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Regulation of Glucocorticoid Responsiveness in Glaucomatous Trabecular Meshwork Cells by Glucocorticoid Receptor-ß

¹From the Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas; and ²Alcon Research, Ltd., Fort Worth, Texas.

PURPOSE. Glucocorticoid administration can lead to increased intraocular pressure in greater than 90% of patients with primary open-angle glaucoma (POAG), compared with 30% to 40% of the general population. The molecular mechanisms for increased steroid responsiveness among patients with glaucoma are unknown. An alternative splicing variant of the human glucocorticoid receptor GRß has dominant negative activity and has been implicated in a variety of steroid-resistant diseases. GRß also may play a role in glucocorticoid hyperresponsiveness in glaucoma.

METHODS. Western blot analysis was performed to detect the expression of GR and GRß in TM cells and its regulation by dexamethasone (DEX). Immunocytochemistry was used to compare the subcellular expression of GRß between normal and glaucomatous TM cell lines. DEX transgene induction in a luciferase reporter was performed to investigate the differential glucocorticoid responsiveness between multiple normal and glaucomatous TM cell lines. Overexpression of GRß was conducted in glaucomatous TM cell lines, and the regulation of GRß in the Dex-induced reporter gene luciferase or endogenous myocilin and fibronectin expression were determined.

RESULTS. Trabecular meshwork (TM) cell lines derived from normal individuals expressed higher levels of GRß than did glaucomatous TM cells. Glaucomatous TM cells were more susceptible to DEX induction of a luciferase reporter gene than were TM cells derived from normal donors. Overexpression of GRß in glaucomatous TM cells inhibited DEX induction of a luciferase reporter gene as well as the endogenous genes MYOC and fibronectin.

CONCLUSIONS. The decreased amount of GRß in glaucomatous TM cells could result in enhanced glucocorticoid responsiveness and ocular hypertension.

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