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

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.

Duke Scholars

Author W Daniel Stamer Ophthalmology, Glaucoma