NDLI: Unique response profile of trabecular meshwork cells to the novel selective glucocorticoid receptor agonist, GW870086X.

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Unique response profile of trabecular meshwork cells to the novel selective glucocorticoid receptor agonist, GW870086X.

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Unique response profile of trabecular meshwork cells to the novel selective glucocorticoid receptor agonist, GW870086X.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Stamer, W. Daniel Krauss, Achim H. Hoffman, Emely A. Kurali, Edit
Description	Country affiliation: United States Author Affiliation: Stamer WD ( Department of Ophthalmology, Duke University, Durham, North Carolina 27710, USA. dan.stamer@duke.edu)
Abstract	PURPOSE: Glucocorticoid (GC)-induced glaucoma is an undesirable side effect of traditional GCs. Ocular hypertension responsible for GC-induced glaucoma is due to alterations in conventional outflow homeostasis. The present study evaluates a novel selective GC receptor agonist (SEGRA), GW870086X, in two different in vitro models of the human conventional outflow pathway. METHODS: Primary cultures of human trabecular meshwork (TM) cell monolayers were treated with dexamethasone (DEX), prednisolone (PRED), or GW870086X for 5 days and then assayed for cellular expression and secretion of fibronectin, myocilin, tissue plasminogen activator (tPA), and/or matrix metalloproteinase-2 (MMP2). In parallel, TM cell monolayers on permeable filters treated for 5 days with GCs were assayed for changes in hydraulic conductivity. RESULTS: All three GCs increased fibronectin and myocilin secretion in a concentration-dependent manner (P < 0.05). In addition, DEX increased cellular fibronectin and both DEX and PRED significantly increased cellular myocilin (P < 0.0001), while GW870086X did neither. Interestingly, DEX and PRED significantly decreased tPA expression (P ≤ 0.01), while GW870086X had the opposite effect and increased tPA expression in a concentration-dependent manner (P = 0.01). For MMP2, only DEX treatment consistently decreased secretion (P < 0.01). In a functional assay, only PRED treatment significantly decreased hydraulic conductivity of TM cell monolayers (P < 0.05). CONCLUSIONS: All three GCs induced differential responses from TM cells. While the novel SEGRA GW870086X increases fibronectin and myocilin secretion similar to two traditional GCs, effects on the matrix degradation enzymes MMP2 and tPA differed significantly, suggesting that GW870086X favors matrix turnover. Consequently, effects on conventional outflow homeostasis may also be dissimilar.
ISSN	01460404
e-ISSN	15525783
DOI	10.1167/iovs.12-11298
Journal	Investigative Opthalmology & Visual Science
Issue Number	3
Volume Number	54
Language	English
Publisher	Association for Research in Vision and Ophthalmology
Publisher Date	2013-03-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Hormone Antagonists Pharmacology Receptors, Glucocorticoid Agonists Steroids Trabecular Meshwork Drug Effects Blotting, Western Cells, Cultured Cytoskeletal Proteins Metabolism Dexamethasone Eye Proteins Fibronectins Glucocorticoids Glycoproteins Matrix Metalloproteinase 2 Prednisolone Tissue Plasminogen Activator Research Support, Non-u.s. Gov't Discipline Ophthalmology
Content Type	Text
Resource Type	Article
Subject	Ophthalmology Sensory Systems Cellular and Molecular Neuroscience

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