Skip to main content

How the Revolution in Cell Biology Will Affect Glaucoma: Biomarkers

  • Chapter
  • First Online:
The Glaucoma Book

Abstract

Multiple biomarker panels of common, multifactorial diseases - such as cardiovascular and Alzheimer’s disease - have recently been described, facilitating the diagnosis and risk management of these diseases. In principle, a biomarker is an indicator of a biochemical feature or facet that can be used to diagnose or monitor the progress of a disease. Detection technology has been identified for possible types of biomarkers in primary open-angle glaucoma (POAG). We will summarize known biomarkers with the intent of cataloging the biomarkers in the aqueous humor, trabecular meshwork (TM), optic nerve, and blood in patients with POAG. To facilitate comparisons and to offer mechanistic clues, biochemical changes such as up- or downregulation of proteins that have been reported in POAG are organized into three categories: namely, extra­cellular matrix (ECM) changes, cytokine/signaling molecules, and aging/stress (listed respectively in Tables 82.1, 82.2, and 82.3).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. de Lemos JA, Lloyd-Jones DM. Multiple biomarker panels for cardiovascular risk assessment. N Eng J Med. 2008;358:2172–4.

    Article  Google Scholar 

  2. Parikh SV, de Lemos JA. Biomarkers in cardiovascular disease: integrating pathophysiology into clinical practice. Amer J Med Sci. 2006;332:186–97.

    Article  PubMed  Google Scholar 

  3. Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Eng J Med. 2006;355:2631–9.

    Article  CAS  Google Scholar 

  4. Ray S, Britschgi M, Herbert C, et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nature Med. 2007;13:1359–62.

    Article  CAS  PubMed  Google Scholar 

  5. Simonsen AH, McGuire J, Hansson O, et al. Novel panel of cerebrospinal fluid biomarkers for the prediction of progression to Alzheimer dementia in patients with mild cognitive impairment. Arch Neurol. 2007;64:366–70.

    Article  PubMed  Google Scholar 

  6. Ross JS, Symmans WF, Pusztai L, Hortobagyi GN. Pharma­cogenomics and clinical biomarkers in drug discovery and development. Amer J Clin Path. 2005;124(Suppl):S29–41.

    CAS  Google Scholar 

  7. Golubnitschaja O, Flammer J. What are the biomarkers for glaucoma? Surv Ophthalmol. 2007;52(Suppl 2):S155–61.

    Article  PubMed  Google Scholar 

  8. Knepper PA, Goossens W, Mayanil CS. CD44H localization in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1998;39: 673–680.

    CAS  PubMed  Google Scholar 

  9. Picciani R, Desai K, Guduric-Fuchs J, et al. Cochlin in the eye. Prog Retin Eye Res. 2007;26:453–469.

    Article  CAS  PubMed  Google Scholar 

  10. Knepper PA, Goossens W, Hvizd M, et al. Glycosaminoglycans of the human trabecular meshwork in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1996;37:1360–1367.

    CAS  PubMed  Google Scholar 

  11. Hann CR, Springett MJ, Wang X, et al. Ultrastructural localization of collagen IV, fibronectin, and laminin in the trabecular meshwork of normal and glaucomatous eyes. Ophthalmic Res. 2001;33:314–324.

    Article  CAS  PubMed  Google Scholar 

  12. Umihira J, Nagata S, Nohara M, et al. Localization of elastin in the normal and glaucomatous human trabecular meshwork. Invest Ophthalmol Vis Sci. 1994;35:486–494.

    CAS  PubMed  Google Scholar 

  13. Pena JD, Netland PA, Vidal I, et al. Elastosis of the lamina cribrosa in glaucomatous optic neuropathy. Exp Eye Res. 1998;67:517–524.

    Article  CAS  PubMed  Google Scholar 

  14. Vesaluoma M, Mertaniemi P, Mannonen S, et al. Cellular and plasma fibronectin in the aqueous humour of primary open-angle glaucoma, exfoliative glaucoma and cataract patients. Eye. 1998;12:886–890.

    PubMed  Google Scholar 

  15. Navajas EV, Martins JR, Melo LA Jr, et al. Concentration of hyaluronic acid in primary open-angle glaucoma aqueous humor. Exp Eye Res. 2005;80:853–857.

    Article  CAS  PubMed  Google Scholar 

  16. Gong H, Ye W, Freddo TF, et al. Hyaluronic acid in the normal and glaucomatous optic nerve. Exp Eye Res. 1997;4:587–595.

    Article  Google Scholar 

  17. Pena JD, Varela HJ, Ricard CS, et al. Enhanced tenascin expression associated with reactive astrocytes in human optic nerve heads with primary open angle glaucoma. Exp Eye Res. 1999;68:29–40.

    Article  CAS  PubMed  Google Scholar 

  18. Flugel-Koch C, Ohlmann A, Fuchshofer R, et al. Thrombospondin-1 in the trabecular meshwork: localization in normal and glaucomatous eyes, and induction by TGF-β1 and dexamethasone in vitro. Exp Eye Res. 2004;79:649–663.

    Article  PubMed  Google Scholar 

  19. Ronkko S, Rekonen P, Kaarniranta K, et al. Matrix metalloproteinases and their inhibitors in the chamber angle of normal eyes and patients with primary open-angle glaucoma and exfoliation glaucoma. Graefes Arch Clin Exp Ophthalmol. 2007;245:697–704.

    Article  PubMed  Google Scholar 

  20. Yan X, Tezel G, Wax MB, et al. Matrix metalloproteinases and tumor necrosis factor-α in glaucomatous optic nerve head. Arch Ophthalmol. 2000;118:666–673.

    CAS  PubMed  Google Scholar 

  21. Schlotzer-Schrehardt U, Lommatzsch J, Kuchle M, et al. Matrix metalloproteinases and their inhibitors in aqueous humor of patients with pseudoexfoliation syndrome/glaucoma and primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2003;44:1117–1125.

    Article  PubMed  Google Scholar 

  22. Golubnitschaja O, Yeghiazaryan K, Liu R, et al. Increased expression of matrix metalloproteinases in mononuclear blood cells of normal-tension glaucoma patients. J Glaucoma. 2004;13:66–72.

    Article  PubMed  Google Scholar 

  23. Maatta M, Tervahartiala T, Harju M, et al. Matrix metalloproteinases and their tissue inhibitors in aqueous humor of patients with primary open-angle glaucoma, exfoliation syndrome, and exfoliation glaucoma. J Glaucoma. 2005;14:64–69.

    Article  PubMed  Google Scholar 

  24. Tezel G, Kass MA, Kolker AE, et al. Plasma and aqueous humor endothelin levels in primary open-angle glaucoma. J Glaucoma. 1997;6:83–89.

    Article  CAS  PubMed  Google Scholar 

  25. Emre M, Orgul S, Haufschild T, et al. Increased plasma endothelin-1 levels in patients with progressive open angle glaucoma. Br J Ophthalmol. 2005;89:60–63.

    Article  CAS  PubMed  Google Scholar 

  26. Hu DN, Ritch R. Hepatocyte growth factor is increased in the aqueous humor of glaucomatous eyes. J Glaucoma. 2001;10:152–157.

    Article  CAS  PubMed  Google Scholar 

  27. Yang J, Patil RV, Yu H, et al. T cell subsets and sIL-2R/IL-2 levels in patients with glaucoma. Am J Ophthalmol. 2001;31:421–426.

    Article  Google Scholar 

  28. Ronkko S, Rekonen P, Kaarniranta K, et al. Phospholipase A2 in chamber angle of normal eyes and patients with primary open angle glaucoma and exfoliation glaucoma. Mol Vis. 2007;13:408–417.

    CAS  PubMed  Google Scholar 

  29. Nolan MJ, Giovingo MC, Miller AM, et al. Aqueous humor sCD44 concentration and visual field loss in primary open-angle glaucoma. J Glaucoma. 2007;16:419–429.

    Article  PubMed  Google Scholar 

  30. Picht G, Welge-Luessen U, Grehn F, et al. Transforming growth factor β2 levels in the aqueous humor in different types of glaucoma and the relation to filtering bleb development. Graefes Arch Clin Exp Ophthalmol. 2001;239:199–207.

    Article  CAS  PubMed  Google Scholar 

  31. Noureddin BN, Al-Haddad CE, Bashshur Z, et al. Plasma thymulin and nerve growth factor levels in patients with primary open angle glaucoma and elevated intraocular pressure. Graefes Arch Clin Exp Ophthalmol. 2006;244:750–752.

    Article  CAS  PubMed  Google Scholar 

  32. Hu DN, Ritch R, Liebmann J, et al. Vascular endothelial growth factor is increased in aqueous humor of glaucomatous eyes. J Glaucoma. 2002;1:406–410.

    Article  Google Scholar 

  33. Lip PL, Felmeden DC, Blann AD, et al. Plasma vascular endothelial growth factor, soluble VEGF receptor FLT-1, and von Willebrand factor in glaucoma. Br J Ophthalmol. 2002;86:1299–1302.

    Article  CAS  PubMed  Google Scholar 

  34. Zabala L, Saldanha C, Martins e Silva J, et al. Red blood cell membrane integrity in primary open angle glaucoma: ex vivo and in vitro studies. Eye. 1999;13:101–103.

    PubMed  Google Scholar 

  35. Lutjen-Drecoll E, May CA, Polansky JR, et al. Localization of the stress proteins αB-crystallin and trabecular meshwork inducible glucocorticoid response protein in normal and glaucomatous trabecular meshwork. Invest Ophthalmol Vis Sci. 1998;39:517–525.

    CAS  PubMed  Google Scholar 

  36. Weinstein BI, Iyer RB, Binstock JM, et al. Decreased 3α-hydroxysteroid dehydrogenase activity in peripheral blood lymphocytes from patients with primary open angle glaucoma. Exp Eye Res. 1996;62: 39–45.

    Article  CAS  PubMed  Google Scholar 

  37. Lee P, Lam KW, Lai M. Aqueous humor ascorbate concentration and open-angle glaucoma. Arch Ophthalmol. 1977;95:308–310.

    CAS  PubMed  Google Scholar 

  38. McCarty GR, Schwartz B. Reduced plasma cortisol binding to albumin in ocular hypertension and primary open-angle glaucoma. Curr Eye Res. 1999;18:467–476.

    Article  CAS  PubMed  Google Scholar 

  39. Ren H, Magulike N, Ghebremeskel K, et al. Primary open-angle glaucoma patients have reduced levels of blood docosahexaenoic and eicosapentaenoic acids. Prostaglandins Leukot Essent Fatty Acids. 2006;74:157–163.

    Article  CAS  PubMed  Google Scholar 

  40. Ferreira SM, Lerner SF, Brunzini R, et al. Oxidative stress markers in aqueous humor of glaucoma patients. Am J Ophthalmol. 2004;137:62–69.

    Article  CAS  PubMed  Google Scholar 

  41. Gherghel D, Griffiths HR, Hilton EJ, et al. Systemic reduction in glutathione levels occurs in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2005;46:877–883.

    Article  PubMed  Google Scholar 

  42. Tezel G, Wax MB. Hypoxia-inducible factor-1α in the glaucomatous retina and optic nerve head. Arch Ophthalmol. 2004;122:1348–1356.

    Article  CAS  PubMed  Google Scholar 

  43. Tsai DC, Hsu WM, Chou CK, et al. Significant variation of the elevated nitric oxide levels in aqueous humor from patients with different types of glaucoma. Ophthalmologica. 2002;216:346–350.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. Liton PB, Challa P, Stinnett S, et al. Cellular senescence in the glaucomatous outflow pathway. Exp Geront. 2005;40:745–748.

    Article  CAS  Google Scholar 

  46. 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;49:1916–23.

    Article  PubMed  Google Scholar 

  47. Mukesh BN, McCarty CA, Rait JL, Taylor HR. Five-year incidence of open-angle glaucoma: the visual impairment project. Ophthalmology. 2002;109:1047–1051.

    Article  PubMed  Google Scholar 

  48. Quigley HA. Open-angle glaucoma. N Eng J Med. 1993;328:097–1106.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  50. Yue BYJT. Cellular mechanisms in the trabecular meshwork affecting the aqueous humor outflow pathway. In: Albert DM, Miller JW, eds. Albert and Jacobiec’s principles and practice of ophthalmology.Chap. 192. 3rd ed. Oxford, UK: Elsevier; 2007:2457–2474.

    Google Scholar 

  51. Knepper PA, Yue BYJT: Cellular mechanisms in the trabecular meshwork affecting the aqueous humor outflow pathway. In: Levine LA, Albert DM (eds) Ocular disease: mechanisms and management. Elsevier, Oxford, UK (In Press).

    Google Scholar 

  52. Acott TS, Kelley MJ. Extracellular matrix in the trabecular meshwork. Exp Eye Res. 2008;86:543–61.

    Article  CAS  PubMed  Google Scholar 

  53. Lutjen-Drecoll RJW. Morphology of aqueous outflow pathways in normal and glaucomatous eyes. In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas, vol. 1. 2nd ed. CV Mosby: St. Louis; 1996:89–123.

    Google Scholar 

  54. Tan JCH, Peters DM, Kaufman PL. Recent developments in understanding the pathophysiology of elevated intraocular pressure. Curr Opin Ophthalmol. 2006;17:168–174.

    PubMed  Google Scholar 

  55. Barany EH. The effect of different kinds of hyaluronidase on the resistance to flow through the angle of the anterior chamber. Acta Ophthalmol. 1956;33:397–403.

    Google Scholar 

  56. Knepper PA, Fadel JR, Miller AM, et al. Reconstitution of trabecular meshwork GAGs: influence of hyaluronic acid and chondroitin sulfate on flow rates. J Glaucoma. 2005;14:230–238.

    Article  PubMed  Google Scholar 

  57. Keller KE, Bradley JM, Kelley MJ, Acott TS. Effects of modifiers of glycosaminoglycan biosynthesis on outflow facility in perfusion culture. Invest Ophthalmol Vis Sci. 2008;49:2495–505.

    Article  PubMed  Google Scholar 

  58. 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. 2006;46:214–222.

    Article  Google Scholar 

  59. Tane N, Dhar S, Roy S, et al. Effect of excess synthesis of extracellular matrix components by trabecular meshwork cells: Possible consequence on aqueous outflow. Exp Eye Res. 2007;84:832–842.

    Article  CAS  PubMed  Google Scholar 

  60. Vittal V, Rose A, Gregory KE, et al. Changes in gene expression by trabecular meshwork cells in response to mechanical stretching. Invest Ophthalmol Vis Sci. 2005;46:2857–2868.

    Article  PubMed  Google Scholar 

  61. Gottanka J, Chan D, Eichhorn M, Lutjen-Drecoll E, Ethier CR. Effects of TGF-β2 in perfused human eyes. Invest Ophthalmol Vis Sci. 2004;45:153–8.

    Article  PubMed  Google Scholar 

  62. Kelley MJ, Rose AY, Songg K, et al. Synergism of TNF and IL-1 in the induction of matrix metalloproteinases-3 in the trabecular meshwork. Invest Ophthalmol Vis Sci. 2007;48:2634–2643.

    Article  PubMed  Google Scholar 

  63. Tian B, Geiger B, Epstein DL, Kaufman PL. Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest Ophthalmol Vis Sci. 2000;41:619–623.

    CAS  PubMed  Google Scholar 

  64. Rao PV, Epstein DL. Rho GTPase/Rho kinase inhibition as a novel target for the treatment of glaucoma. BioDrugs. 2007;21:167–177.

    Article  CAS  PubMed  Google Scholar 

  65. Fautsch MP, Howell KG, Vrabel AM, et al. Primary trabecular meshwork cells incubated in human aqueous humor differ from cells incubated in serum supplements. Invest Ophthalmol Vis Sci. 2005;46:2848–2856.

    Article  PubMed  Google Scholar 

  66. Knepper PA, Miller AM, Wertz CJ, et al. Hypophosphorylation of aqueous humor sCD44 and primary open angle glaucoma. Invest Ophthalmol Vis Sci. 2005;46:2829–2837.

    Article  PubMed  Google Scholar 

  67. Alvarado JA, Murphy CG, Polansky JR, Juster R. Age-related changes in trabecular meshwork cellularity. Invest Ophthalmol Vis Sci. 1981;21:714–727.

    CAS  PubMed  Google Scholar 

  68. Alvarado J, Murphy C, Juster R. Trabecular meshwork cellularity in primary open-angle glaucoma and non-glaucomatous normals. Ophthalmology. 1984;91:564–579.

    CAS  PubMed  Google Scholar 

  69. Gabelt BT, Kaufman PL. Changes in aqueous humor dynamics with age and glaucoma. Prog Retina Eye Res. 2005;24:612–637.

    Article  CAS  Google Scholar 

  70. Sacca SC, Izzotti A, Rossi P, Traverso C. Glaucomatous outflow pathway and oxidative stress. Exp Eye Res. 2007;84:389–399.

    Article  CAS  PubMed  Google Scholar 

  71. De La Paz MA, Epstein DL. Effect of age on superoxide dismutase activity of human trabecular meshwork. Invest Ophthalmol Vis Sci. 1996;37:1849–1853.

    Google Scholar 

  72. Abu-Amero KK, Morales J, Bosley TM. Mitochondrial abnormalities in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2006;47:2533–2541.

    Article  PubMed  Google Scholar 

  73. 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;118:1056–64.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Knepper, P.A., Nolan, M.J., Yue, B.Y.J.T. (2010). How the Revolution in Cell Biology Will Affect Glaucoma: Biomarkers. In: Schacknow, P., Samples, J. (eds) The Glaucoma Book. Springer, New York, NY. https://doi.org/10.1007/978-0-387-76700-0_82

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-76700-0_82

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-0-387-76699-7

  • Online ISBN: 978-0-387-76700-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics