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Myocilin in the trabecular meshwork of eyes with primary open-angle glaucoma

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Abstract

Background

Mutations in myocilin, a 55–57 kDa secreted glycoprotein, are causative for some forms of primary open-angle glaucoma (POAG). In vitro studies indicate that myocilin can modulate the hydrodynamic outflow resistance in the trabecular meshwork (TM) and that elevated amounts of myocilin can obstruct the TM outflow system in POAG. In this study, we analyzed the localization of myocilin in the trabecular meshwork (TM) of eyes with primary open-angle glaucoma (POAG), and compared it with that of normal eyes.

Methods

Immunohistochemistry for myocilin was performed in the eyes of human donors (nine normal and 14 with POAG, including one with steroid-induced glaucoma).

Results

Staining for myocilin was observed in the extracellular spaces of the juxtacanalicular tissue (JCT) in all normal eyes. Some normal eyes did also show cytoplasmic staining for myocilin in TM cells. In the eyes of six donors with POAG, staining of the JCT was more widespread and intense than in normal eyes. In the other eyes with POAG, immunoreactivity for myocilin in the JCT was not markedly different to that of normal eyes. Staining intensity in the JCT of POAG eyes did not obviously correlate with intraocular pressure or clinical severity. In the eyes of one patient with steroid-induced POAG, cells of the TM, Schlemm’s canal endothelium, and the anterior stroma of the iris showed an immunoreactivity for myocilin which was considerably more intense than in normal eyes, or in the eyes with other forms of POAG.

Conclusions

In some cases of POAG, the structural changes in the JCT include an increase in myocilin in the extracellular pathways of aqueous humor. Treatment with steroids appears to increase myocilin synthesis in TM and iris of human eyes in situ.

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References

  1. Tamm ER (2002) Myocilin and glaucoma: facts and ideas. Prog Retin Eye Res 21:395–428

    Article  CAS  PubMed  Google Scholar 

  2. Ricard CS, Tamm ER (2005) Focus on molecules: myocilin/TIGR. Exp Eye Res 81:501–502

    Article  CAS  PubMed  Google Scholar 

  3. Stone EM, Fingert JH, Alward WLM, Nguyen TD, Polansky JR, Sunden SLF, Nishimura D, Clark AF, Nystuen A, Nichols BE, Mackey DA, Ritch R, Kalenak JW, Craven ER, Sheffield VC (1997) Identification of a gene that causes primary open-angle glaucoma. Science 275:668–670

    Article  CAS  PubMed  Google Scholar 

  4. Liu Y, Vollrath D (2004) Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma. Hum Mol Genet 13:1193–1204

    Article  CAS  PubMed  Google Scholar 

  5. Tomarev SI, Wistow G, Raymond V, Dubois S, Malyukova I (2003) Gene expression profile of the human trabecular meshwork: NEIBank sequence tag analysis. Invest Ophthalmol Vis Sci 44:2588–2596

    Article  PubMed  Google Scholar 

  6. Tamm ER (2008) The functional role of myocilin in glaucoma. In: Shields MB, Tombran-Tink J, Barnstable CJ (eds) Ophthalmology research: mechanisms of the glaucomas. Humana Press, Totawa, NJ, pp 219–231

    Chapter  Google Scholar 

  7. Resch ZT, Fautsch MP (2009) Glaucoma-associated myocilin: a better understanding but much more to learn. Exp Eye Res 88:704–712

    Article  CAS  PubMed  Google Scholar 

  8. Nguyen TD, Chen P, Huang WD, Chen H, Johnson D, Polansky JR (1998) Gene structure and properties of TIGR, an olfactomedin-related glycoprotein cloned from glucocorticoid-induced trabecular meshwork cells. J Biol Chem 273:6341–6350

    Article  CAS  PubMed  Google Scholar 

  9. Tamm E, Russell P, Epstein DL, Johnson DH, Piatigorsky J (1999) Modulation of Myocilin/TIGR expression in human trabecular meshwork. Invest Ophthalmol Vis Sci 40:2577–2582

    CAS  PubMed  Google Scholar 

  10. Wang X, Johnson DH (2000) mRNA in situ hybridization of TIGR/MYOC in human trabecular meshwork. Invest Ophthalmol Vis Sci 41:1724–1729

    CAS  PubMed  Google Scholar 

  11. Russell P, Tamm ER, Grehn FJ, Picht G, Johnson M (2001) The presence and properties of myocilin in the aqueous humor. Invest Ophthalmol Vis Sci 42:983–986

    CAS  PubMed  Google Scholar 

  12. Fautsch MP, Bahler CK, Vrabel AM, Howell KG, Loewen N, Teo WL, Poeschla EM, Johnson DH (2006) Perfusion of his-tagged eukaryotic myocilin increases outflow resistance in human anterior segments in the presence of aqueous humor. Invest Ophthalmol Vis Sci 47:213–221

    Article  PubMed  Google Scholar 

  13. Zillig M, Wurm A, Grehn FJ, Russell P, Tamm ER (2005) Overexpression and properties of wild-type and Tyr437His mutated myocilin in the eyes of transgenic mice. Invest Ophthalmol Vis Sci 46:223–234

    Article  PubMed  Google Scholar 

  14. Gould DB, Miceli-Libby L, Savinova OV, Torrado M, Tomarev SI, Smith RS, John SW (2004) Genetically increasing Myoc expression supports a necessary pathologic role of abnormal proteins in glaucoma. Mol Cell Biol 24:9019–9025

    Article  CAS  PubMed  Google Scholar 

  15. Paper W, Kroeber M, Heersink S, Stephan DA, Fuchshofer R, Russell P, Tamm ER (2008) Elevated amounts of myocilin in the aqueous humor of transgenic mice cause significant changes in ocular gene expression. Exp Eye Res 87:257–267

    Article  CAS  PubMed  Google Scholar 

  16. Khare PD, Loewen N, Teo W, Barraza RA, Saenz DT, Johnson DH, Poeschla EM (2008) Durable, safe, multi-gene lentiviral vector expression in feline trabecular meshwork. Mol Ther 16:97–106

    Article  CAS  PubMed  Google Scholar 

  17. Kim BS, Savinova OV, Reedy MV, Martin J, Lun Y, Gan L, Smith RS, Tomarev SI, John SW, Johnson RL (2001) Targeted disruption of the myocilin gene (Myoc) suggests that human glaucoma-causing mutations are gain of function. Mol Cell Biol 21:7707–7713

    Article  CAS  PubMed  Google Scholar 

  18. Karali A, Russell P, Stefani FH, Tamm ER (2000) Localization of myocilin/trabecular meshwork inducible glucocorticoid response protein in the human eye. Invest Ophthalmol Vis Sci 41:729–740

    CAS  PubMed  Google Scholar 

  19. Ueda J, Wentz-Hunter K, Yue BY (2002) Distribution of myocilin and extracellular matrix components in the juxtacanalicular tissue of human eyes. Invest Ophthalmol Vis Sci 43:1068–1076

    PubMed  Google Scholar 

  20. Johnson M (2006) What controls aqueous humour outflow resistance? Exp Eye Res 82:545–557

    Article  CAS  PubMed  Google Scholar 

  21. Tamm ER (2009) The trabecular meshwork outflow pathways: structural and functional aspects. Exp Eye Res 88:648–655

    Article  CAS  PubMed  Google Scholar 

  22. Lütjen-Drecoll E, May CA, Polansky JR, Johnson DH, Bloemendal H, Nguyen TD (1998) Localization of the stress proteins αB-crystallin and trabecular meshwork inducible glucocorticoid response protein in normal and glaucomatous trabecular meshwork. Invest Ophthalmol Vis Sci 39:517–525

    PubMed  Google Scholar 

  23. Flügel-Koch C, Ohlmann A, Fuchshofer R, Welge-Lüssen U, Tamm ER (2004) Thrombospondin-1 in the trabecular meshwork: localization in normal and glaucomatous eyes, and induction by TGF-beta1 and dexamethasone in vitro. Exp Eye Res 79:649–663

    Article  PubMed  Google Scholar 

  24. Lütjen-Drecoll E (1999) Functional morphology of the trabecular meshwork in primate eyes. Prog Retin Eye Res 18:91–119

    Article  PubMed  Google Scholar 

  25. Rohen JW, Lütjen-Drecoll E, Flügel C, Meyer M, Grierson I (1993) Ultrastructure of the trabecular meshwork in untreated cases of primary open-angle glaucoma (POAG). Exp Eye Res 56:683–692

    Article  CAS  PubMed  Google Scholar 

  26. Lütjen-Drecoll E, Shimizu T, Rohrbach M, Rohen JW (1986) Quantitative analysis of “plaque material” in the inner and outer wall of Schlemm’s canal in normal and glaucomatous eyes. Exp Eye Res 42:443–455

    Article  PubMed  Google Scholar 

  27. Tamm ER, Fuchshofer R (2007) What increases outflow resistance in primary open-angle glaucoma? Surv Ophthalmol 52(Suppl 2):S101–S104

    Article  PubMed  Google Scholar 

  28. Tektas OY, Lütjen-Drecoll E (2009) Structural changes of the trabecular meshwork in different kinds of glaucoma. Exp Eye Res 88:769–775

    Article  CAS  PubMed  Google Scholar 

  29. Gottanka J, Johnson DH, Martus P, Lütjen-Drecoll E (1997) Severity of optic nerve damage in eyes with POAG is correlated with changes in the trabecular meshwork. J Glaucoma 6:123–132

    Article  CAS  PubMed  Google Scholar 

  30. Hann CR, Springett MJ, Wang X, Johnson DH (2001) Ultrastructural localization of collagen IV, fibronectin, and laminin in the trabecular meshwork of normal and glaucomatous eyes. Ophthalmic Res 33:314–324

    Article  CAS  PubMed  Google Scholar 

  31. Filla MS, Liu X, Nguyen TD, Polansky JR, Brandt CR, Kaufman PL, Peters DM (2002) In vitro localization of TIGR/MYOC in trabecular meshwork extracellular matrix and binding to fibronectin. Invest Ophthalmol Vis Sci 43:151–161

    PubMed  Google Scholar 

  32. Clark AF, Steely HT, Dickerson JE Jr, English-Wright S, Stropki K, McCartney MD, Jacobson N, Shepard AR, Clark JI, Matsushima H, Peskind ER, Leverenz JB, Wilkinson CW, Swiderski RE, Fingert JH, Sheffield VC, Stone EM (2001) Glucocorticoid induction of the glaucoma gene MYOC in human and monkey trabecular meshwork cells and tissues. Invest Ophthalmol Vis Sci 42:1769–1780

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by a grant from the Deutsche Forschungsgemeinschaft (Research Unit (Forschergruppe) 1075, TP 5). Donor eyes with glaucoma were kindly provided by the Glaucoma Research Eye Donor Network of the Glaucoma Research Foundation in San Francisco, CA.

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Authors and Affiliations

  1. Department of Anatomy, University of Erlangen–Nürnberg, Erlangen, Germany

    Cassandra Flügel-Koch

  2. Institute of Human Anatomy and Embryology, University of Regensburg, Universitätsstr. 31, 93053, Regensburg, Germany

    Dirk D. Konz, Andreas Ohlmann & Ernst R. Tamm

Authors
  1. Dirk D. Konz
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  2. Cassandra Flügel-Koch
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  3. Andreas Ohlmann
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  4. Ernst R. Tamm
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Correspondence to Ernst R. Tamm.

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Konz, D.D., Flügel-Koch, C., Ohlmann, A. et al. Myocilin in the trabecular meshwork of eyes with primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol 247, 1643–1649 (2009). https://doi.org/10.1007/s00417-009-1152-0

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  • DOI: https://doi.org/10.1007/s00417-009-1152-0

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