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From 1 Glaucoma Research, Alcon Research, Ltd., Fort Worth, Texas; the 2 Department of Biological Structure, University of Washington, Seattle; the 3 Departments of Psychiatry and Behavioral Science and Neurology, University of Washington School of Medicine and Veterans Affairs Puget Sound Health Care System, Seattle; and the 4 Departments of Pediatrics and 6 Ophthalmology and the 5 Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City.
PURPOSE. To examine the intracellular and extracellular expression of myocilin in the human and primate trabecular meshwork (TM) in the presence and absence of glucocorticoids.
METHODS. Myocilin expression was examined in cultured human TM cells by Northern blot analysis and myocilin antibody–mediated immunoprecipitation. Myocilin expression was quantified using high-resolution two-dimensional polyacrylamide gel electrophoresis of radiolabeled proteins from human TM cells, TM tissue explants, and perfused human anterior segments cultured with and without dexamethasone (DEX) for 14 to 21 days, as well as TM tissue from pigtailed monkeys treated orally for 1 year with cortisone acetate. Immunofluorescence with anti-myocilin antibodies was used to localize cellular and extracellular expression of myocilin in cultured human TM cells.
RESULTS. Glucocorticoid treatment caused a significant induction of myocilin
mRNA, a tetrad of cell-associated proteins, and 8 to 20 secreted
proteins (molecular mass [Mr] 56 and 59 kDa and
isoelectric point [pI] 5.2 and 5.3) in some, but not all the cultured
human TM cells and explanted tissues. Western immunoblot analysis using
anti-myocilin peptide antibodies identified these proteins as encoded
by the MYOC gene. There was significant induction of the
myocilin proteins in three perfusion-cultured human eyes, in which
DEX-induced elevated intraocular pressure developed. Monkeys treated 1
year with cortisol acetate showed steroid glaucoma-like morphologic
changes in the TM that correlated with the induction of myocilin in the
TM. Immunofluorescence analysis of cultured TM cells localized myocilin
intracellularly in discrete perinuclear and cytoplasmic vesicular
deposits as well as extracellularly on the cell surface associated with
the extracellular matrix. In several DEX-treated TM cell lines, there
were significant levels of myocilin secreted into the media. Enzymatic
deglycosylation of proteins in the TM media converted the higher
molecular weight isoforms of myocilin (
57 kDa) to the lower
molecular weight isoforms (55 kDa).
CONCLUSIONS. Although the function of myocilin is unknown, induction of these TM proteins was found in eyes in which glucocorticoid-induced ocular hypertension developed. Therefore, myocilin may play an important pathogenic role in ocular hypertension in addition to its role in certain forms of POAG.
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