kin, Y., Senger, D. R., Dvorak, H. F., and Van De Water, L., 1992, Expression of vascular permiability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing, J. Exp. Med. 176:1375–1379.CrossRefPubMedGoogle Scholar
  8. Castellot, J. J., Favreau, L. V., Karnovsky, M. J., and Rosenberg, R. D., 1982, Inhibition of vascular smooth muscle cell growth by endothelial cell-derived heparin: Possible role of a platelet endoglycosidase, J. Biol. Chem. 257:11256–11260.PubMedGoogle Scholar
  9. Casu, B., Petitou, M., Provasoli, M., and Sinay, P., 1988, Conformational flexibility: A new concept for explaining binding and biological properties of iduronic acid-containing glycosaminoglycans, Trends Biochem. Sci. 13:221–225.CrossRefPubMedGoogle Scholar
  10. Choay, J., Pititous, M., Lormeau, J. E., Sinay, P., Lasu, B., and Gatti, G., 1983, Structure-activity relationship in heparin: A synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity, Biochem. Biophys. Res. Commun. 116:492–499.CrossRefPubMedGoogle Scholar
  11. Danielsson, Å., Raub, E., Lindahl, U., and Björk, I., 1986, Role of ternary complexes, in which heparin binds both antithrombin and proteinase, in the acceleration of the reactions between antithrombin and throm-bin or factor Xa, J. Biol. Chem. 261:15467–15473.PubMedGoogle Scholar
  12. David, G., 1993, Integral membrane heparan sulfate proteoglycans, FASEB J. 7:1023–1030.PubMedGoogle Scholar
  13. David, G., van der Schueren, B., Marynen, P., Cassiman, J-J., and van den Berghe, H., 1992, Molecular cloning of amphiglycan, a novel integral membrane heparan sulfate proteoglycan expressed by epithelial and fibroblastic cells, J. Cell Biol. 118:961–969.CrossRefPubMedGoogle Scholar
  14. Dunphy, J. E., and Upuda, K. N., 1955, Chemical and histochemical sequences in the normal healing of wounds, N. Engl. J. Med. 253:847–851.CrossRefPubMedGoogle Scholar
  15. Elenius, K., Vainio, S., Laato, M., Salmivirta, M., Theslef, I., and Jalkanen, M., 1991, Induced expression of syndecan in healing wounds, J. Cell Biol. 114:585–595.CrossRefPubMedGoogle Scholar
  16. Elenius, K., Määttä, A., Salmivirta, M., and Jalkanen, M., 1992, Growth factors induce 3T3 cells to express bFGF-binding syndecan, J. Biol. Chem. 267:6435–6441.PubMedGoogle Scholar
  17. Forrester, J. V., and Lackie, J. M., 1981, Effect of hyaluronic acid on neutrophil adhesion, J. Cell. Sci. 50:329–344.PubMedGoogle Scholar
  18. Forrester, J. V., and Wilkinson, P. C., 1981, Inhibition of leukocyte locomotion by hyaluronic acid, J. Cell Sci. 48:315–331.PubMedGoogle Scholar
  19. Gallo, R. L., Ono, M., Povsic, T., Page, C., Eriksson, E., Klagsbrun, M., and Bernfield, M., 1994, Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds, Proc. Natl. Acad. Sci. USA 91:11035–11039.CrossRefPubMedGoogle Scholar
  20. Ginsberg, M. H., and Jaques, B. C., 1983, Platelet membrane proteins, in: Measurements of Platelet Function (L. A. Harker and T. S. Zimmerman, eds.), pp. 158–176, Churchill-Livingston, Edinburgh.Google Scholar
  21. Gitay-Goren, H., Soker, S., Vlodavsky, I., and Neufeld, G., 1992, The binding of vascular endothelial growth factor to its receptors is dependent on cell surface-associated heparin-like molecules, J. Biol. Chem. 267:6093–6098.PubMedGoogle Scholar
  22. Gruskin-Lerner, L. S., and Trinkaus-Randall, V., 1991, Localization of integrin and syndecan in vivo in a corneal epithelial abrasion and keratectomy, Curr. Eye Res. 10:75–85.CrossRefGoogle Scholar
  23. Guimond, S., Maccarana, M., Olwin, B. B., Lindahl, U., and Rapraeger, A. C., 1993, Activating and inhibitory heparin sequences for FGF-2 (basic FGF): Distinct requirements for FGF-1, FGF-2 and FGF-4, J. Biol. Chem. 268:23906–23914.PubMedGoogle Scholar
  24. Hardingham, T. E., and Fosang, A. J., 1992, Proteoglycans: Many forms and many functions, FASEB J. 6:861–870.PubMedGoogle Scholar
  25. Heinegard, D., and Oldberg, A., 1989, Structure and biology of cartilage and bone matrix noncollagenous macromolecules, FASEB J. 3:2042–2051.PubMedGoogle Scholar
  26. Hildebrand, A., Romans, M., Rasmussen, L. M., Heinegard, K., Twardzik, D. R., Border, W. A., and Ruoslahti, E., 1994, Interaction of the small interstitial proteoglycans biglycan, decorin and fi-bromodulin with transforming growth factor β, Biochem. J. 302:527–534.PubMedGoogle Scholar
  27. Imai, Y., Singer, M. S., Fennie, C., Lasky, L. A., and Rosen, S. D., 1991, Identification of a carbohydrate-based endothelial ligand for a lymphocyte homing receptor, J. Cell Biol. 113:1213–1221.CrossRefPubMedGoogle Scholar
  28. Iozzo, R. V., 1994, Perlecan: A gem of a proteoglycan, Matrix Biol 14:203–208.CrossRefPubMedGoogle Scholar
  29. Jackson, R. L., Busch, S. J., and Cardin, A. D., 1991, Glycosaminoglycans: Molecular properties, protein interactions, and role in physiological processes, Physiol. Rev. 71:481–539.PubMedGoogle Scholar
  30. Kato, M., Wang, H., Bernfield, M., Gallagher, J. T., and Turnbull, J. E., 1994, Cell surface syndecan-1 on distinct cell types differs in fine structure and ligand binding of its heparan sulfate chains, J. Biol. Chem. 269:18881–18890.PubMedGoogle Scholar
  31. Kim, C. W., Goldberger, O. A., Gallo, R. L., and Bernfield, M., 1994, Members of the syndecan family of heparan sulfate proteoglycans are expressed in distinct cell-, tissue, and development-specific patterns, Mol. Biol. Cell 5:797–805.PubMedGoogle Scholar
  32. Kjellen, L., and Lindahl, U., 1991, Proteoglycans: Structures and interactions, Annu. Rev. Biochem. 60:443–475.CrossRefPubMedGoogle Scholar
  33. Klagsbrun, M., and Baird, A., 1991, A dual receptor system is required for basic fibroblast growth factor activity, Cell 67:229–231.CrossRefPubMedGoogle Scholar
  34. Knox, P., and Wells, P., 1979, Cell adhesion and proteoglycans, J. Cell Sci. 40:77–88.PubMedGoogle Scholar
  35. Kojima, T.; Leone, C., Marchildon, G. A., Marcum, J. A., and Rosenberg, R. D., 1992a, Isolation and characterization of heparan sulfate proteoglycans produced by cloned rat microvascular endothelial cells, J. Biol. Chem. 267:4859–4869.PubMedGoogle Scholar
  36. Kojima, T., Shworak, N. W., and Rosenberg, R. D., 1992b, Molecular cloning and expression of two distinct cDNA-encoding heparan sulfate proteoglycan core proteins from a rat endothelial cell line, J. Biol. Chem. 267:4870–4877.PubMedGoogle Scholar
  37. Kokenyesi, R., and Bernfield, M., 1994, Core protein structure and sequence determine the site and presence of heparan sulfate and chondroitin sulfate on syndecan-1, J. Biol. Chem. 269:12305–12309.Google Scholar
  38. Kreis, T., and Vale, R., 1993, Guidebook to the Extracellular Matrix and Adhesion Proteins, Oxford University Press, New York.Google Scholar
  39. Kresse, H., Hausser, H., and Schonherr, E., 1993, Small proteoglycans, Experientia 49:403–416.CrossRefPubMedGoogle Scholar
  40. Lasky, L. A., Singer, M. S., Dowbenko, D., Imai, Y., Henzel, W. J., Grimley, C., Fennie, C., Gillet, N., Watson, S. R., and Rosen, S. D., 1992, An endothelial ligand for 1-selectin is a novel mucin-like molecule, Cell 69:927–938.CrossRefPubMedGoogle Scholar
  41. Lindahl, U., Bäckström, G., Höök, M., Thunberg, L., Fransson, L., and Linker, A., 1979, Structure of the antithrombin-binding site in heparin, Proc. Natl. Acad. Sci. USA 76:3198–3202.CrossRefPubMedGoogle Scholar
  42. Lindahl, U., Backstrom, G., Thunberg, L., and Leder, L G., 1980, Evidence for a 3-O-sulfated D-glucosamine residue in the antithrombin-binding sequence of heparin, Proc. Natl. Acad. Sci. USA 77:6551–6555.CrossRefPubMedGoogle Scholar
  43. Lindahl, U., Thunberg, L., Bäckström, G., Riesenfeld, J., Nordling, K., and Björk, I., 1984, Extension and structural variability of the antithrombin-binding sequence in heparin, J. Biol. Chem. 259:12368–12376.PubMedGoogle Scholar
  44. Lories, V., Cassiman, J-J., van den Berghe, H., and David, G., 1992, Differential expression of cell surface heparan sulfate proteoglycans in human mammary epithelial cells and lung fibroblasts, J. Biol. Chem. 267:1116–1122.PubMedGoogle Scholar
  45. Maccarana, M., Casu, B., and Lindahl, U., 1993, Minimal sequence in heparin/heparan sulfate required for binding of basic fibroblast growth factor, J. Biol. Chem. 268:23898–23905.PubMedGoogle Scholar
  46. Marcum, J. A., and Rosenberg, R. D., 1984, Anticoagulantly active heparin-like molecules from vasular tissue, Biochemistry 23:1730–1737.CrossRefPubMedGoogle Scholar
  47. McEver, R. P., 1992, Leukocyte-endothelial cell interactions, Curr. Opin. Cell Biol. 4:840–849.CrossRefPubMedGoogle Scholar
  48. McGee, G. S., Davidson, J. M., Buckley, A., Sommer, A., Woodward, S. C., Aquino, A. M., Barbour, R., and Demitrium, A. A., 1988, Recominant basic fibroblast growth factor accelerates wound healing, J. Surg. Res. 45:145–153.CrossRefPubMedGoogle Scholar
  49. Neame, P. J., 1993, Extracellular matrix of cartilage: Proteoglycans, in: Joint Cartilage Degradation: Basic and Clinical Aspects (J. E. Woessner and D. S. Howell, eds.), pp. 109–138, Marcel Dekker, New York.Google Scholar
  50. Nishiyama, A., and Stallcup, W. B., 1993, Expression of NG2 proteoglycan causes retention of type VI collagen on the cell surface, Mol. Biol. Cell 4:1097–1108.PubMedGoogle Scholar
  51. Norgard-Sumnicht, K. E., Varki, N. M., and Varki, A., 1993, Calcium-dependent heparin-like ligands for L-selectin in nonlymphoid endothelial cells, Science 261:480–483.CrossRefPubMedGoogle Scholar
  52. Parkinson, J. F., Koyama, T., Bang, N. Y., and Preissner, K. T., 1992, Thrombomoduline: An anticoagulant cell surface proteoglycan with physiologically relevant glycosaminoglycan moiety, Adv. Exp. Med. Biol. 313:177–188.CrossRefPubMedGoogle Scholar
  53. Prehm, P., 1983, Synthesis of hyaluronate in differentiated teratocarcinoma cells: Mechanism of chain growth, Biochem J. 211:191–198.PubMedGoogle Scholar
  54. Rapraeger, A., 1989, Transforming growth factor (type β) promotes the addition of chondroitin sulfate chains to the cell surface proteoglycan (syndecan) of mouse mammary epithelia, J. Cell Biol. 109:2509–2518.CrossRefPubMedGoogle Scholar
  55. Rapraeger, A., Jalkanen, M., and Bernfield, M., 1986, Cell surface proteoglycan associates with the cyto-skeleton at the basolateral cell surface of mouse mammary epithelial cells, J. Cell Biol. 103:2683–2696.CrossRefPubMedGoogle Scholar
  56. Rapraeger, A. C., Krufka, A., and Olwin, B. B., 1991, Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation, Science 252:1705–1708.CrossRefPubMedGoogle Scholar
  57. Rauch, U., Karthikeyan, L., Maurel, P., Margolis, R. U., and Margolis, R. K., 1992, Cloning and primary structure of neurocan, a developmentally regulated, aggregating chondroitin sulfate proteoglycan of brain, J. Biol. Chem. 267:19536–19547.PubMedGoogle Scholar
  58. Reich-Slotky, R., Bonneh-Barkay, D., Shaoul, E., Bluma, B., Svahn, C. M., and Ron, D., 1994, Differential effect of cell-associated heparan sulfates on the binding of keratinocyte growth factor (KGF) and acidic fibroblast growth factor to the KGH receptor, J. Biol. Chem. 269:32279–32285.PubMedGoogle Scholar
  59. Rich, A. M., Pearlstein, E., Weissman, G., and Hoffstein, S. T., 1981, Cartilage proteoglycans inhibit fibronectin-mediated adhesion, Nature 293:224–226.CrossRefPubMedGoogle Scholar
  60. Roden, L., Campbell, P., Fraser, J. R. E., Laurent, T. E., Perloft, H., and Thompson, J. N., 1989, Enzymatic pathways of hyaluronan catabolism, in: The Biology of Hyaluronan (D. Evered and J. Whelan, eds.), pp. 60–86, Ciba Foundation Symposium, 143, Chichester, Wiley.Google Scholar
  61. Ruoslahti, E., and Engvall, E., 1980, Complexing of fibronectin, glycosaminoglycans and collagen, Biochim. Biophys. Acta 631:350–358.CrossRefPubMedGoogle Scholar
  62. Sanderson, R. D., Lalor, P., and Bernfield, M., 1989, B lymphocytes express and lose syndecan at specific stages of differentiation, Cell Reg. 1:27–35.Google Scholar
  63. Sanderson, R. D., Hinkes, M. D., and Bernfield, M., 1992a, Syndecan-1, a cell-surface proteoglycan, changes in size and abundance when keratinocytes stratify, J. Invest. Derm. 99:1–7.CrossRefGoogle Scholar
  64. Sanderson, R. D., Sneed, T., Young, L., Sullivan, G., and Lander, A., 1992b, Adhesion of B lymphoid (MPC-11) cells to type I collagen is mediated by the integral membrane proteoglycan, syndecan, J. Immunol. 148:3902–3911.PubMedGoogle Scholar
  65. Sanderson, R. D., Turnbull, J. E., Gallagher, J. T., and Lander, A. D., 1994, Fine structure of heparan sulfate regulates syndecan-1 function and cell behavior, J. Biol. Chem. 269:13100–13106.PubMedGoogle Scholar
  66. Scott, J. E., 1993, Proteoglycan-fibrillar collagen interactions in tissues: Dermatan sulfate proteoglycan as a tissue organizer, in: Dermatan Sulphate Proteoglycans: Chemistry, Biology, Chemical Pathology (J. E. Scott, ed.), pp. 165–181, Portland Press, London.Google Scholar
  67. Silbert, J. L., Bernfield, M., and Kokenyesi, R., 1995, Proteoglycans: A very special class of glycoproteins, in: Glycoproteins (J. Montreuil, H. Schachter, and J. F. G. Vliegenthart, eds.), Elsevier, Amsterdam, in press.Google Scholar
  68. Soker, S., Svahn, C. M., and Neufeld, G., 1993, Vascular endothelial growth factor is inactivated by binding to a2-macroglobulin and the binding is inhibited by heparin, J. Biol. Chem. 268:7685–7691.PubMedGoogle Scholar
  69. Spillman, D., and Lindahl, U., 1994, Glycosaminoglycan-protein interactions: A question of specificity, Curr. Opin. Struct. Biol. 4:677–682.CrossRefGoogle Scholar
  70. Spivak-Kroizman, T., Lemmon, M. A., Dikic, I., Ladbury, J. E., Pinchasi, D., Huang, F., Jaye, M., Crumley, G., Schlessinger, J., and Lax, I., 1994, Heparin-induced oligomerization of FGF molecules is responsible for FGf receptor dimerization, activation and cell proliferation, Cell 79:1015–1024.CrossRefPubMedGoogle Scholar
  71. Stevens, R. L., and Austen, K. F., 1989, Recent advances in the cellular and molecular biology of mast cells, Immunol. Today 10:381–386.CrossRefPubMedGoogle Scholar
  72. Tessler, S., Rockwell, P., Hicklin, D., Cohen, T., Levi, B-Z., Witte, L., Limischka, I. R., and Neufeld, G., 1994, Heparin modulates the interaction of VEGF165 with soluble and cell associated flk-1 receptors, J. Biol. Chem. 269:12456–12461.PubMedGoogle Scholar
  73. Thunberg, L., Backstron, G., and Lindahl, U., 1982, Further characterization of the antithrombin binding sequence in heparin, Carbohydr. Res. 100:393–410.CrossRefPubMedGoogle Scholar
  74. Tsen, G., Halfter, W., Kroger, S., and Cole, G. J., 1995, Agrin is a heparan sulfate proteoglycan, J. Biol. Chem. 270:3392–3399.CrossRefPubMedGoogle Scholar
  75. Turnbull, J. E., and Gallagher, J. E., 1990, Molecular organization of heparan sulfate from human skin fibroblasts, Biochem J. 265:715–724.PubMedGoogle Scholar
  76. Turnbull, J. E., Fernig, D. G., Ke, Y., Wilkinson, M. C., and Gallagher, J. T., 1992, Identification of the basic fibroblast growth factor binding sequence in fibroblast heparan sulfate, J. Biol. Chem. 267:10337–10341.PubMedGoogle Scholar
  77. Vertel, B. M., Walters, L. M., Flay, N., Kearns, A. E., and Schwartz, N. B., 1993, Xylosylation is an endoplasmic reticulum to Golgi event, J. Biol. Chem. 268:11105–11112.PubMedGoogle Scholar
  78. Werner, S., Peters, K. G., Longaker, M. T., Fuller-Pace, F., Banda, M. J., and Williams, L. T., 1992, Large induction of keratinocyte growth factor expression in the dermis during wound healing, Proc. Natl. Acad. Sci. USA 89:6896–6900.CrossRefPubMedGoogle Scholar
  79. Werner, S., Smola, H., Liao, X., Longaker, M. T., Krieg, T., Hofschneider, P. H., and Williams, L. T., 1994, The function of KGF in morphogenesis of epithelium and reepithelialization of wounds, Science 266:819–822.CrossRefPubMedGoogle Scholar
  80. Wight, T. N., Heinegard, D. K., and Hascall, V. C., 1991, Proteoglycans: Structure and function, in: Cell Biology of Extracellular Matrix (E. D. Hay, ed.), pp. 45–78, Plenum Press, New York.CrossRefGoogle Scholar
  81. Woods, A., and Couchman, J. R., 1994, Syndecan-4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion components, Mol. Biol. Cell 5:183–192.PubMedGoogle Scholar
  82. Yamada, H., Watanabe, K., Shimonaka, M., and Yamaguchi, Y., 1994, Molecular cloning of brevican, a novel brain proteoglycan of the aggrecan/versican family, J. Biol. Chem. 269:10119–10126.PubMedGoogle Scholar
  83. Yamagata, M., Saga, S., Kato, M., Bernfield, M., and Kimata, K., 1993, Selective distributions of proteoglycans and their ligands in pericellular matrix of cultured fibroblasts. Implications for their roles in cell-substratum adhesion, J. Cell Sci. 106:55–65.PubMedGoogle Scholar
  84. Yayon, A., Klagsbrun, M., Esko, J. D., Leder, P., and Ornitz, D. M., 1991, Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor, Cell 64:841–848.CrossRefPubMedGoogle Scholar
  85. Yeaman, C., and Rapraeger, A. C., 1993, Post-transcriptional regulation of syndecan-1 expression by cAMP in peritoneal macrophages, J. Cell Biol. 122:945–950.CrossRefGoogle Scholar
  86. Yeo, T-K., Brown, L., and Dvorak, H. F., 1991, Alterations in proteoglycan synthesis common to healing wounds and tumors, Am. J. Pathol. 138:1437–1450.PubMedGoogle Scholar
  87. Zhang, L., and Esko, J. D., 1994, Amino acid determinants that drive heparan sulfate assembly in a proteoglycan, J. Biol. Chem. 269:19295–19299.PubMedGoogle Scholar
  88. Zimmerman, D. R., and Ruoslahti, E., 1989, Multiple domains of the large fibroblast proteoglycan versican, EMBO J. 8:2975–2981.Google Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Richard L. Gallo
    • 1
  • Merton Bernfield
    • 2
  1. 1.Department of DermatologyHarvard Medical School, Boston Childrens’ HospitalBostonUSA
  2. 2.Joint Program in NeonatologyHarvard Medical School, Boston Children’s HospitalBostonUSA

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