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D.L. Fleenor, A. Shepard, P. Hellberg, N. Jacobson, I.–H. Pang, A. Clark; TGFß2–Induced Changes in Trabecular Meshwork Matrix Component Expression: Implications for Intraocular Pressure . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3774.
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Purpose: Excess extracellular matrix (ECM) material is believed to contribute to glaucoma etiology via increased resistance through the trabecular meshwork (TM) region. Transforming growth factor–ß2 (TGFß2) is known to modulate expression of a variety of ECM molecules, therefore we investigated its effects on human TM cell cultures and perfused ocular tissues. Methods: Human TM cells were treated with TGFß2 and/or other test agents, followed by ELISA analysis of culture supernatants for secreted fibronectin. Total RNA was isolated from pooled TM cell monolayers and used for Affymetrix microarray analysis. TGFß2 was also evaluated for intraocular pressure (IOP) effects in a perfused organ culture (POC) model using human anterior segments and POC eluates were analyzed for fibronectin content. Results: Average basal fibronectin secretion from TM cells was 1.6–53.5 µg/mL/24 h, depending upon cell line and passage number. TM cell fibronectin secretion was stimulated in a time– and dose–dependent manner by TGFß2. At 5 ng/mL TGFß2 increased GTM–3 fibronectin secretion 11 ± 2 fold. In the POC model, TGFß2 (5 ng/mL) treatment elevated IOP (155 ± 19% at Day 3, n = 5), as well as increased eluate fibronectin content (9.9 ± 3.0 fold). Overnight treatment of TM cells with TGFß2 (5 ng/mL) resulted in > 2 fold upregulation of more than 40 ECM–related genes, such as collagen IVα and Vα, and chondroitin sulfate proteoglycan 2. Conclusions: TGFß2 effects on IOP may be transduced via changes in TM ECM composition. Modulation of TGFß2–induced changes in ECM, such as fibronectin secretion, may provide a novel and viable therapeutic approach to the management of glaucoma. [Supported by Alcon Research, Ltd.]
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