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Ankur Jain, Olga Borodovitsyna, Robert J. Wordinger, Abbot F. Clark; Dexamethasone and Connective Tissue Growth Factor Interactions in Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3262.
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Glucocorticoids (GCs) and transforming growth factor beta-2 (TGF-β2) cause similar pathological changes in the trabecular meshwork (TM) and mimic clinical symptoms that are associated with primary open angle glaucoma, a leading cause of irreversible blindness worldwide. Dexamethasone (DEX), a potent GC, and TGF-β2 cause extracellular matrix synthesis and accumulation, cytoskeletal changes in TM, increased outflow resistance, and elevated intraocular pressure. Connective tissue growth factor (CTGF) is a downstream mediator of TGF-β2 signaling and is responsible for many of the fibrotic effects associated with TGF-β2. The purpose of this study was to evaluate possible interactions between DEX and CTGF and cross-talk between the GC and TGFβ signaling pathways.
Real time PCR and western-immunoblotting were used to study the effect of DEX (100 nM) on CTGF mRNA and protein expression, respectively, in cultured TM cells. GRE-luciferase reporter assays and siRNA against CTGF was used to observe the effect of CTGF on DEX activity.
DEX significantly induces both CTGF mRNA and protein levels (1.6X increase, p<0.05). The effect was seen as early as 6 hours for mRNA and 12 hours for protein induction. The results were comparable in both serum-free and serum containing medium. DEX treatment significantly increased GRE-luciferase activity (p<0.05), and this activity was further enhanced by CTGF siRNA treatment. siRNA mediated CTGF knock down shows CTGF controls DEX activity in-vitro.
We have discovered a novel interaction between DEX and CTGF, a component of TGFβ signaling. Additional studies will determine the functional implications of this cross-talk between these 2 different glaucoma pathogenic pathways that may lead to the discovery of novel therapeutic targets.
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