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CD44 and Primary Open Angle Glaucoma

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Abstract

In our view, primary open-angle glaucoma (POAG) is a common neurodegenerative disease caused by a variety of molecular defects and/or cellular insults that result in cell stress and death of the trabecular meshwork (TM) and retinal ganglion cells (RGC). One potential biological marker of POAG is CD44, which is one of the adhesion/homing molecules. Direct evidence for CD44’s very central role in POAG includes: (1) aqueous humor of patients with POAG contains an increased amount of the soluble extracellular 32-kDa fragment of CD44 (sCD44) in comparison with the aqueous humor of age-matched normal individuals; (2) increased levels of sCD44 in the aqueous correlates with the extent of visual field loss in POAG patients; (3) sCD44, particularly hypo-phosphorylated sCD44, is a potent and specific toxic protein to TM and RGC in vitro; and (4) overexpression of both full-length CD44 and truncated sCD44 in transgenic mouse eyes is sufficient to cause ocular hypertension. The increase in intraocular pressure (IOP) lasted more than 90 days accompanied by optic nerve damage. The overexpression of CD44 may thus be the first documented animal model that closely mimics the human disease POAG. Other models have been cytodestructive and nonphysiologic.

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References

  1. Knepper PA, Mayanil CSK, Goossens W, et al. Aqueous humor in primary open-angle glaucoma contains an increased level of CD44S. Invest Ophthalmol Vis Sci. 2002;343:133–139.

    Google Scholar 

  2. Nolan MJ, Giovingo MC, Miller AM, et al. Influence of race on visual field loss and aqueous humor soluble CD44 concentration in primary open-angle glaucoma. J Glaucoma. 2007;16:419–429.

    Article  PubMed  Google Scholar 

  3. Choi J, Miller AM, Nolan MJ, et al. Soluble CD44 is cytotoxic to trabecular meshwork and retinal ganglion cells in vitro. Invest Ophthalmol Vis Sci. 2005;46:214–222.

    Article  PubMed  Google Scholar 

  4. Shepard AR, Nolan MJ, Millar JC, et al. CD44 Overexpression Causes Ocular Hypertension in the Mouse. ARVO annual meeting; 2008

    Google Scholar 

  5. Knepper PA, Goossens W, Palmberg PF. Glycosaminoglycan profile of the human trabecular meshwork in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1996;37:1360–1367.

    CAS  PubMed  Google Scholar 

  6. Knepper PA, Goossens W, Palmberg PF. Glycosaminoglycan stratification in normal and primary open-angle glaucoma juxtacanalicular tissue. Invest Ophthalmol Vis Sci. 1996;37:2414–2425.

    CAS  PubMed  Google Scholar 

  7. Tammi MI, Day AJ, Turley EA. Hyaluronan and homeostasis: a balancing act. J Biol Chem. 2002;277:4581–4584.

    Article  CAS  PubMed  Google Scholar 

  8. Lee JY, Spicer AP. Hyaluronan: a multifunctional, megaDalton, stealth molecule. Curr Opin Cell Biol. 2000;12:581–586.

    Article  CAS  PubMed  Google Scholar 

  9. Gong H, Ye W, Freddo TF, Hernandez MR. Hyaluronic acid in the normal and glaucomatous optic nerve. Exp Eye Res. 1997;64:587–595.

    Article  CAS  PubMed  Google Scholar 

  10. Toole BP. Hyaluronan is not just a goo! J Clin Invest. 2000;106:335–338.

    Article  CAS  PubMed  Google Scholar 

  11. Day AJ, Prestwich GD. Hyaluronan-binding proteins: tying up the giant. J Biol Chem. 2002;277:4585–4588.

    Article  CAS  PubMed  Google Scholar 

  12. Knepper PA, Lukas R, Wills J, Goossens W, Mayanil CSK. Hyaluronic acid receptors of the human trabecular meshwork. Invest Ophthalmol Vis Sci. 1997;38:S451.

    Google Scholar 

  13. Gunthert U, Johansson B. CD44-a protein family involved in autoimmune diseases and apoptosis. Immunologist. 2001;8:4–5.

    Google Scholar 

  14. Lokeshwar VB, Iida N, Bourguignon LY. The cell adhesion molecule, GP116, is a new CD44 variant (ex4/v10) involved in hyaluronic acid binding and endothelial cell proliferation. J Biol Chem. 1996;271:23853–23864.

    Article  CAS  PubMed  Google Scholar 

  15. Gunthert U. CD44 in malignant disorders. Curr Top Microbiol Immunol. 1996;213:271–285.

    PubMed  Google Scholar 

  16. Gee K, Kryworuchko M, Kumar A. Recent advances in the regulation of CD44 expression and its role in inflammation and autoimmune diseases. Arch Immunol Ther Exp (Warsz). 2004;52:13–26.

    CAS  Google Scholar 

  17. Naor D, Nedvetzki S, Walmsley M, et al. CD44 involvement in autoimmune inflammations: the lesson to be learned from CD44-targeting by antibody or from knockout mice. Ann N Y Acad Sci. 2007;1110:233–247.

    Article  CAS  PubMed  Google Scholar 

  18. Eshkar Sebban L, Ronen D, Levartovsky D, et al. The involvement of CD44 and its novel ligand galectin-8 in apoptotic regulation of autoimmune inflammation. J Immunol. 2007;179:1225–1235.

    CAS  PubMed  Google Scholar 

  19. Vachon E, Martin R, Plumb J, et al. CD44 is a phagocytic receptor. Blood. 2006;107:4149–4158.

    Article  CAS  PubMed  Google Scholar 

  20. Vachon E, Martin R, Kwok V, et al. CD44-mediated phagocytosis induces inside-out activation of complement receptor-3 in murine macrophages. Blood. 2007;110:4492–4502.

    Article  CAS  PubMed  Google Scholar 

  21. Ghatak S, Misra S, Toole BP. Hyaluronan oligosaccharides inhibit anchorage-independent growth of tumor cells by suppressing the phosphoinositide 3-kinase/Akt cell survival pathway. J Biol Chem. 2002;277:38013–38020.

    Article  CAS  PubMed  Google Scholar 

  22. Singleton PA, Salgia R, Moreno-Vinasco L, et al. CD44 regulates hepatocyte growth factor-mediated vascular integrity. Role of c-Met, Tiam1/Rac1, dynamin 2, and cortactin. J Biol Chem. 2007;282:30643–30657.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang M, Wang MH, Singh RK, Wells A, Siegal GP. Epidermal growth factor induces CD44 gene expression through a novel regulatory element in mouse fibroblasts. J Biol Chem. 1997;272:14139–14146.

    Article  CAS  PubMed  Google Scholar 

  24. Weiss L, Botero-Anug AM, Hand C, Slavin S, Naor D. CD44 gene vaccination for insulin-dependent diabetes mellitus in non-obese diabetic mice. Isr Med Assoc J. 2008;10:20–25.

    PubMed  Google Scholar 

  25. Garin T, Rubinstein A, Grigoriadis N, et al. CD44 variant DNA vaccination with virtual lymph node ameliorates experimental autoimmune encephalomyelitis through the induction of apoptosis. J Neuro Sci. 2007;258:17–26.

    Article  CAS  Google Scholar 

  26. Yu Q, Toole BP, Stamenkovic I. Induction of apoptosis of metastatic mammary carcinoma cells in vivo by disruption of tumor cell surface CD44 function. J Exp Med. 1997;186:1985–1996.

    Article  CAS  PubMed  Google Scholar 

  27. Cichy J, Pure E. The liberation of CD44. J Cell Biol. 2003;161:839–843.

    Article  CAS  PubMed  Google Scholar 

  28. Kajita M, Itoh Y, Chiba T, et al. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol. 2001;153:893–904.

    Article  CAS  PubMed  Google Scholar 

  29. Lesley J, Hyman R. CD44 structure and function. Front Biosci. 1998;1:616–630.

    Google Scholar 

  30. Kincade PW, Zheng Z, Katoh S, Hanson L. The importance of cellular environment to function of the CD44 matrix receptor. Curr Opin Cell Biol. 1997;9:635–642.

    Article  CAS  PubMed  Google Scholar 

  31. Isacke CM, Yarwood H. The hyaluronan receptor, CD44. Int J Biochem Cell Biol. 2002;34:718–721.

    Article  CAS  PubMed  Google Scholar 

  32. Naor D, Wallach-Dayan SB, Zahalka MA, Sionov RV. Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin Cancer Biol. 2008 [Epub ahead of print]

    Google Scholar 

  33. Toyama-Sorimachi N, Miyasaka M. A sulfated proteoglycan as a novel ligand for CD44. J Dermatol. 1994;21:795–801.

    CAS  PubMed  Google Scholar 

  34. Jalkanen S, Jalkanen M. Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin. J Cell Biol. 1992;116:817–825.

    Article  CAS  PubMed  Google Scholar 

  35. Weber GF, Ashkar S, Glimcher MJ, Cantor H. Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science. 1996;271:509–512.

    Article  CAS  PubMed  Google Scholar 

  36. Lukashev ME, Werb Z. ECM signalling: orchestrating cell behaviour and misbehaviour. J Cell Biol. 1998;8:438–442.

    Google Scholar 

  37. Clark AF. New discoveries on the roles of matrix metalloproteinases in ocular cell biology and pathology. Invest Ophthalmol Vis Sci. 1998;39:2514–2516.

    CAS  PubMed  Google Scholar 

  38. Bradley JMB, Vranka J, Colvis CM, et al. Effect of matrix metalloproteinases activity on outflow in perfused human organ culture. Invest Ophthalmol Vis Sci. 1998;39:2649–2658.

    CAS  PubMed  Google Scholar 

  39. Sherman L, Sleeman J, Dall P, et al. The CD44 proteins in embryonic development and in cancer. Curr Top Microbiol Immunol. 1996;213:249–269.

    CAS  PubMed  Google Scholar 

  40. Tsukita A, Oishi K, Sato N, et al. ERM family members are molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeleton. J Cell Biol. 1994;126:391–401.

    Article  CAS  PubMed  Google Scholar 

  41. Jiang H, Peterson RS, Wang W, et al. A requirement for the CD44 cytoplasmic domain for hyaluronan binding, pericellular matrix assembly, and receptor-mediated endocytosis in COS-7 cells. J Biol Chem. 2002;277:10531–10533.

    Article  CAS  PubMed  Google Scholar 

  42. Sretavan DW, Feng L, Pure E, Reichardt LF. Embryonic neurons of the developing optic chiasm express L1 and CD44, cell surface molecules with opposing effects on retinal axon growth. Neuron. 1994;12:957–975.

    Article  CAS  PubMed  Google Scholar 

  43. Flurkey K, Stadecker M, Miller RA. Memory T lymphocyte hyporesponsiveness to noncognate stimuli: a key factor in age-related immunodeficiency. Eur J Immunol. 1992;2:931–935.

    Article  Google Scholar 

  44. Hirano F, Hirano H, Hino E, et al. CD44 isoform expression in periodontal tissues: cell-type specific regulation of alternative splicing. J Periodontal Res. 1997;32:634–645.

    Article  CAS  PubMed  Google Scholar 

  45. Naot D, Sionov RV, Ish-Shalom D. CD44: structure, function, and association with the malignant process. Adv Cancer Res. 1997;71:241–319.

    Article  Google Scholar 

  46. Liu N, Xu XM, Chen J, et al. Hyaluronan-binding peptide can inhibit tumor growth by interacting with Bcl-2. Int J Cancer. 2004;109:49–57.

    Article  CAS  PubMed  Google Scholar 

  47. Knepper PA, Koga T, Nolan M, Yue BYJT, Sheppard A, Clark A. Multidrug resistance proteins and trabecular meshwork. ARVO annual meeting; 2007

    Google Scholar 

  48. Knepper PA, Goossens W, Mayanil CSK. CD44 localization in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1998;39:673–680.

    CAS  PubMed  Google Scholar 

  49. Camp RL, Krauss TA, Pure E. Variations in the cytoskeletal interaction and posttranslational modifications of the CD44 homing receptor in macrophages. J Cell Biol. 1991;115:1283–1292.

    Article  CAS  PubMed  Google Scholar 

  50. Lesley J, English N, Perschl A, et al. Variant cell lines selected for alterations in the function of the hyaluronan receptor CD44 show differences in glycosylation. J Exp Med. 1995;182:431–437.

    Article  PubMed  Google Scholar 

  51. Thankamony SP, Knudson W. Acylation of CD44 and its association with lipid rafts are required for receptor and hyaluronan endocytosis. J Biol Chem. 2006;281:34601–34609.

    Article  CAS  PubMed  Google Scholar 

  52. Seiki M. The cell surface: the stage for matrix metalloproteinase regulation of migration. Curr Opin Cell Biol. 2002;14:624–632.

    Article  CAS  PubMed  Google Scholar 

  53. Stoeck A, Keller S, Riedle S, et al. A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44. Biochem J. 2006;393:609–618.

    Article  CAS  PubMed  Google Scholar 

  54. Yang P, Baker KA, Hagg T. The ADAMs family: coordinators of nervous system development, plasticity and repair. Prog Neurobiol. 2006;79:73–94.

    Article  CAS  PubMed  Google Scholar 

  55. Lammich S, Okochi M, Takeda M, et al. Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J Biol Chem. 2002;277:44754–44759.

    Article  CAS  PubMed  Google Scholar 

  56. Liu F, Su Y, Li B, et al. Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35/Cdk5 and p25/Cdk5. FEBS Lett. 2003;547:193–196.

    Article  CAS  PubMed  Google Scholar 

  57. Tamura H, Kawakami H, Kanamoto T, et al. High frequency of open-angle glaucoma in Japanese patients with Alzheimer's disease. J Neurol Sci. 2006;246:79–83.

    Article  PubMed  Google Scholar 

  58. Bayer AU, Ferrari F, Erb C. High occurrence rate of glaucoma among patients with Alzheimer’s disease. Eur Neurol. 2002;47:165–168.

    Article  CAS  PubMed  Google Scholar 

  59. Rajendran L, Schneider A, Schlechtingen G, et al. Efficient inhibition of the Alzheimer’s disease beta-secretase by membrane targeting. Science. 2008;320:520–523.

    Article  CAS  PubMed  Google Scholar 

  60. Tesco G, Koh YH, Kang EL, et al. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron. 2007;54:721–737.

    Article  CAS  PubMed  Google Scholar 

  61. Werb Z, Yan Y. A cellular striptease act. Science. 1998;282:1279–1280.

    Article  CAS  PubMed  Google Scholar 

  62. Lee MC, Alpaugh ML, Nguyen M, et al. Myoepithelial-specific CD44 shedding is mediated by a putative chymotrypsin-like sheddase. Biochem Biophys Res Commun. 2000;279:116–123.

    Article  CAS  PubMed  Google Scholar 

  63. Li HL, Wang HH, Liu SJ, et al. Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration. Proc Nat Acad Sci U S A. 2007;104:3591–3596.

    Article  CAS  Google Scholar 

  64. Knepper PA, Miller AM, Choi J, et al. Hypo-phosphorylation of aqueous humor sCD44 and primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2005;46:2829–2837.

    Article  PubMed  Google Scholar 

  65. Giovingo MC, Nolan MJ, Koga T, et al. Aqueous humor sCD44 concentration in Diabetes and Primary Open-Angle Glaucoma. ARVO annual meeting; 2008

    Google Scholar 

  66. Cavin LG, Romieu-Mourez R, Panta GR, et al. Inhibition of CK2 activity by TGF-beta1 promotes IkappaB-alpha protein stabilization and apoptosis of immortalized hepatocytes. Hepatology. 2003;38:1540–1551.

    CAS  PubMed  Google Scholar 

  67. Tripathi RC, Li J, Chan WF, Tripathi BJ. Aqueous humor in glaucomatous eyes contains an increased level of TGF-beta 2. Exp Eye Res. 1994;59:723–727.

    Article  CAS  PubMed  Google Scholar 

  68. Wang WH, McNatt LG, Pang IH, et al. Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure. J Clin Invest. 2008;118:1056–1064.

    CAS  PubMed  Google Scholar 

  69. Chen HK, Fernandez-Funez P, Acevedo SF, et al. Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell. 2003;113:457–468.

    Article  CAS  PubMed  Google Scholar 

  70. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–1657.

    Article  CAS  PubMed  Google Scholar 

  71. Wei W, Wang X, Kusiak JW. Signaling events in amyloid beta-peptide-induced neuronal death and insulin-like growth factor I protection. J Biol Chem. 2002;277:17649–17656.

    Article  CAS  PubMed  Google Scholar 

  72. Sherman LS, Rizvi TA, Karyala S, Ratner N. CD44 enhances neuregulin signaling by Schwann cells. J Cell Biol. 2000;150:1071–1084.

    Article  CAS  PubMed  Google Scholar 

  73. Suo Z, Risberg B, Karlsson MG, et al. The expression of EGFR family ligands in breast carcinomas. Int J Surg Pathol. 2002;10:91–99.

    Article  CAS  PubMed  Google Scholar 

  74. Alexander JP, Acott TS. Involvement of protein kinase C in TNF alpha regulation of trabecular matrix metalloproteinases and TIMPs. Invest Ophthalmol Vis Sci. 2001;42:2831–2838.

    CAS  PubMed  Google Scholar 

  75. Limb GA, Daniels JT, Pleass R, et al. Differential expression of matrix metalloproteinases 2 and 9 by glial Muller cells: response to soluble and extracellular matrix-bound tumor necrosis factor-alpha. Am J Pathol. 2002;160:1847–1855.

    CAS  PubMed  Google Scholar 

  76. Weinreb RN, Lindsey JD. Metalloproteinase gene transcription in human ciliary muscle cells with latanoprost. Invest Ophthalmol Vis Sci. 2002;43:716–722.

    PubMed  Google Scholar 

  77. OH J, Takahashi R, Kondo S, et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell. 2001;107:789–800.

    Article  CAS  PubMed  Google Scholar 

  78. Xu XM, Chen Y, Chen J, et al. A peptide with three hyaluronan binding motifs inhibits tumor growth and inducesapoptosis. Cancer Res. 2003;63:5685–5690.

    CAS  PubMed  Google Scholar 

  79. Sy MS, Guo YJ, Stamenkovic I. Inhibition of tumor growth in vivo with a soluble CD44-immunoglobulin fusion protein. J Exp Med. 1992;176:623–637.

    Article  CAS  PubMed  Google Scholar 

  80. Mohapatra S, Yang X, Wright JA, Turley EA, Greenberg AH. Soluble hyaluronan receptor RHAMM induces mitotic arrest by suppressing Cdc2 and cyclin B1 expression. J Exp Med. 1996;183:1663–1668.

    Article  CAS  PubMed  Google Scholar 

  81. Wisniewski HG, Naime D, Hua JC, Vilcek J, Cronstein BN. TSG-6, a glycoprotein associated with arthritis, and its ligand hyaluronan exert opposite effects in a murine model of inflammation. Pflugers Arch. 1996;431(6 Suppl 2):R225-R226.

    Article  CAS  PubMed  Google Scholar 

  82. Rubinstein DB, Stortchevoi A, Boosalis M, et al. Receptor for the globular heads of C1q (gC1q-R, p33, hyaluronan-binding protein) is preferentially expressed by adenocarcinoma cells. Int J Cancer. 2004;110:741–750.

    Article  CAS  PubMed  Google Scholar 

  83. Liu N, Lapcevich RK, Underhill CB, et al. Metastatin: a hyaluronan-binding complex from cartilage that inhibits tumor growth. Cancer Res. 2001;61:1022–1028.

    CAS  PubMed  Google Scholar 

  84. Yu Q, Toole BP. A new alternatively spliced exon between v9 and v10 provides a molecular basis for synthesis of soluble CD44. J Biol Chem. 1996;271:20603–20607.

    Article  CAS  PubMed  Google Scholar 

  85. Zeng CX, Toole BP, Kinney SD, Kuo JW, Stamenkovic I. Inhibition of tumor growth in vivo by hyaluronan oligomers. Int J Cancer. 1998;77:396–401.

    Article  CAS  PubMed  Google Scholar 

  86. Wang N, Chintala SK, Fini ME, Schuman JS. Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype. Nat Med. 2001;7:304–309.

    Article  CAS  PubMed  Google Scholar 

  87. Fitzgerald KA, Bowie AG, Skeffington BS, O'Neill LA. Ras, protein kinase C zeta, and I kappa B kinases 1 and 2 are downstream effectors of CD44 during the activation of NFkappa B by hyaluronic acid fragments in T-24 carcinoma cells. J Immunol. 2000;164:2053–2063.

    CAS  PubMed  Google Scholar 

  88. Miller AM, Nolan MJ, Choi J, et al. Lactate treatment causes NK-κB activation and CD44 shedding in cultured trabecular meshwork cells. Invest Ophthalmol Vis Sci. 2007;48:1615–1621.

    Article  PubMed  Google Scholar 

  89. Schwamborn K, Weil R, Courtois G, Whiteside ST, Israel A. Phorbol esters and cytokines regulate the expression of the NEMO-related protein, a molecule involved in a NF-kappa B-independent pathway. J Biol Chem. 2000;275:22780–22788.

    Article  CAS  PubMed  Google Scholar 

  90. Stern R, Shuster S, Neudecker BA, Formby B. Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited. Exp Cell Res. 2002;276:24–31.

    Article  CAS  PubMed  Google Scholar 

  91. Pache M, Flammer J. A sick eye in a sick body? Systemic findings in patients with primary open-angle glaucoma. Surv Ophthalmol. 2006;51:179–212.

    Article  PubMed  Google Scholar 

  92. Wang WH, McNatt LG, Pang IH, et al. Increased expression of serum amyloid A in glaucoma and its effect on intraocular pressure. Invest Ophthalmol Vis Sci. 2008;49:1916–1923.

    Article  PubMed  Google Scholar 

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Knepper, P.A., Nolan, M.J., Yue, B.Y.J.T. (2010). CD44 and Primary Open Angle Glaucoma. In: Schacknow, P., Samples, J. (eds) The Glaucoma Book. Springer, New York, NY. https://doi.org/10.1007/978-0-387-76700-0_83

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