Cellular and Molecular Life Sciences

, Volume 67, Issue 6, pp 891–906 | Cite as

Structural and biochemical aspects of keratan sulphate in the cornea

  • Andrew J. QuantockEmail author
  • Robert D. Young
  • Tomoya O. Akama


Keratan sulphate (KS) is the predominant glycosaminoglycan (GAG) in the cornea of the eye, where it exists in proteoglycan (PG) form. KS-PGs have long been thought to play a pivotal role in the establishment and maintenance of the array of regularly-spaced and uniformly-thin collagen fibrils which make up the corneal stroma. This characteristic arrangement of fibrils allows light to pass through the cornea. Indeed, perturbations to the synthesis of KS-PG core proteins in genetically altered mice lead to structural matrix alterations and corneal opacification. Similarly, mutations in enzymes responsible for the sulphation of KS-GAG chains are causative for the inherited human disease, macular corneal dystrophy, which is manifested clinically by progressive corneal cloudiness starting in young adulthood.


Keratan sulphate Proteoglycan Glycosaminoglycan Cornea Collagen 



Our research programmes are funded by BBSRC Project Grant BB/D001919/1 (UK), NIH/NEI Research Grant EY014620 (USA), MRC Programme Grant G0600755 (UK), and EPSRC Project Grant EP/F034970/1 (UK).


  1. 1.
    Meyer K, Linker A, Davidson EA, Weissmann B (1953) The mucopolysaccharides of bovine cornea. J Biol Chem 205:611–616PubMedGoogle Scholar
  2. 2.
    Hassell JR, Newsome DA, Krachmer JH, Rodrigues MM (1980) Macular corneal dystrophy: failure to synthesize a mature keratan sulfate proteoglycan. Proc Natl Acad Sci USA 77:3705–3709PubMedGoogle Scholar
  3. 3.
    Hassell JR, Cintron C, Kublin C, Newsome DA (1983) Proteoglycan changes during restoration of transparency in corneal scars. Arch Biochem Biophys 222:362–369PubMedGoogle Scholar
  4. 4.
    Blochberger TC, Vergnes JP, Hempel J, Hassell JR (1992) cDNA to chick lumican (corneal keratan sulfate proteoglycan) reveals homology to the small interstitial proteoglycan gene family and expression in muscle and intestine. J Biol Chem 267:347–352PubMedGoogle Scholar
  5. 5.
    Corpuz LM, Funderburgh JL, Funderburgh ML, Bottomley GS, Prakash S, Conrad GW (1996) Molecular cloning and tissue distribution of keratocan. Bovine corneal keratan sulfate proteoglycan 37A. J Biol Chem 271:9759–9763PubMedGoogle Scholar
  6. 6.
    Funderburgh JL, Corpuz LM, Roth MR, Funderburgh ML, Tasheva ES, Conrad GW (1997) Mimecan, the 25-kDa corneal keratan sulfate proteoglycan, is a product of the gene producing osteoglycin. J Biol Chem 272:28089–28095PubMedGoogle Scholar
  7. 7.
    Poole RA (1986) Proteoglycans in health and disease: structures and functions. Biochem J 236:1–14PubMedGoogle Scholar
  8. 8.
    Funderburgh JL, Funderburgh ML, Mann MM, Conrad GW (1991) Physical and biological properties of keratan sulphate proteoglycan. Biochem Soc Trans 19:871–876PubMedGoogle Scholar
  9. 9.
    Hardingham TE, Fosang AJ (1992) Proteoglycans: many forms and many functions. FASEB J 6:861–870PubMedGoogle Scholar
  10. 10.
    Scott JE (1992) Supramolecular organization of extracellular matrix glycosaminoglycans, in vitro and in the tissues. FASEB J 6:2639–2645PubMedGoogle Scholar
  11. 11.
    Funderburgh JL (2000) Keratan sulphate: structure, biosynthesis, and function. Glycobiology 10:951–958PubMedGoogle Scholar
  12. 12.
    Funderburgh JL (2002) Keratan sulphate biosynthesis. IUBMB Life 54:187–194PubMedGoogle Scholar
  13. 13.
    Chakravarti S (2002) Functions of lumican and fibromodulin: lessons from knockout mice. Glycoconj J 19:287–293PubMedGoogle Scholar
  14. 14.
    Chakravarti S (2006) Focus on molecules: keratocan (KERA). Exp Eye Res 82:183–184PubMedGoogle Scholar
  15. 15.
    Kao WW, Funderburgh JL, Xia Y, Liu CY, Conrad GW (2006) Focus on molecules: lumican. Exp Eye Res 82:3–4PubMedGoogle Scholar
  16. 16.
    Kao WW, Liu CY (2002) Roles of lumican and keratocan on corneal transparency. Glycoconj J 19:275–285PubMedGoogle Scholar
  17. 17.
    Hogan MJ, Alvarado JA, Weddell JE (1971) The cornea. In: Histology of the human eye. An Atlas and textbook, chapter 3. Saunders, Philadelphia, p 89Google Scholar
  18. 18.
    Komai Y, Ushiki T (1991) The three-dimensional organization of collagen fibrils in the human cornea and sclera. Invest Ophthalmol Vis Sci 32:2244–2258PubMedGoogle Scholar
  19. 19.
    Meek KM, Leonard DW (1993) Ultrastructure of the corneal stroma: a comparative study. Biophys J 64:273–280PubMedGoogle Scholar
  20. 20.
    Quantock AJ, Meek KM, Fullwood NJ, Zabel RW (1993) Scheie’s syndrome: the architecture of corneal collagen and distribution of corneal proteoglycans. Can J Ophthalmol 28:266–272PubMedGoogle Scholar
  21. 21.
    Craig AS, Robertson JG, Parry DA (1986) Preservation of corneal collagen fibril structure using low-temperature procedures for electron microscopy. J Ultrastruct Mol Struct Res 96:172–175PubMedGoogle Scholar
  22. 22.
    Maurice DM (1957) The structure and transparency of the corneal stroma. J Physiol 136:263–286PubMedGoogle Scholar
  23. 23.
    Hart RW, Farrell RA (1969) Light scattering in the cornea. J Opt Soc Am 59:766–774PubMedGoogle Scholar
  24. 24.
    Benedek GB (1971) Theory and transparency of the eye. Appl Opt 10:459–473PubMedGoogle Scholar
  25. 25.
    Sayers Z, Whitburn SB, Koch MHJ, Meek KM, Elliott GF (1982) Synchrotron X-ray diffraction study of corneal stroma. J Mol Biol 160:593–607PubMedGoogle Scholar
  26. 26.
    Worthington CR (1984) The structure of the cornea. Quart Rev Biophys 17:423–451Google Scholar
  27. 27.
    Worthington CR, Inouye H (1985) X-ray diffraction study of the cornea. Int J Biol Macromol 7:2–8Google Scholar
  28. 28.
    Freund DE, McCally RL, Farrell RA (1986) Direct summation of fields for light scattering by fibrils with applications to normal corneas. Appl Opt 25:2739–2746PubMedGoogle Scholar
  29. 29.
    Møller-Pedersen T, Ehlers N (1995) A three-dimensional study of the human corneal keratocyte density. Curr Eye Res 14:459–464PubMedGoogle Scholar
  30. 30.
    Møller-Pedersen T (1997) A comparative study of human corneal keratocyte and endothelial cell density during aging. Cornea 16:333–338PubMedGoogle Scholar
  31. 31.
    Kaye GI (1969) Stereologic measurement of cell volume fraction of rabbit corneal stroma. Arch Ophthalmol 82:792–794PubMedGoogle Scholar
  32. 32.
    Jester JV, Møller-Pedersen T, Huang J, Sax CM, Kays WT, Cavangh HD, Petroll WM, Piatigorsky J (1999) The cellular basis of corneal transparency: evidence for ‘corneal crystallins’. J Cell Sci 112:613–622PubMedGoogle Scholar
  33. 33.
    Jester JV (2008) Corneal crystallins and the development of cellular transparency. Semin Cell Dev Biol 19:82–93PubMedGoogle Scholar
  34. 34.
    Bettelheim FA, Plessy B (1975) The hydration of proteoglycans of bovine cornea. Biochim Biophys Acta 381:203–214PubMedGoogle Scholar
  35. 35.
    Bettelheim FA, Goetz D (1976) Distribution of hexosamines in bovine cornea. Invest Ophthalmol 15:301–304PubMedGoogle Scholar
  36. 36.
    Castoro JA, Bettelheim AA, Bettelheim FA (1988) Water gradients across bovine cornea. Invest Ophthalmol Vis Sci 29:963–968PubMedGoogle Scholar
  37. 37.
    Rada J, Cornuet PK, Hassell JR (1993) Regulation of corneal collagen fibrillogenesis in vitro by corneal proteoglycan (lumican and decorin) core proteins. Exp Eye Res 56:635–648PubMedGoogle Scholar
  38. 38.
    Borcherding MS, Blacik LJ, Sittig RA, Bizzell JW, Breen M, Weinstein HG (1975) Proteoglycans and collagen fibre organization in human corneoscleral tissue. Exp Eye Res 21:59–70PubMedGoogle Scholar
  39. 39.
    Oeben M, Keller R, Stuhlsatz HW, Greiling H (1987) Constant and variable domains of different disaccharide structure in corneal keratan sulphate chains. Biochem J 248:85–93PubMedGoogle Scholar
  40. 40.
    Tai GH, Huckerby TN, Nieduszynski IA (1996) Multiple non-reducing chain termini isolated from bovine corneal keratan sulfates. J Biol Chem 271:23535–23546PubMedGoogle Scholar
  41. 41.
    Tai GH, Nieduszynski IA, Fullwood NJ, Huckerby TN (1997) Human corneal keratan sulfates. J Biol Chem 272:28227–28231PubMedGoogle Scholar
  42. 42.
    Plaas AH, West LA, Thonar EJ, Karcioglu ZA, Smith CJ, Klintworth GK, Hascall VC (2001) Altered fine structures of corneal and skeletal keratan sulfate and chondroitin/dermatan sulfate in macular corneal dystrophy. J Biol Chem 276:39788–39796PubMedGoogle Scholar
  43. 43.
    Nilsson B, Nakazawa K, Hassell JR, Newsome DA, Hascall VC (1983) Structure of oligosaccharides and the linkage region between keratan sulfate and the core protein on proteoglycans from monkey cornea. J Biol Chem 258:6056–6063PubMedGoogle Scholar
  44. 44.
    Caterson B, Christner JE, Baker JR (1983) Identification of a monoclonal antibody that specifically recognises corneal and skeletal keratan sulfate. Monoclonal antibodies to cartilage proteoglycan. J Biol Chem 258:8848–8854PubMedGoogle Scholar
  45. 45.
    Mehmet H, Scudder P, Tang PW, Hounsell EF, Caterson B, Feizi T (1986) The antigenic determinants recognised by three monoclonal antibodies to keratan sulphate involve sulphated hepta- or larger oligosaccharides of the poly(N-acetyllactosamine) series. Eur J Biochem 157:385–391PubMedGoogle Scholar
  46. 46.
    Thonar EJ, Meyer RF, Dennis RF, Lenz ME, Maldonado B, Hassell JR, Hewitt AT, Stark WJ, Stock EL, Kuettner KE, Klintworth GK (1986) Absence of normal keratan sulfate in the blood of patients with macular corneal dystrophy. Am J Ophthalmol 102:561–569PubMedGoogle Scholar
  47. 47.
    Young RD, Akama TO, Liskova P, Ebenezer ND, Allan B, Kerr B, Caterson B, Fukuda MN, Quantock AJ (2007) Differential immunogold localisation of sulphated and unsulphated keratan sulphate proteoglycans in normal and macular dystrophy cornea using sulphation motif-specific antibodies. Histochem Cell Biol 127:115–120PubMedGoogle Scholar
  48. 48.
    Akhtar S, Kerr BC, Hayes AJ, Hughes CE, Meek KM, Caterson B (2008) Immunochemical localization of keratan sulfate proteoglycans in cornea, sclera, and limbus using a keratanase-generated neoepitope monoclonal antibody. Invest Ophthalmol Vis Sci 49:2424–2431PubMedGoogle Scholar
  49. 49.
    Fukuda MN, Matsumura G (1976) Endo-beta-galactosidase of Escherichia freundii. Purification and endoglycosidic action on keratan sulfates, oligosaccharides, and blood group active glycoprotein. J Biol Chem 251:6218–6225PubMedGoogle Scholar
  50. 50.
    Nakagawa H, Yamada T, Chien JL, Gardas A, Kitamikado M, Li SC, Li YT (1980) Isolation and characterization of an endo-beta-galactosidase from a new strain of Escherichia freundii. J Biol Chem 255:5955–5959PubMedGoogle Scholar
  51. 51.
    Nakazawa K, Suzuki N, Suzuki S (1975) Sequential degradation of keratan sulfate by bacterial enzymes and purification of a sulfatase in the enzymatic system. J Biol Chem 250:905–911PubMedGoogle Scholar
  52. 52.
    Nakazawa K, Ito M, Yamagata T, Suzuki S (1989) Substrate specificity of keratan sulphate-degrading enzymes (endo-ß-galactosidase, keratanase and keratanase II) from microorganisms. In: Greiling H, Scott JE (eds) Keratan sulphate: chemistry, biology, chemical pathology. Biochemical Society, London, pp 99–110Google Scholar
  53. 53.
    Fukuta M, Inazawa J, Torii T, Tsuzuki K, Shimada E, Habuchi O (1997) Molecular cloning and characterization of human keratan sulfate Gal-6-sulfotransferase. J Biol Chem 272:32321–32328PubMedGoogle Scholar
  54. 54.
    Akama TO, Nakayama J, Nishida K, Hiraoka N, Suzuki M, McAuliffe J, Hindsgaul O, Fukuda M, Fukuda MN (2001) Human corneal GlcNac 6-O-sulfotransferase and mouse intestinal GlcNac 6-O-sulfotransferase both produce keratan sulfate. J Biol Chem 276:16271–16278PubMedGoogle Scholar
  55. 55.
    Fukuda M, Hiraoka N, Akama TO, Fukuda MN (2001) Carbohydrate-modifying sulfotransferases: structure, function, and pathophysiology. J Biol Chem 276:47747–47750PubMedGoogle Scholar
  56. 56.
    Akama TO, Misra AK, Hindsgaul O, Fukuda MN (2002) Enzymatic synthesis in vitro of the disulfated disaccharide unit of corneal keratan sulfate. J Biol Chem 277:42505–42513PubMedGoogle Scholar
  57. 57.
    Torii T, Fukuta M, Habuchi O (2000) Sulfation of sialyl N-acetyllactosamine oligosaccharides and fetuin oligosaccharides by keratan sulfate Gal-6-sulfotransferase. Glycobiology 10:203–211PubMedGoogle Scholar
  58. 58.
    Seko A, Dohmae N, Takio K, Yamashita K (2003) Beta 1, 4-galactosyltransferase (beta 4GalT)-IV is specific for GlcNAc 6-O-sulfate. Beta 4GalT-IV acts on keratan sulfate-related glycans and a precursor glycan of 6-sulfosialyl-Lewis X. J Biol Chem 278:9150–9158PubMedGoogle Scholar
  59. 59.
    Seko A, Yamashita K (2004) beta1, 3-N-Acetylglucosaminyltransferase-7 (beta3Gn-T7) acts efficiently on keratan sulfate-related glycans. FEBS Lett 556:216–220PubMedGoogle Scholar
  60. 60.
    Kitayama K, Hayashida Y, Nishida K, Akama TO (2007) Enzymes responsible for synthesis of corneal keratan sulfate glycosaminoglycans. J Biol Chem 282:30085–30096PubMedGoogle Scholar
  61. 61.
    Shiraishi N, Natsume A, Togayachi A, Endo T, Akashima T, Yamada Y, Imai N, Nakagawa S, Koizumi S, Sekine S, Narimatsu H, Sasaki K (2001) Identification and characterization of three novel beta 1, 3-N-acetylglucosaminyltransferases structurally related to the beta 1, 3-galactosyltransferase family. J Biol Chem 276:3498–3507PubMedGoogle Scholar
  62. 62.
    Scott JE, Orford CR, Hughes EW (1981) Proteoglycan-collagen arrangements in developing rat tail tendon. An electron microscopical and biochemical investigation. Biochem J 195:573–581PubMedGoogle Scholar
  63. 63.
    Scott JE, Haigh M (1985) ‘Small’-proteoglycan:collagen interactions: keratan sulphate proteoglycan associates with rabbit corneal collagen fibrils at the ‘a’ and ‘c’ bands. Biosci Rep 5:765–774PubMedGoogle Scholar
  64. 64.
    Meek KM, Elliott GF, Nave C (1986) A synchrotron X-ray diffraction study of bovine cornea stained with cupromeronic blue. Coll Relat Res 6:203–218PubMedGoogle Scholar
  65. 65.
    Maurice D (1962) Clinical physiology of the cornea. Int Ophthalmol Clin 2:561–572PubMedGoogle Scholar
  66. 66.
    Scott JE (1992) Morphometry of cupromeronic blue-stained proteoglycan molecules in animal corneas, versus that of purified proteoglycans stained in vitro, implies that tertiary structures contribute to corneal ultrastructure. J Anat 180:155–164PubMedGoogle Scholar
  67. 67.
    Muller LJ, Pels E, Schurmans LRHM, Vrensen GFJM (2004) A new three-dimensional model of the organization of proteoglycans and collagen fibrils in the human corneal stroma. Exp Eye Res 78:493–501PubMedGoogle Scholar
  68. 68.
    Knupp C, Pinali C, Lewis PN, Parfitt GJ, Young RD, Meek KM, Quantock AJ (2009) The architecture of the cornea and structural basis of its transparency. Adv Prot Chem Struct Biol (in press)Google Scholar
  69. 69.
    Lewis PN, Pinali C, Young RD, Meek KM, Quantock AJ, Knupp C (2010) Structural interactions between collagen and proteoglycans are elucidated by three-dimensional electron tomography of bovine cornea. Structure (in press)Google Scholar
  70. 70.
    Scott JE, Bosworth TR (1990) A comparative biochemical and ultrastructural study of proteoglycan-collagen interactions in corneal stroma. Biochem J 270:491–497PubMedGoogle Scholar
  71. 71.
    Young RD, Tudor D, Hayes AJ, Kerr B, Hayashida Y, Nishida K, Meek KM, Caterson B, Quantock AJ (2005) Atypical composition and ultrastructure of proteoglycans in the mouse corneal stroma. Invest Ophthalmol Vis Sci 46:1973–1978PubMedGoogle Scholar
  72. 72.
    Takahashi T, Cho HI, Kublin CL, Cintron C (1993) Keratan sulphate and dermatan sulphate proteoglycans associate with trype VI collagen in fetal rabbit cornea. J Histochem Cytochem 41:1447–1457PubMedGoogle Scholar
  73. 73.
    Haigh M, Gibson S, Scott JE (1987) Keratan sulphate and the ultrastructure of the cornea: a comparison of rabbit, rat and mouse. Biochem Soc Trans 15:711–712Google Scholar
  74. 74.
    Scott JE, Haigh M, Ali P (1988) Keratan sulphate is unevenly distributed from back to front of bovine cornea. Biochem Soc Trans 16:333–334Google Scholar
  75. 75.
    Stockwell RA (1970) Changes in the acid glycosaminoglycan content of the matrix of ageing human articular cartilage. Ann Rheum Dis 29:509–515PubMedGoogle Scholar
  76. 76.
    Stockwell RA (1991) Morphometry of cytoplasmic components of mammalian articular chondrocytes and corneal keratocytes: species and zonal variations of mitochondria in relation to nutrition. J Anat 175:251–261PubMedGoogle Scholar
  77. 77.
    Stockwell RA, Scott JE (1965) Observations on the acid glycosaminoglycan (mucopolysaccharide) content of the matrix of aging cartilage. Ann Rheum Dis 24:341–350PubMedGoogle Scholar
  78. 78.
    Scott JE (1988) Proteoglycan-fibrillar collagen interactions. Biochem J 252:313–323PubMedGoogle Scholar
  79. 79.
    Cooper LJ, Bentley AJ, Nieduszynski IA, Talabani S, Thomson A, Utani A, Shinkai H, Fullwood NJ, Brown GM (2006) The role of dermatopontin in the stromal organization of the cornea. Invest Ophthalmol Vis Sci 47:3303–3310PubMedGoogle Scholar
  80. 80.
    Scott JE, Haigh M (1988) Keratan sulphate and the ultrastructure of cornea and cartilage: a ‘stand-in’ for chondroitin sulphate in conditions of oxygen lack? J Anat 158:95–108PubMedGoogle Scholar
  81. 81.
    Scott JE (1991) Chondroitin sulphate and keratan sulphate are almost isosteric. Biochem J 275:267–268PubMedGoogle Scholar
  82. 82.
    Scott JE (1994) Keratan sulphate—a ‘reserve’ polysaccharide. Eur J Clin Chem Clin Biochem 32:217–223PubMedGoogle Scholar
  83. 83.
    Funderburgh JL, Funderburgh ML, Rodrigues MM, Krachmer JH, Conrad GW (1990) Altered antigenicity of keratan sulfate proteoglycan in selected corneal diseases. Invest Ophthalmol Vis Sci 31:419–428PubMedGoogle Scholar
  84. 84.
    Rodrigues M, Nirankari V, Rajagopalan S, Jones K, Funderburgh JL (1992) Clinical and histopathologic changes in the host cornea after epikeratoplasty for keratoconus. Am J Ophthalmol 114:161–170PubMedGoogle Scholar
  85. 85.
    Hahnel C, Somodi S, Weiss DG, Guthoo RF (2000) The keratocyte network of human cornea: a three-dimensional study using confocal laser scanning fluorescence microscopy. Cornea 19:185–193PubMedGoogle Scholar
  86. 86.
    Alvord LA, Hall WJ, Keyes LD, Morgan CF, Winterton LC (2007) Corneal oxygen distribution with contact lens wear. Cornea 26:654–664PubMedGoogle Scholar
  87. 87.
    Fink B, Hill RM (2006) Corneal oxygen uptake—a review of polarographic techniques, applications and variables. Cont Lens Anterior Eye 29:221–229PubMedGoogle Scholar
  88. 88.
    Chakravarti S, Magnuson T, Lass JH, Jepsen KJ, LaMantia C, Carroll H (1998) Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican. J Cell Biol 141:1277–1286PubMedGoogle Scholar
  89. 89.
    Saika S, Shiraishi A, Liu CY, Funderburgh JL, Kao CW, Converse RL, Kao WW (2000) Role of lumican in the corneal epithelium during wound healing. J Biol Chem 275:2607–2612PubMedGoogle Scholar
  90. 90.
    Tasheva ES, Koester A, Paulsen AQ, Garrett AS, Boyle DL, Davidson HJ, Song M, Fox N, Conrad GW (2002) Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities. Mol Vis 8:407–415PubMedGoogle Scholar
  91. 91.
    Liu C-Y, Birk DE, Hassell JR, Kane B, Kao WW-Y (2003) Keratocan-deficient mice display alterations in corneal structure. J Biol Chem 278:21672–21677PubMedGoogle Scholar
  92. 92.
    Hayashida Y, Akama TO, Beecher N, Lewis P, Young RD, Meek KM, Kerr B, Hughes CE, Caterson B, Tanigami A, Nakayama J, Fukada MN, Tano Y, Nishida K, Quantock AJ (2006) Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6-O sulfotransferase. Proc Natl Acad Sci USA 103:13333–13338PubMedGoogle Scholar
  93. 93.
    Chakravarti S, Petroll WM, Hassell JR, Jester JV, Lass JH, Paul J, Birk DE (2000) Corneal opacity in lumican-null mice: defects in collagen fibril structure and packing in the posterior stroma. Invest Ophthalmol Vis Sci 41:3365–3373PubMedGoogle Scholar
  94. 94.
    Quantock AJ, Meek KM, Chakravarti S (2001) An x-ray diffraction investigation of corneal structure in lumican-deficient mice. Invest Ophthalmol Vis Sci 42:1750–1756PubMedGoogle Scholar
  95. 95.
    Meek KM, Quantock AJ, Boote C, Liu CY, Kao WW-Y (2003) An x-ray scattering investigation of corneal structure in keratocan-deficient mice. Matrix Biol 22:467–475PubMedGoogle Scholar
  96. 96.
    Carlson EC, Liu C-Y, Chikama T-I, Hayashi Y, Kao CW-C, Birk DE, Funderburgh JL, Jester JV, Kao WW (2005) Keratocan, a cornea-specific keratan sulphate proteoglycan, is regulated by lumican. J Biol Chem 280:25541–25547PubMedGoogle Scholar
  97. 97.
    Chakravarti S, Zhang G, Chervoneva I, Roberts L, Birk DE (2006) Collagen fibril assembly during postnatal development and dysfunctional regulation in the lumican-deficient murine cornea. Dev Dyn 235:2493–2506PubMedGoogle Scholar
  98. 98.
    Song J, Lee YG, Houston J, Petroll WM, Chakravarti S, Cavanagh HD, Jester JV (2003) Neonatal corneal stromal development in the normal and lumican-deficient mouse. Invest Ophthalmol Vis Sci 44:548–557PubMedGoogle Scholar
  99. 99.
    Beecher N, Chakravarti S, Joyce S, Meek KM, Quantock AJ (2006) Neonatal development of the corneal stroma in wild-type and lumican-null mice. Invest Ophthalmol Vis Sci 47:146–150PubMedGoogle Scholar
  100. 100.
    Meij JT, Carlson EC, Wang L, Liu CY, Jester JV, Birk DE, Kao WW (2007) Targeted expression of a lumican transgene rescues corneal deficiencies in lumican-null mice. Mol Vis 13:2012–2018PubMedGoogle Scholar
  101. 101.
    Du Y, Carlson EC, Funderburgh ML, Birk DE, Pearlman E, Guo N, Kao WW, Funderburgh JL (2009) Stem cell therapy restores transparency to defective murine corneas. Stem Cells 27:1635–1642PubMedGoogle Scholar
  102. 102.
    Anseth A (1961) Glycosaminoglycans in the developing corneal stroma. Exp Eye Res 1:116–121PubMedGoogle Scholar
  103. 103.
    Funderburgh JL, Caterson B, Conrad GW (1986) Keratan sulfate proteoglycan during embryonic development of the chicken cornea. Dev Biol 116:267–277PubMedGoogle Scholar
  104. 104.
    Takahashi I, Nakamura Y, Hamada Y, Nakazawa K (1999) Immunohistochemical analysis of proteoglycan biosynthesis during early development of the chicken cornea. J Biochem 126:804–814PubMedGoogle Scholar
  105. 105.
    Young RD, Gealy EC, Liles M, Caterson B, Ralphs JR, Quantock AJ (2007) Keratan sulfate glycosaminoglycan and the association with collagen fibrils in rudimentary lamellae in the developing avian cornea. Invest Ophthalmol Vis Sci 48:3083–3088PubMedGoogle Scholar
  106. 106.
    Cornuet PK, Blochberger TC, Hassell JR (1994) Molecular polymorphism of lumican during corneal development. Invest Ophthalmol Vis Sci 35:870–877PubMedGoogle Scholar
  107. 107.
    Hart GW (1976) Biosynthesis of glycosaminoglycans during corneal development. J Biol Chem 251:6513–6521PubMedGoogle Scholar
  108. 108.
    Cai CX, Gibney E, Gordon MK, Marchant JK, Birk DE, Linsenmayer TF (1996) Characterization and developmental regulation of avian corneal-1, 4-galactosyltransferase mRNA. Exp Eye Res 63:193–200PubMedGoogle Scholar
  109. 109.
    Conrad GW, Woo ML (1979) Synthesis of 3’-phosphoadenosine-5’-phosphosulfate (PAPS) increases during corneal development. J Biol Chem 255:3086–3091Google Scholar
  110. 110.
    Liles M, Palka BP, Harris A, Kerr B, Hughes CE, Young RD, Meek KM, Caterson B, Quantock AJ (2009) Differential relative sulphation of keratan sulfate glycosaminoglycan in the chick cornea during embryonic development. Invest Ophthalmol Vis Sci (in press)Google Scholar
  111. 111.
    Keller R, Stuhlsatz HW, Greiling H (1989) Sulphation, chain elongation and chain termination in keratan sulphate biosynthesis. In: Greiling H, Scott JE (eds) Keratan sulphate: chemistry, biology and chemical pathology. The Biochemical Society, London, pp 39–52Google Scholar
  112. 112.
    Zhang Y, Schmack I, Dawson DG, Grossniklaus HE, Conrad AH, Kariya Y, Suzuki K, Edelhauser HF, Conrad GW (2006) Keratan sulfate and chondroitin/dermatan sulfate in maximally recovered hypocellular stromal interface scars of postmortem human LASIK corneas. Invest Ophthalmol Vis Sci 47:2390–2396PubMedGoogle Scholar
  113. 113.
    Dunlevy JR, Beales MP, Berryhill BL, Cornuet PK, Hassell JR (2000) Expression of the keratan sulfate proteoglycans lumican, keratocan and osteoglycin/mimecan during chick corneal development. Exp Eye Res 70:349–362PubMedGoogle Scholar
  114. 114.
    Nakazawa K, Suzuki S, Wada K, Nakazawa K (1995) Proteoglycan synthesis by corneal explants from developing embryonic chicken. J Biochem 117:707–718PubMedGoogle Scholar
  115. 115.
    Scott JE, Caterson B (1998) Postscript on possum cartilage and oxygen; what is keratan sulphate? J Anat 192:299–301PubMedGoogle Scholar
  116. 116.
    Funderburgh JL, Funderburgh ML, Mann MM, Conrad GW (1991) Arterial lumican. Properties of a corneal-type keratan sulfate proteoglycan from bovine aorta. J Biol Chem 266:24773–24777PubMedGoogle Scholar
  117. 117.
    Gealy EC, Kerr BC, Young RD, Tudor D, Hayes AJ, Hughes CE, Caterson B, Quantock AJ, Ralphs JR (2007) Differential expression of the keratan sulphate proteoglycan, keratocan, during chick corneal embryogenesis. Histochem Cell Biol 128:551–555PubMedGoogle Scholar
  118. 118.
    Gregory JD, Coster L, Damle SP (1982) Proteoglycans of rabbit corneal stroma. Isolation and partial characterization. J Biol Chem 257:6965–6970PubMedGoogle Scholar
  119. 119.
    Cintron C, Schneider H, Kublin CL (1973) Corneal scar formation. Exp Eye Res 17:251–259PubMedGoogle Scholar
  120. 120.
    Cintron C, Kublin CL (1977) Regeneration of corneal tissue. Dev Biol 61:346–357PubMedGoogle Scholar
  121. 121.
    Cintron C, Hassinger LC, Kublin CL, Cannon DJ (1978) Biochemical and ultrastructural changes in collagen during corneal wound healing. J Ultrastruct Res 65:13–22PubMedGoogle Scholar
  122. 122.
    Rawe IM, Meek KM, Leonard DW, Takahashi T, Cintron C (1994) Structure of corneal scar tissue: an X-ray diffraction study. Biophys J 67:1743–1748PubMedGoogle Scholar
  123. 123.
    Hassell JR, Cintron C, Kublin C, Newsome DA (1983) Proteoglycan changes during restoration of transparency in corneal scars. Arch Biochem Biophys 222:362–369PubMedGoogle Scholar
  124. 124.
    Funderburgh JL, Cintron C, Covington HI, Conrad GW (1988) Immunoanalysis of keratan sulfate proteoglycan from corneal scars. Invest Opthalmol Vis Sci 29:1116–1124Google Scholar
  125. 125.
    Cintron C, Covington HI, Kublin CL (1990) Morphologic analyses of proteoglycans in rabbit corneal scars. Invest Ophthalmol Vis Sci 31:1789–1798PubMedGoogle Scholar
  126. 126.
    Rawe IM, Tuft SJ, Meek KM (1992) Proteoglycan and collagen morphology in superficially scarred rabbit cornea. Histochem J 24:311–318PubMedGoogle Scholar
  127. 127.
    Cintron C, Gregory JD, Damle SP, Kublin CL (1990) Biochemical analysis of proteoglycans in rabbit corneal scars. Invest Ophthalmol Vis Sci 31:1975–1981PubMedGoogle Scholar
  128. 128.
    Funderburgh JL, Mann MM, Funderburgh ML (2003) Keratocyte phenotype mediates proteoglycan structure: a role for fibroblasts in corneal fibrosis. J Biol Chem 278:45629–45637PubMedGoogle Scholar
  129. 129.
    Carlson EC, Wang IJ, Liu CY, Brannan P, Kao CW, Kao WW (2003) Altered KSPG expression by keratocytes following corneal injury. Mol Vis 9:615–623PubMedGoogle Scholar
  130. 130.
    Vij N, Roberts L, Joyce S, Chakravarti S (2004) Lumican suppresses cell proliferation and aids Fas-Fas ligand mediated apoptosis: implications in the cornea. Exp Eye Res 78:957–971PubMedGoogle Scholar
  131. 131.
    Vij N, Roberts L, Joyce S, Chakravarti S (2005) Lumican regulates corneal inflammatory responses by modulating Fas-Fas ligand signaling. Invest Ophthalmol Vis Sci 46:88–95PubMedGoogle Scholar
  132. 132.
    Quantock AJ, Assil KK (1993) Wound healing in response to keratorefractive surgery. Surv Ophthalmol 38:289–302PubMedGoogle Scholar
  133. 133.
    Tuft SJ, Gartry DS, Rawe IM, Meek KM (1993) Photorefractive keratectomy: implications of corneal wound healing. Br J Ophthalmol 77:243–247PubMedGoogle Scholar
  134. 134.
    Quantock AJ, Padroni S, Connon CJ, Milne G, Schanzlin DJ (2003) Proteoglycan alterations in the rabbit corneal stroma after a lamellar incision. J Cat Ref Surg 29:821–824Google Scholar
  135. 135.
    Dawson DG, Edelhauser HF, Grossniklaus HE (2005) Long-term histopathologic findings in human corneal wounds after refractive surgical procedures. Am J Ophthalmol 139:168–178PubMedGoogle Scholar
  136. 136.
    Dawson DG, Kramer TR, Grossniklaus HE, Waring GO, Edelhauser HF (2005) Histologic, ultrastructural, and immunofluorescent evaluation of human laser-assisted in situ keratomileusis corneal wounds. Arch Ophthalmol 123:741–756PubMedGoogle Scholar
  137. 137.
    SundarRaj N, Geiss MJ, Fantes F, Hanna K, Anderson SC, Thompson KP, Thoft RA, Waring GO (1990) Healing of excimer laser ablated monkey corneas. An immunohistochemical evaluation. Arch Ophthalmol 108:1604–1610PubMedGoogle Scholar
  138. 138.
    Zhang Y, Schmack I, Dawson DG, Grossniklaus HE, Conrad AH, Kariya Y, Suzuki K, Edelhauser HF, Conrad GW (2006) Keratan sulfate and chondroitin/dermatan sulfate in maximally recovered hypocellular stromal interface scars of postmortem human LASIK corneas. Invest Ophthalmol Vis Sci 47:2390–2396PubMedGoogle Scholar
  139. 139.
    Dawson DG, Hardten DR, Albert DM (2003) Pocket of fluid in the lamellar interface after penetrating keratoplasty and laser in situ keratomileusis. Arch Ophthalmol 121:894–896PubMedGoogle Scholar
  140. 140.
    Saika S, Shiraishi A, Liu CY, Funderburgh JL, Kao CW, Converse RL, Kao WW (2000) Role of lumican in the corneal epithelium during wound healing. J Biol Chem 275:2607–2612PubMedGoogle Scholar
  141. 141.
    Yeh LK, Chen WL, Li W, Espana EM, Ouyang J, Kawakita T, Kao WW, Tseng SC, Liu CY (2005) Soluble lumican glycoprotein purified from human amniotic membrane promotes corneal epithelial wound healing. Invest Ophthalmol Vis Sci 46:479–486PubMedGoogle Scholar
  142. 142.
    Seomun Y, Joo CK (2008) Lumican induces human corneal epithelial cell migration and integrin expression via ERK 1/2 signaling. Biochem Biophys Res Commun 372:221–225PubMedGoogle Scholar
  143. 143.
    Fullwood NJ, Davies Y, Nieduszynski IA, Marcynuik B, Ridgway AEA, Quantock AJ (1996) Cell surface-associated keratan sulfate on normal and migrating corneal endothelium. Invest Ophthalmol Vis Sci 37:1256–1270PubMedGoogle Scholar
  144. 144.
    Quantock AJ, Bairaktaris G, Fullwood NJ, Ito M, Suzuki T, Kinoshita S (1999) Endothelial cell surface-associated keratan sulfate after excimer laser photoablation of the anterior rabbit cornea. J Refract Surg 15:349–356PubMedGoogle Scholar
  145. 145.
    Nakamura T, Inatomi T, Sotozono C, Ang LP, Koizumi N, Yokoi N, Kinoshita S (2006) Transplantation of autologous serum-derived cultivated corneal epithelial equivalents for the treatment of severe ocular surface disease. Ophthalmology 113:1765–1772PubMedGoogle Scholar
  146. 146.
    Sumide T, Nishida K, Yamato M, Ide T, Hayashida Y, Watanabe K, Yang J, Kohno C, Kikuchi A, Maeda N, Watanabe H, Okano T, Tano Y (2006) Functional human corneal endothelial cell sheets harvested from temperature-responsive culture surfaces. FASEB J 20:392–394PubMedGoogle Scholar
  147. 147.
    Koizumi N, Sakamoto Y, Okumura N, Okahara N, Tsuchiya H, Torii R, Cooper LJ, Ban Y, Tanioka H, Kinoshita S (2007) Cultivated corneal endothelial cell sheet transplantation in a primate model. Invest Ophthalmol Vis Sci 48:4519–4526Google Scholar
  148. 148.
    Liu W, Merrett K, Griffith M, Fagerholm P, Dravida S, Heyne B, Scaiano JC, Watsky MA, Shinozaki N, Lagali N, Munger R, Li F (2008) Recombinant human collagen for tissue engineered corneal substitutes. Biomaterials 29:1147–1158PubMedGoogle Scholar
  149. 149.
    Torbet J, Malbouyres M, Builles N, Justin V, Roulet M, Damour O, Oldberg A, Ruggiero F, Hulmes DJ (2007) Orthogonal scaffold of magnetically aligned collagen lamellae for corneal stroma reconstruction. Biomaterials 28:4268–4276PubMedGoogle Scholar
  150. 150.
    Garagorri N, Fermanian S, Thibault R, Ambrose WM, Schein OD, Chakravarti S, Elisseeff J (2008) Keratocyte behavior in three-dimensional photopolymerizable poly(ethylene glycol) hydrogels. Acta Biomater 4:1139–1147PubMedGoogle Scholar
  151. 151.
    Ren R, Hutcheon AE, Guo XQ, Saeidi N, Melotti SA, Ruberti JW, Zieske JD, Trinkaus-Randall V (2008) Human primary corneal fibroblasts synthesize and deposit proteoglycans in long-term 3-D cultures. Dev Dyn 237:2705–2715PubMedGoogle Scholar
  152. 152.
    Musselmann K, Kane B, Alexandrou B, Hassell JR (2006) Stimulation of collagen synthesis by insulin and proteoglycan accumulation by ascorbate in bovine keratocytes in vitro. Invest Ophthalmol Vis Sci 47:5260–5266PubMedGoogle Scholar
  153. 153.
    Hassell JR, Kane BP, Etheredge LT, Valkov N, Birk D (2008) Increased stromal extracellular matrix synthesis and assembly by insulin activated bovine keratocytes cultured under agarose. Exp Eye Res 87:604–611PubMedGoogle Scholar
  154. 154.
    Beales MP, Funderburgh JL, Jester JV, Hassell JR (1999) Proteoglycan synthesis by bovine keratocytes and corneal fibroblasts: maintenance of the keratocyte phenotype in culture. Invest Ophthalmol Vis Sci 40:1658–1663PubMedGoogle Scholar
  155. 155.
    Long CJ, Roth MR, Tasheva ES, Funderburgh M, Smit R, Conrad GW, Funderburgh JL (2000) Fibroblast growth factor-2 promotes keratan sulfate proteoglycan expression by keratocytes in vitro. J Biol Chem 275:13918–13923PubMedGoogle Scholar
  156. 156.
    Funderburgh JL, Funderburgh ML, Mann MM, Corpuz L, Roth MR (2001) Proteoglycan expression during transforming growth factor beta-induced keratocyte-myofibroblast transdifferentiation. J Biol Chem 276:44173–44178PubMedGoogle Scholar
  157. 157.
    Funderburgh JL, Mann MM, Funderburgh ML (2003) Keratocyte phenotype mediates proteoglycan structure: a role for fibroblasts in corneal fibrosis. J Biol Chem 278:45629–45637PubMedGoogle Scholar
  158. 158.
    Etheredge L, Kane BP, Hassell JR (2009) The effect of growth factor signaling on keratocytes in vitro and its relationship to the phases of stromal wound repair. Invest Ophthalmol Vis Sci 50:3128–3136PubMedGoogle Scholar
  159. 159.
    Chen J, Guerriero E, Sado Y, SundarRaj N (2009) Rho-mediated regulation of TGF-beta1- and FGF-2-induced activation of corneal stromal keratocytes. Invest Ophthalmol Vis Sci 50:3662–3670PubMedGoogle Scholar
  160. 160.
    Rodrigues M, Nirankari V, Rajagopalan S, Jones K, Funderburgh J (1992) Clinical and histopathologic changes in the host cornea after epikeratoplasty for keratoconus. J Ophthalmol 114:161–170Google Scholar
  161. 161.
    Funderburgh ML, Mann MM, Funderburgh JL (2009) A role for cadherin 11 in corneal keratan sulfate synthesis. ARVO 2009 Annual Meeting. Abstr #2555Google Scholar
  162. 162.
    Morquio L (1929) Sur une forme de dystrophie osseuse familial. Arch Med Enfants 32:129–140Google Scholar
  163. 163.
    Matalon R, Arbogast B, Justice P, Brandt IK, Dorfman A (1974) Morquio’s syndrome: deficiency of a chondroitin sulfate N-acetylhexosamine sulfate sulfatase. Biochem Biophys Res Commun 61:759–765PubMedGoogle Scholar
  164. 164.
    Leslie T, Siddiqui MAR, Aitken DA, Kirkness CM, Lee WR, Fern AI (2005) Morquio syndrome: electron microscopic findings. Br J Ophthalmol 89:925–926PubMedGoogle Scholar
  165. 165.
    Iwamoto M, Nawa Y, Maumenee IH, Young-Ramsaran J, Matalon R, Green WR (1990) Ocular histopathology and ultrastructure of Morquio syndrome (systemic mucopolysaccharidosis IV A). Graefes Arch Clin Exp Ophthalmol 228:342–349PubMedGoogle Scholar
  166. 166.
    Ghosh M, McCulloch C (1974) The Morquio syndrome: light and electron microscopic findings from two corneas. Can J Ophthalmol 9:445–452PubMedGoogle Scholar
  167. 167.
    Rawe IM, Leonard DW, Meek KM, Zabel RW (1997) X-ray diffraction and transmission electron microscopy of Morquio syndrome type A: a structural analysis. Cornea 16:369–376PubMedGoogle Scholar
  168. 168.
    Minami R, Ikeno T, Igarashi C, Tsugawa S, Nakao T (1983) Characterisation of keratan sulphate isolated from liver affected by Morquio syndrome. Tohoku J Exp Med 139:321–326PubMedGoogle Scholar
  169. 169.
    Akhtar S, Tullo A, Caterson B, Davies JR, Bennett K, Meek KM (2002) Clinical and morphological features including expression of betaig-h3 and keratan sulphate proteoglycans in Maroteaux-Lamy syndrome type B and in normal cornea. Br J Ophthalmol 86:147–151PubMedGoogle Scholar
  170. 170.
    Pellegata NS, Dieguez-Lucena JL, Joensuu T, Lau S, Montgomery KT, Krahe R, Kivela T, Kucherlapati R, Forsius H, de la Chapelle A (2000) Mutations in KERA, encoding keratocan, cause cornea plana. Nat Genet 25:91–95PubMedGoogle Scholar
  171. 171.
    Liu CY, Shiraishi A, Kao CW, Converse RL, Funderburgh JL, Corpuz LM, Conrad GW, Kao WW (1998) The cloning of mouse keratocan cDNA and genomic DNA and the characterization of its expression during eye development. J Biol Chem 273:22584–22588PubMedGoogle Scholar
  172. 172.
    Akama TO, Nishida K, Nakayama J, Watanabe H, Ozaki K, Nakamura T, Dota A, Kawasaki S, Inoue Y, Maeda N, Yamamoto S, Fujiwara T, Thonar EJ, Shimomura Y, Kinoshita S, Tanigami A, Fukuda MN (2000) Macular corneal dystrophy type I and type II are caused by distinct mutations in a new sulphotransferase gene. Nat Genet 26:237–241PubMedGoogle Scholar
  173. 173.
    Quantock AJ (1994) An erroneous glycosaminoglycan metabolism leads to corneal opacification in macular corneal dystrophy. Glycosylation Dis 1:143–151Google Scholar
  174. 174.
    Klintworth GK (2008) Genetic disorders of the cornea. In: Klintworth GK, Garner A (eds) Pathobiology of ocular disease, 3rd edn. Informa Healthcare, New York, pp 615–713Google Scholar
  175. 175.
    Yang CJ, SundarRaj N, Thonar EJ, Klintworth GK (1988) Immunohistochemical evidence of heterogeneity in macular corneal dystrophy. Am J Ophthalmol 106:65–71PubMedGoogle Scholar
  176. 176.
    Klintworth GK, Oshima E, al-Rajhi A, al-Saif A, Thonar EJ, Karcioglu ZA (1997) Macular corneal dystrophy in Saudi Arabia: a study of 56 cases and recognition of a new immunophenotype. Am J Ophthalmol 124:9–18PubMedGoogle Scholar
  177. 177.
    Meek KM, Quantock AJ, Elliott GF, Ridgway AEA, Tullo AB, Bron AJ, Thonar EJ-MA (1989) Macular corneal dystrophy: the macromolecular structure of the stroma observed using electron microscopy and synchrotron x-ray diffraction. Exp Eye Res 49:941–958PubMedGoogle Scholar
  178. 178.
    Quantock AJ, Meek KM, Ridgway AEA, Bron AJ, Thonar EJ-MA (1990) Macular corneal dystrophy: reduction in both corneal thickness and collagen interfibrillar spacing. Curr Eye Res 9:393–398PubMedGoogle Scholar
  179. 179.
    Quantock AJ, Meek KM, Thonar EJ-MA (1992) Analysis of high-angle synchrotron x-ray diffraction patterns obtained from macular dystrophy corneas. Cornea 11:185–190PubMedGoogle Scholar
  180. 180.
    Quantock AJ, Meek KM, Thonar EJ-MA, Assil KK (1993) Synchrotron x-ray diffraction in atypical macular dystrophy. Eye 7:779–784PubMedGoogle Scholar
  181. 181.
    Quantock AJ, Fullwood NJ, Thonar EJ-MA, Waltman SR, Capel MC, Ito M, Verity SM, Schanzlin DJ (1997) Macular corneal dystrophy type II: multiple studies on a cornea with low levels of sulphated keratan sulphate. Eye 11:57–67PubMedGoogle Scholar
  182. 182.
    Palka BP, Tanioka H, Sotozono C, Yagi N, Boote C, Young RD, Meek KM, Kinoshita S, Quantock AJ (2008) Reduced collagen interfibrillar spacing in macular corneal dystrophy occurs predominantly in deep stromal layers. Invest Ophthalmol Vis Sci 49:E-Abstract 3926Google Scholar
  183. 183.
    Lewis D, Davies Y, Nieduszynski IA, Lawrence F, Quantock AJ, Bonshek R, Fullwood NJ (2000) Ultrastructural localization of sulfated and unsulfated keratan sulfate in normal and macular corneal dystrophy type I. Glycobiology 10:305–312PubMedGoogle Scholar
  184. 184.
    Saito T, Nishida K, Nakayama J, Akama TO, Fukuda MN, Watanabe K, Quantock AJ, Maeda N, Watanabe H, Tano Y (2008) Sulfation patterns of keratan sulfate in different macular corneal dystrophy immunophenotypes using three different probes. Br J Ophthalmol 92:1434–1436PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  • Andrew J. Quantock
    • 1
    Email author
  • Robert D. Young
    • 1
  • Tomoya O. Akama
    • 2
    • 3
  1. 1.Structural Biophysics Group, School of Optometry and Vision SciencesCardiff UniversityCardiffWales, UK
  2. 2.Tumor Microenvironment ProgramBurnham Institute for Medical ResearchLa JollaUSA
  3. 3.Department of PharmacologyKansai Medical UniversityMoriguchiJapan

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