Glycoconjugate Journal

, Volume 32, Issue 3–4, pp 93–103 | Cite as

Biology and biotechnology of hyaluronan

  • Manuela Viola
  • Davide Vigetti
  • Evgenia Karousou
  • Maria Luisa D’Angelo
  • Ilaria Caon
  • Paola Moretto
  • Giancarlo De Luca
  • Alberto PassiEmail author


The hyaluronan (HA) polymer is a critical component of extracellular matrix with a remarkable structure: is a linear and unbranched polymer without sulphate or phosphate groups. It is ubiquitous in mammals showing several biological functions, ranging from cell proliferation and migration to angiogenesis and inflammation. For its critical biological functions the amount of HA in tissues is carefully controlled by different mechanisms including covalent modification of the synthetic enzymes and epigenetic control of their gene expression. The concentration of HA is also critical in several pathologies including cancer, diabetes and inflammation. Beside these biological roles, the structural properties of HA allow it to take advantage of its capacity to form gels even at concentration of 1 % producing scaffolds with very promising applications in regenerative medicine as biocompatible material for advanced therapeutic uses. In this review we highlight the biological aspects of HA addressing the mechanisms controlling the HA content in tissues as well as its role in important human pathologies. In the second part of the review we highlight the different use of HA polymers in the modern biotechnology.


Proteoglycans Glycosaminoglycans Extracellular matrix UDP-sugars O-GlcNAcylation AMPK Hydrogel 





UDP-D-glucuronic acid


UDP- N-acetyl-D-glucosamine

HAS1 2 and 3

Hyaluronan synthase 1, 2 and 3


O-GlcNAc transferase


High molecular weight hyaluronan


Low molecular weight hyaluronan


Extra cellular matrix





The authors acknowledge the PhD School in Biological and Medical Sciences for I.C. and M.L.D.A. fellowships, the University of Insubria FAR funds to A.P., FR/ IRSES “Inflama” project to A.P.


The authors declare that they have no conflict of interest.


  1. 1.
    Fraser, J.R., Laurent, T.C., Laurent, U.B.: Hyaluronan: its nature, distribution, functions and turnover. J. Intern. Med. 242(1), 27–33 (1997)PubMedGoogle Scholar
  2. 2.
    Csoka, A.B., Stern, R.: Hypotheses on the evolution of hyaluronan: a highly ironic acid. Glycobiology 23(4), 398–411 (2013)PubMedCentralPubMedGoogle Scholar
  3. 3.
    Lee, J.Y., Spicer, A.P.: Hyaluronan: a multifunctional, megaDalton, stealth molecule. Curr. Opin. Cell Biol. 12(5), 581–586 (2000)PubMedGoogle Scholar
  4. 4.
    Weigel, P.H., DeAngelis, P.L.: Hyaluronan synthases: a decade-plus of novel glycosyltransferases. J. Biol. Chem. 282(51), 36777–36781 (2007)PubMedGoogle Scholar
  5. 5.
    Itano, N., Kimata, K.: Mammalian hyaluronan synthases. IUBMB Life 54(4), 195–199 (2002)PubMedGoogle Scholar
  6. 6.
    Suzuki, M., Asplund, T., Yamashita, H., Heldin, C.H., Heldin, P.: Stimulation of hyaluronan biosynthesis by platelet-derived growth factor-BB and transforming growth factor-beta 1 involves activation of protein kinase C. Biochem. J. 307(Pt 3), 817–821 (1995)PubMedCentralPubMedGoogle Scholar
  7. 7.
    Vigetti, D., Clerici, M., Deleonibus, S., Karousou, E., Viola, M., Moretto, P., Heldin, P., Hascall, V.C., De Luca, G., Passi, A.: Hyaluronan synthesis is inhibited by adenosine monophosphate-activated protein kinase through the regulation of HAS2 activity in human aortic smooth muscle cells. J. Biol. Chem. 286(10), 7917–7924 (2011)PubMedCentralPubMedGoogle Scholar
  8. 8.
    Vigetti, D., Deleonibus, S., Moretto, P., Karousou, E., Viola, M., Bartolini, B., Hascall, V.C., Tammi, M., De Luca, G., Passi, A.: Role of UDP-N-acetylglucosamine (GlcNAc) and O-GlcNAcylation of hyaluronan synthase 2 in the control of chondroitin sulfate and hyaluronan synthesis. J. Biol. Chem. 287(42), 35544–35555 (2012)PubMedCentralPubMedGoogle Scholar
  9. 9.
    Karousou, E., Kamiryo, M., Skandalis, S.S., Ruusala, A., Asteriou, T., Passi, A., Yamashita, H., Hellman, U., Heldin, C.H., Heldin, P.: The activity of hyaluronan synthase 2 is regulated by dimerization and ubiquitination. J. Biol. Chem. 285(31), 23647–23654 (2010)PubMedCentralPubMedGoogle Scholar
  10. 10.
    Deen, A.J., Rilla, K., Oikari, S., Karna, R., Bart, G., Hayrinen, J., Bathina, A.R., Ropponen, A., Makkonen, K., Tammi, R.H., Tammi, M.I.: Rab10-mediated endocytosis of the hyaluronan synthase HAS3 regulates hyaluronan synthesis and cell adhesion to collagen. J. Biol. Chem. 289(12), 8375–8389 (2014)PubMedCentralPubMedGoogle Scholar
  11. 11.
    Stern, R.: Hyaluronan catabolism: a new metabolic pathway. Eur. J. Cell Biol. 83(7), 317–325 (2004)PubMedGoogle Scholar
  12. 12.
    Iijima, J., Konno, K., Itano, N.: Inflammatory alterations of the extracellular matrix in the tumor microenvironment. Cancers (Basel) 3(3), 3189–3205 (2011)Google Scholar
  13. 13.
    Jiang, D., Liang, J., Fan, J., Yu, S., Chen, S., Luo, Y., Prestwich, G.D., Mascarenhas, M.M., Garg, H.G., Quinn, D.A., Homer, R.J., Goldstein, D.R., Bucala, R., Lee, P.J., Medzhitov, R., Noble, P.W.: Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat. Med. 11(11), 1173–1179 (2005)PubMedGoogle Scholar
  14. 14.
    Jiang, D., Liang, J., Noble, P.W.: Hyaluronan as an immune regulator in human diseases. Physiol. Rev. 91(1), 221–264 (2011)PubMedCentralPubMedGoogle Scholar
  15. 15.
    Stern, R., Asari, A.A., Sugahara, K.N.: Hyaluronan fragments: an information-rich system. Eur. J. Cell Biol. 85(8), 699–715 (2006)PubMedGoogle Scholar
  16. 16.
    Laurent, T.C., Fraser, J.R.: Hyaluronan. FASEB J. 6(7), 2397–2404 (1992)PubMedGoogle Scholar
  17. 17.
    Vigetti, D., Ori, M., Viola, M., Genasetti, A., Karousou, E., Rizzi, M., Pallotti, F., Nardi, I., Hascall, V.C., De Luca, G., Passi, A.: Molecular cloning and characterization of UDP-glucose dehydrogenase from the amphibian Xenopus laevis and its involvement in hyaluronan synthesis. J. Biol. Chem. 281(12), 8254–8263 (2006)PubMedGoogle Scholar
  18. 18.
    Motolese, A., Vignati, F., Brambilla, R., Cerati, M., Passi, A.: Interaction between a regenerative matrix and wound bed in non healing ulcers: results with 16 cases. BioMed Res. Int. 2013, 849321 (2013)PubMedCentralPubMedGoogle Scholar
  19. 19.
    Vigetti, D., Rizzi, M., Viola, M., Karousou, E., Genasetti, A., Clerici, M., Bartolini, B., Hascall, V.C., De Luca, G., Passi, A.: The effects of 4-methylumbelliferone on hyaluronan synthesis, MMP2 activity, proliferation, and motility of human aortic smooth muscle cells. Glycobiology 19(5), 537–546 (2009)PubMedGoogle Scholar
  20. 20.
    Vigetti, D., Rizzi, M., Moretto, P., Deleonibus, S., Dreyfuss, J.M., Karousou, E., Viola, M., Clerici, M., Hascall, V.C., Ramoni, M.F., De Luca, G., Passi, A.: Glycosaminoglycans and glucose prevent apoptosis in 4-methylumbelliferone-treated human aortic smooth muscle cells. J. Biol. Chem. 286(40), 34497–34503 (2011)PubMedCentralPubMedGoogle Scholar
  21. 21.
    Toole, B.P.: Hyaluronan: from extracellular glue to pericellular cue. Nat. Rev. Cancer 4(7), 528–539 (2004)PubMedGoogle Scholar
  22. 22.
    Vigetti, D., Viola, M., Karousou, E., Deleonibus, S., Karamanou, K., De Luca, G., Passi, A.: Epigenetics in extracellular matrix remodeling and hyaluronan metabolism. FEBS J. 281(22), 4980–4992 (2014)PubMedGoogle Scholar
  23. 23.
    Merrilees, M.J., Beaumont, B.W., Braun, K.R., Thomas, A.C., Kang, I., Hinek, A., Passi, A., Wight, T.N.: Neointima formed by arterial smooth muscle cells expressing versican variant V3 is resistant to lipid and macrophage accumulation. Arterioscler. Thromb. Vasc. Biol. 31(6), 1309–1316 (2011)PubMedCentralPubMedGoogle Scholar
  24. 24.
    Bollyky, P.L., Bogdani, M., Bollyky, J.B., Hull, R.L., Wight, T.N.: The role of hyaluronan and the extracellular matrix in islet inflammation and immune regulation. Curr. Diab. Rep. 12(5), 471–480 (2012)PubMedCentralPubMedGoogle Scholar
  25. 25.
    Weigel, P.H., Padgett-McCue, A.J., Baggenstoss, B.A.: Methods for measuring class I membrane-bound hyaluronan synthase activity. Methods Mol. Biol. 1022, 229–247 (2013)PubMedGoogle Scholar
  26. 26.
    Piccioni, F., Malvicini, M., Garcia, M.G., Rodriguez, A., Atorrasagasti, C., Kippes, N., Piedra Buena, I.T., Rizzo, M.M., Bayo, J., Aquino, J., Viola, M., Passi, A., Alaniz, L., Mazzolini, G.: Antitumor effects of hyaluronic acid inhibitor 4-methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice. Glycobiology 22(3), 400–410 (2012)PubMedGoogle Scholar
  27. 27.
    Hart, G.W.: Minireview series on the thirtieth anniversary of research on O-GlcNAcylation of nuclear and cytoplasmic proteins: nutrient regulation of cellular metabolism and physiology by O-GlcNAcylation. J. Biol. Chem. 289(50), 34422–34423 (2014)PubMedGoogle Scholar
  28. 28.
    Torres, C.R., Hart, G.W.: Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J. Biol. Chem. 259(5), 3308–3317 (1984)PubMedGoogle Scholar
  29. 29.
    Dias, W.B., Hart, G.W.: O-GlcNAc modification in diabetes and Alzheimer’s disease. Mol. BioSyst. 3(11), 766–772 (2007)PubMedGoogle Scholar
  30. 30.
    Hart, G.W., Housley, M.P., Slawson, C.: Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446(7139), 1017–1022 (2007)PubMedGoogle Scholar
  31. 31.
    Lewis, B.A., Hanover, J.A.: O-GlcNAc and the epigenetic regulation of gene expression. J. Biol. Chem. 289(50), 34440–34448 (2014)PubMedGoogle Scholar
  32. 32.
    Vigetti, D., Viola, M., Gornati, R., Ori, M., Nardi, I., Passi, A., De Luca, G., Bernardini, G.: Molecular cloning, genomic organization and developmental expression of the Xenopus laevis hyaluronan synthase 3. Matrix Biol. 22(6), 511–517 (2003)PubMedGoogle Scholar
  33. 33.
    Sainio, A., Jokela, T., Tammi, M.I., Jarvelainen, H.: Hyperglycemic conditions modulate connective tissue reorganization by human vascular smooth muscle cells through stimulation of hyaluronan synthesis. Glycobiology 20(9), 1117–1126 (2010)PubMedGoogle Scholar
  34. 34.
    Kultti, A., Rilla, K., Tiihonen, R., Spicer, A.P., Tammi, R.H., Tammi, M.I.: Hyaluronan synthesis induces microvillus-like cell surface protrusions. J. Biol. Chem. 281(23), 15821–15828 (2006)PubMedGoogle Scholar
  35. 35.
    Tammi, R.H., Passi, A.G., Rilla, K., Karousou, E., Vigetti, D., Makkonen, K., Tammi, M.I.: Transcriptional and post-translational regulation of hyaluronan synthesis. FEBS J. 278(9), 1419–1428 (2011)PubMedGoogle Scholar
  36. 36.
    Majors, A.K., Austin, R.C., de la Motte, C.A., Pyeritz, R.E., Hascall, V.C., Kessler, S.P., Sen, G., Strong, S.A.: Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion. J. Biol. Chem. 278(47), 47223–47231 (2003)PubMedGoogle Scholar
  37. 37.
    Viola, M., Bartolini, B., Vigetti, D., Karousou, E., Moretto, P., Deleonibus, S., Sawamura, T., Wight, T.N., Hascall, V.C., De Luca, G., Passi, A.: Oxidized low density lipoprotein (LDL) affects hyaluronan synthesis in human aortic smooth muscle cells. J. Biol. Chem. 288(41), 29595–29603 (2013)PubMedCentralPubMedGoogle Scholar
  38. 38.
    Vigetti, D., Deleonibus, S., Moretto, P., Bowen, T., Fischer, J.W., Grandoch, M., Oberhuber, A., Love, D.C., Hanover, J.A., Cinquetti, R., Karousou, E., Viola, M., D’Angelo, M.L., Hascall, V.C., De Luca, G., Passi, A.: Natural antisense transcript for hyaluronan synthase 2 (HAS2-AS1) induces transcription of HAS2 via protein O-GlcNAcylation. J. Biol. Chem. 289(42), 28816–28826 (2014)PubMedGoogle Scholar
  39. 39.
    Kaya, G., Rodriguez, I., Jorcano, J.L., Vassalli, P., Stamenkovic, I.: Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation. Genes Dev. 11(8), 996–1007 (1997)PubMedGoogle Scholar
  40. 40.
    Fenderson, B.A., Stamenkovic, I., Aruffo, A.: Localization of hyaluronan in mouse embryos during implantation, gastrulation and organogenesis. Differentiation 54(2), 85–98 (1993)PubMedGoogle Scholar
  41. 41.
    Deed, R., Rooney, P., Kumar, P., Norton, J.D., Smith, J., Freemont, A.J., Kumar, S.: Early-response gene signalling is induced by angiogenic oligosaccharides of hyaluronan in endothelial cells. Inhibition by nonangiogenic, high-molecular-weight hyaluronan. Int. J. Cancer 71(2), 251–256 (1997)PubMedGoogle Scholar
  42. 42.
    Rooney, P., Wang, M., Kumar, P., Kumar, S.: Angiogenic oligosaccharides of hyaluronan enhance the production of collagens by endothelial cells. J. Cell Sci. 105(Pt 1), 213–218 (1993)PubMedGoogle Scholar
  43. 43.
    Tian, X., Azpurua, J., Hine, C., Vaidya, A., Myakishev-Rempel, M., Ablaeva, J., Mao, Z., Nevo, E., Gorbunova, V., Seluanov, A.: High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499(7458), 346–349 (2013)PubMedCentralPubMedGoogle Scholar
  44. 44.
    Powell, J.D., Horton, M.R.: Threat matrix: low-molecular-weight hyaluronan (HA) as a danger signal. Immunol. Res. 31(3), 207–218 (2005)PubMedGoogle Scholar
  45. 45.
    Itano, N.: Simple primary structure, complex turnover regulation and multiple roles of hyaluronan. J. Biochem. 144(2), 131–137 (2008)PubMedGoogle Scholar
  46. 46.
    Aruffo, A., Stamenkovic, I., Melnick, M., Underhill, C.B., Seed, B.: CD44 is the principal cell surface receptor for hyaluronate. Cell 61(7), 1303–1313 (1990)PubMedGoogle Scholar
  47. 47.
    Sherman, L., Sleeman, J., Herrlich, P., Ponta, H.: Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression. Curr. Opin. Cell Biol. 6(5), 726–733 (1994)PubMedGoogle Scholar
  48. 48.
    Vigetti, D., Karousou, E., Viola, M., Deleonibus, S., De Luca, G., Passi, A.: Hyaluronan: biosynthesis and signaling. Biochim. Biophys. Acta 1840(8), 2452–2459 (2014)PubMedGoogle Scholar
  49. 49.
    Vigetti, D., Viola, M., Karousou, E., Rizzi, M., Moretto, P., Genasetti, A., Clerici, M., Hascall, V.C., De Luca, G., Passi, A.: Hyaluronan-CD44-ERK1/2 regulate human aortic smooth muscle cell motility during aging. J. Biol. Chem. 283(7), 4448–4458 (2008)PubMedGoogle Scholar
  50. 50.
    Yu, Q., Stamenkovic, I.: Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 14(2), 163–176 (2000)PubMedCentralPubMedGoogle Scholar
  51. 51.
    Clark, R.A., Lin, F., Greiling, D., An, J., Couchman, J.R.: Fibroblast invasive migration into fibronectin/fibrin gels requires a previously uncharacterized dermatan sulfate-CD44 proteoglycan. J. Invest. Dermatol. 122(2), 266–277 (2004)PubMedGoogle Scholar
  52. 52.
    Acharya, P.S., Majumdar, S., Jacob, M., Hayden, J., Mrass, P., Weninger, W., Assoian, R.K., Pure, E.: Fibroblast migration is mediated by CD44-dependent TGF beta activation. J. Cell Sci. 121(9), 1393–1402 (2008)PubMedGoogle Scholar
  53. 53.
    Hardwick, C., Hoare, K., Owens, R., Hohn, H.P., Hook, M., Moore, D., Cripps, V., Austen, L., Nance, D.M., Turley, E.A.: Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J. Cell Biol. 117(6), 1343–1350 (1992)PubMedGoogle Scholar
  54. 54.
    Savani, R.C., Cao, G., Pooler, P.M., Zaman, A., Zhou, Z., DeLisser, H.M.: Differential involvement of the hyaluronan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis. J. Biol. Chem. 276(39), 36770–36778 (2001)PubMedGoogle Scholar
  55. 55.
    Hall, C.L., Yang, B., Yang, X., Zhang, S., Turley, M., Samuel, S., Lange, L.A., Wang, C., Curpen, G.D., Savani, R.C., Greenberg, A.H., Turley, E.A.: Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell 82(1), 19–26 (1995)PubMedGoogle Scholar
  56. 56.
    Hofmann, M., Assmann, V., Fieber, C., Sleeman, J.P., Moll, J., Ponta, H., Hart, I.R., Herrlich, P.: Problems with RHAMM: a new link between surface adhesion and oncogenesis? Cell 95(5), 591–592 (1998). author reply 592-593 PubMedGoogle Scholar
  57. 57.
    Tolg, C., Hamilton, S.R., Nakrieko, K.A., Kooshesh, F., Walton, P., McCarthy, J.B., Bissell, M.J., Turley, E.A.: Rhamm−/− fibroblasts are defective in CD44-mediated ERK1,2 motogenic signaling, leading to defective skin wound repair. J. Cell Biol. 175(6), 1017–1028 (2006)PubMedCentralPubMedGoogle Scholar
  58. 58.
    Zaman, A., Cui, Z., Foley, J.P., Zhao, H., Grimm, P.C., Delisser, H.M., Savani, R.C.: Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury. Am. J. Respir. Cell Mol. Biol. 33(5), 447–454 (2005)PubMedCentralPubMedGoogle Scholar
  59. 59.
    Tolg, C., Poon, R., Fodde, R., Turley, E.A., Alman, B.A.: Genetic deletion of receptor for hyaluronanmediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor). Oncogene 22(44), 6873–6882 (2003)PubMedGoogle Scholar
  60. 60.
    Zhou, B., Weigel, J.A., Fauss, L., Weigel, P.H.: Identification of the hyaluronan receptor for endocytosis (HARE). J. Biol. Chem. 275(48), 37733–37741 (2000)PubMedGoogle Scholar
  61. 61.
    Nonaka, H., Tanaka, M., Suzuki, K., Miyajima, A.: Development of murine hepatic sinusoidal endothelial cells characterized by the expression of hyaluronan receptors. Dev. Dyn. 236(8), 2258–2267 (2007)PubMedGoogle Scholar
  62. 62.
    Harris, E.N., Kyosseva, S.V., Weigel, J.A., Weigel, P.H.: Expression, processing, and glycosaminoglycan binding activity of the recombinant human 315-kDa hyaluronic acid receptor for endocytosis (HARE). J. Biol. Chem. 282(5), 2785–2797 (2007)PubMedGoogle Scholar
  63. 63.
    Zhou, B., Weigel, J.A., Saxena, A., Weigel, P.H.: Molecular cloning and functional expression of the rat 175-kDa hyaluronan receptor for endocytosis. Mol. Biol. Cell 13(8), 2853–2868 (2002)PubMedCentralPubMedGoogle Scholar
  64. 64.
    Prevo, R., Banerji, S., Ferguson, D.J., Clasper, S., Jackson, D.G.: Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J. Biol. Chem. 276(22), 19420–19430 (2001)PubMedGoogle Scholar
  65. 65.
    Wrobel, T., Dziegiel, P., Mazur, G., Zabel, M., Kuliczkowski, K., Szuba, A.: LYVE-1 expression on high endothelial venules (HEVs) of lymph nodes. Lymphology 38(3), 107–110 (2005)PubMedGoogle Scholar
  66. 66.
    Mouta Carreira, C., Nasser, S.M., di Tomaso, E., Padera, T.P., Boucher, Y., Tomarev, S.I., Jain, R.K.: LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res. 61(22), 8079–8084 (2001)PubMedGoogle Scholar
  67. 67.
    Akishima, Y., Ito, K., Zhang, L., Ishikawa, Y., Orikasa, H., Kiguchi, H., Akasaka, Y., Komiyama, K.: Ishii, T.:Immunohistochemical detection of human small lymphatic vessels under normal and pathological conditions using the LYVE-1 antibody. Virchows Arch. 444(2), 153–157 (2004)PubMedGoogle Scholar
  68. 68.
    Johnson, L.A., Prevo, R., Clasper, S., Jackson, D.G.: Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J. Biol. Chem. 282(46), 33671–33680 (2007)PubMedGoogle Scholar
  69. 69.
    Gale, N.W., Prevo, R., Espinosa, J., Ferguson, D.J., Dominguez, M.G., Yancopoulos, G.D., Thurston, G., Jackson, D.G.: Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol. Cell. Biol. 27(2), 595–604 (2007)PubMedCentralPubMedGoogle Scholar
  70. 70.
    Aderem, A., Ulevitch, R.J.: Toll-like receptors in the induction of the innate immune response. Nature 406(6797), 782–787 (2000)PubMedGoogle Scholar
  71. 71.
    Takeda, K., Kaisho, T., Akira, S.: Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003)PubMedGoogle Scholar
  72. 72.
    Tesar, B.M., Jiang, D., Liang, J., Palmer, S.M., Noble, P.W., Goldstein, D.R.: The role of hyaluronan degradation products as innate alloimmune agonists. Am. J. Transplant. 6(11), 2622–2635 (2006)PubMedGoogle Scholar
  73. 73.
    del Fresno, C., Otero, K., Gomez-Garcia, L., Gonzalez-Leon, M.C., Soler-Ranger, L., Fuentes-Prior, P., Escoll, P., Baos, R., Caveda, L., Garcia, F., Arnalich, F., Lopez-Collazo, E.: Tumor cells deactivate human monocytes by up-regulating IL-1 receptor associated kinase-M expression via CD44 and TLR4. J. Immunol. 174(5), 3032–3040 (2005)PubMedGoogle Scholar
  74. 74.
    Voelcker, V., Gebhardt, C., Averbeck, M., Saalbach, A., Wolf, V., Weih, F., Sleeman, J., Anderegg, U., Simon, J.: Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4. Exp. Dermatol. 17(2), 100–107 (2008)PubMedGoogle Scholar
  75. 75.
    Chang, E.J., Kim, H.J., Ha, J., Kim, H.J., Ryu, J., Park, K.H., Kim, U.H., Lee, Z.H., Kim, H.M., Fisher, D.E., Kim, H.H.: Hyaluronan inhibits osteoclast differentiation via Toll-like receptor 4. J. Cell Sci. 120(Pt 1), 166–176 (2007)PubMedGoogle Scholar
  76. 76.
    Hill, D.R., Kessler, S.P., Rho, H.K., Cowman, M.K., de la Motte, C.A.: Specific-sized hyaluronan fragments promote expression of human beta-defensin 2 in intestinal epithelium. J. Biol. Chem. 287(36), 30610–30624 (2012)PubMedCentralPubMedGoogle Scholar
  77. 77.
    Gariboldi, S., Palazzo, M., Zanobbio, L., Selleri, S., Sommariva, M., Sfondrini, L., Cavicchini, S., Balsari, A., Rumio, C.: Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of beta-defensin 2 via TLR2 and TLR4. J. Immunol. 181(3), 2103–2110 (2008)PubMedGoogle Scholar
  78. 78.
    Csoka, A.B., Frost, G.I., Stern, R.: The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol. 20(8), 499–508 (2001)PubMedGoogle Scholar
  79. 79.
    Soltes, L., Mendichi, R., Kogan, G., Schiller, J., Stankovska, M., Arnhold, J.: Degradative action of reactive oxygen species on hyaluronan. Biomacromolecules 7(3), 659–668 (2006)PubMedGoogle Scholar
  80. 80.
    Takahashi, Y., Li, L., Kamiryo, M., Asteriou, T., Moustakas, A., Yamashita, H., Heldin, P.: Hyaluronan fragments induce endothelial cell differentiation in a CD44- and CXCL1/GRO1-dependent manner. J. Biol. Chem. 280(25), 24195–24204 (2005)PubMedGoogle Scholar
  81. 81.
    Taylor, K.R., Trowbridge, J.M., Rudisill, J.A., Termeer, C.C., Simon, J.C., Gallo, R.L.: Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J. Biol. Chem. 279(17), 17079–17084 (2004)PubMedGoogle Scholar
  82. 82.
    Camenisch, T.D., Spicer, A.P., Brehm-Gibson, T., Biesterfeldt, J., Augustine, M.L., Calabro Jr., A., Kubalak, S., Klewer, S.E., McDonald, J.A.: Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J. Clin. Invest. 106(3), 349–360 (2000)PubMedCentralPubMedGoogle Scholar
  83. 83.
    Balazs, E.A., Denlinger, J.L.: Viscosupplementation: a new concept in the treatment of osteoarthritis. J. Rheumatol. Suppl. 39, 3–9 (1993)PubMedGoogle Scholar
  84. 84.
    Evanko, S.P., Potter-Perigo, S., Petty, L.J., Workman, G.A., Wight, T.N.: Hyaluronan controls the deposition of fibronectin and collagen and modulates TGF-beta1 induction of lung myofibroblasts. Matrix Biol. (2014)Google Scholar
  85. 85.
    Hascall, V.C., Majors, A.K., De La Motte, C.A., Evanko, S.P., Wang, A., Drazba, J.A., Strong, S.A.: Wight, T.N.:Intracellular hyaluronan: a new frontier for inflammation? Biochim. Biophys. Acta 1673(1–2), 3–12 (2004)PubMedGoogle Scholar
  86. 86.
    de La Motte, C.A., Hascall, V.C., Calabro, A., Yen-Lieberman, B., Strong, S.A.: Mononuclear leukocytes preferentially bind via CD44 to hyaluronan on human intestinal mucosal smooth muscle cells after virus infection or treatment with poly(I.C). J. Biol. Chem. 274(43), 30747–30755 (1999)Google Scholar
  87. 87.
    Heickendorff, L., Ledet, T., Rasmussen, L.M.: Glycosaminoglycans in the human aorta in diabetes mellitus: a study of tunica media from areas with and without atherosclerotic plaque. Diabetologia 37(3), 286–292 (1994)PubMedGoogle Scholar
  88. 88.
    McDonald, T.O., Gerrity, R.G., Jen, C., Chen, H.J., Wark, K., Wight, T.N., Chait, A., O’Brien, K.D.: Diabetes and arterial extracellular matrix changes in a porcine model of atherosclerosis. J. Histochem. Cytochem. 55(11), 1149–1157 (2007)PubMedCentralPubMedGoogle Scholar
  89. 89.
    Wang, A., Hascall, V.C.: Hyperglycemia, intracellular hyaluronan synthesis, cyclin D3 and autophagy. Autophagy 5(6), 864–865 (2009)PubMedGoogle Scholar
  90. 90.
    Swaidani, S., Cheng, G., Lauer, M.E., Sharma, M., Mikecz, K., Hascall, V.C., Aronica, M.A.: TSG-6 protein is crucial for the development of pulmonary hyaluronan deposition, eosinophilia, and airway hyperresponsiveness in a murine model of asthma. J. Biol. Chem. 288(1), 412–422 (2013)PubMedCentralPubMedGoogle Scholar
  91. 91.
    Lauer, M.E., Cheng, G., Swaidani, S., Aronica, M.A., Weigel, P.H., Hascall, V.C.: Tumor necrosis factorstimulated gene-6 (TSG-6) amplifies hyaluronan synthesis by airway smooth muscle cells. J. Biol. Chem. 288(1), 423–431 (2013)PubMedCentralPubMedGoogle Scholar
  92. 92.
    Tolg, C., Telmer, P., Turley, E.: Specific sizes of hyaluronan oligosaccharides stimulate fibroblast migration and excisional wound repair. PLoS ONE 9(2), e88479 (2014)PubMedCentralPubMedGoogle Scholar
  93. 93.
    Vigetti, D., Passi, A.: Hyaluronan synthases posttranslational regulation in cancer. Adv. Cancer Res. 123, 95–119 (2014)PubMedGoogle Scholar
  94. 94.
    Tammi, R.H., Kultti, A., Kosma, V.M., Pirinen, R., Auvinen, P., Tammi, M.I.: Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan. Semin. Cancer Biol. 18(4), 288–295 (2008)PubMedGoogle Scholar
  95. 95.
    Tsai, S.W., Fang, J.F., Yang, C.L., Chen, J.H., Su, L.T., Jan, S.H.: Preparation and evaluation of a hyaluronate-collagen film for preventing post-surgical adhesion. J. Int. Med. Res. 33(1), 68–76 (2005)PubMedGoogle Scholar
  96. 96.
    Tamer, T.M.: Hyaluronan and synovial joint: function, distribution and healing. Interdiscip. Toxicol. 6(3), 111–125 (2013)PubMedCentralPubMedGoogle Scholar
  97. 97.
    Morris, E.R., Rees, D.A., Welsh, E.J.: Conformation and dynamic interactions in hyaluronate solutions. J. Mol. Biol. 138(2), 383–400 (1980)PubMedGoogle Scholar
  98. 98.
    Cowman, M.K., Matsuoka, S.: Experimental approaches to hyaluronan structure. Carbohydr. Res. 340(5), 791–809 (2005)PubMedGoogle Scholar
  99. 99.
    Scott, J.E., Cummings, C., Brass, A., Chen, Y.: Secondary and tertiary structures of hyaluronan in aqueous solution, investigated by rotary shadowing-electron microscopy and computer simulation. Hyaluronan is a very efficient network-forming polymer. Biochem. J. 274(Pt 3), 699–705 (1991)PubMedCentralPubMedGoogle Scholar
  100. 100.
    Burdick, J.A., Prestwich, G.D.: Hyaluronic acid hydrogels for biomedical applications. Adv. Mater. 23(12), H41–H56 (2011)PubMedCentralPubMedGoogle Scholar
  101. 101.
    Edsman, K., Nord, L.I., Ohrlund, A., Larkner, H., Kenne, A.H.: Gel properties of hyaluronic acid dermal fillers. Dermatol. Surg. 38(7 Pt 2), 1170–1179 (2012)PubMedGoogle Scholar
  102. 102.
    Simkovic, I.: Unexplored possibilities of all-polysaccharide composites. Carbohydr. Polym. 95(2), 697–715 (2013)PubMedGoogle Scholar
  103. 103.
    Jha, A.K., Hule, R.A., Jiao, T., Teller, S.S., Clifton, R.J., Duncan, R.L., Pochan, D.J., Jia, X.: Structural analysis and mechanical characterization of hyaluronic acid-based doubly cross-linked networks. Macromolecules 42(2), 537–546 (2009)PubMedCentralPubMedGoogle Scholar
  104. 104.
    Damodarasamy, M., Johnson, R.S., Bentov, I., MacCoss, M.J., Vernon, R.B., Reed, M.J.: Hyaluronan enhances wound repair and increases collagen III in aged dermal wounds. Wound Repair Regen. 22(4), 521–526 (2014)PubMedGoogle Scholar
  105. 105.
    Seyfried, N.T., McVey, G.F., Almond, A., Mahoney, D.J., Dudhia, J., Day, A.J.: Expression and purification of functionally active hyaluronan-binding domains from human cartilage link protein, aggrecan and versican: formation of ternary complexes with defined hyaluronan oligosaccharides. J. Biol. Chem. 280(7), 5435–5448 (2005)PubMedGoogle Scholar
  106. 106.
    Bonafe, F., Govoni, M., Giordano, E., Caldarera, C., Guarnieri, C., Muscari, C.: Hyaluronan and cardiac regeneration. J. Biomed. Sci. 21(1), 100 (2014)PubMedCentralPubMedGoogle Scholar
  107. 107.
    Darr, A., Calabro, A.: Synthesis and characterization of tyramine-based hyaluronan hydrogels. J. Mater. Sci. Mater. Med. 20(1), 33–44 (2009)PubMedGoogle Scholar
  108. 108.
    Valimaki, J.O.: Pilot study of glaucoma drainage implant surgery supplemented with reticulated hyaluronic acid gel in severe glaucoma. Eur. J. Ophthalmol. 0 (2014)Google Scholar
  109. 109.
    Lim, S.T., Forbes, B., Berry, D.J., Martin, G.P., Brown, M.B.: In vivo evaluation of novel hyaluronan/chitosan microparticulate delivery systems for the nasal delivery of gentamicin in rabbits. Int. J. Pharm. 231(1), 73–82 (2002)PubMedGoogle Scholar
  110. 110.
    Yang, J.A., Kim, E.S., Kwon, J.H., Kim, H., Shin, J.H., Yun, S.H., Choi, K.Y., Hahn, S.K.: Transdermal delivery of hyaluronic acid – human growth hormone conjugate. Biomaterials 33(25), 5947–5954 (2012)PubMedGoogle Scholar
  111. 111.
    Manuskiatti, W., Maibach, H.I.: Hyaluronic acid and skin: wound healing and aging. Int. J. Dermatol. 35(8), 539–544 (1996)PubMedGoogle Scholar
  112. 112.
    Pao, K.Y., Mancini, R.: Nonsurgical periocular rejuvenation: advanced cosmetic uses of neuromodulators and fillers. Curr. Opin. Ophthalmol. 25(5), 461–469 (2014)PubMedGoogle Scholar
  113. 113.
    Narins, R.S., Brandt, F., Leyden, J., Lorenc, Z.P., Rubin, M., Smith, S.: A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol. Surg. 29(6), 588–595 (2003)PubMedGoogle Scholar
  114. 114.
    Duranti, F., Salti, G., Bovani, B., Calandra, M., Rosati, M.L.: Injectable hyaluronic acid gel for soft tissue augmentation. A clinical and histological study. Dermatol. Surg. 24(12), 1317–1325 (1998)PubMedGoogle Scholar
  115. 115.
    Voigt, J., Driver, V.R.: Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: a systematic review and meta-analysis of randomized controlled trials. Wound Repair Regen. 20(3), 317–331 (2012)PubMedGoogle Scholar
  116. 116.
    Petrey, A.C., de la Motte, C.A.: Hyaluronan, a crucial regulator of inflammation. Front. Immunol. 5, 101 (2014)PubMedCentralPubMedGoogle Scholar
  117. 117.
    Rieder, F., Kessler, S.P., West, G.A., Bhilocha, S., de la Motte, C., Sadler, T.M., Gopalan, B., Stylianou, E., Fiocchi, C.: Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis. Am. J. Pathol. 179(5), 2660–2673 (2011)PubMedCentralPubMedGoogle Scholar
  118. 118.
    Hascall, V.C., Wang, A., Tammi, M., Oikari, S., Tammi, R., Passi, A., Vigetti, D., Hanson, R.W., Hart, G.W.: The dynamic metabolism of hyaluronan regulates the cytosolic concentration of UDP-GlcNAc. Matrix Biol. 35, 14–17 (2014)PubMedCentralPubMedGoogle Scholar
  119. 119.
    Food Drug Administration USA P110005 Approved Medical devices at
  120. 120.
    Lord, M.S., Day, A.J., Youssef, P., Zhuo, L., Watanabe, H., Caterson, B., Whitelock, J.M.: Sulfation of the bikunin chondroitin sulfate chain determines heavy chain · hyaluronan complex formation. J. Biol. Chem. 288(32), 22930–22941 (2013)PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Manuela Viola
    • 1
  • Davide Vigetti
    • 1
  • Evgenia Karousou
    • 1
  • Maria Luisa D’Angelo
    • 1
  • Ilaria Caon
    • 1
  • Paola Moretto
    • 1
  • Giancarlo De Luca
    • 1
  • Alberto Passi
    • 1
    Email author
  1. 1.Department of Surgical and Morphological SciencesUniversity of InsubriaVareseItaly

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