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(Investigative Ophthalmology and Visual Science. 2006;47:226-234.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-1060
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TGFß2-Induced Changes in Human Trabecular Meshwork: Implications for Intraocular Pressure

Debra L. Fleenor, Allan R. Shepard, Peggy E. Hellberg, Nasreen Jacobson, Iok-Hou Pang, and Abbot F. Clark

From Glaucoma Research, Alcon Research, Ltd., Fort Worth, Texas.

PURPOSE. Transforming growth factor (TGF)-ß2 levels are elevated in glaucomatous human aqueous humor. TGFß is a cytokine that alters extracellular matrix (ECM) metabolism, and excess ECM has been proposed to increase aqueous outflow resistance in the trabecular meshwork (TM) of glaucomatous eyes. This study was undertaken to investigate effects of TGFß2 on secretion of fibronectin and the protease inhibitor plasminogen activator inhibitor (PAI)-1 from human TM cell cultures and perfused human ocular anterior segments.

METHODS. Total RNA was isolated from pooled human TM cell monolayers and used for a gene microarray expression analysis. Supernatants from treated human TM cells were analyzed by ELISA for fibronectin or PAI-1 content. TGFß2 effects on intraocular pressure (IOP) were evaluated in a perfused organ culture model using human anterior segments, and eluates were analyzed for fibronectin and PAI-1 content.

RESULTS. Overnight treatment of TM cells with TGFß2 upregulated multiple ECM-related genes, such as PAI-1. TGFß2 also increased secretion of both fibronectin and PAI-1 from TM cells. TGFß2 effects on TM cells were blocked by inhibitors of the TGFß type I receptor. In perfused human anterior segments, TGFß2 treatment elevated IOP and increased eluate fibronectin and PAI-1 content.

CONCLUSIONS. TGFß2 effects on IOP may be transduced by TGFß type-I receptor-mediated changes in TM secretion of ECM-related factors such as fibronectin and PAI-1. Modulation of TGFß2-induced changes in the ECM may provide a novel and viable approach to the management of glaucoma.




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T. Tovar-Vidales, R. Roque, A. F. Clark, and R. J. Wordinger
Tissue Transglutaminase Expression and Activity in Normal and Glaucomatous Human Trabecular Meshwork Cells and Tissues
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K. Sanka, R. Maddala, D. L. Epstein, and P. V. Rao
Influence of Actin Cytoskeletal Integrity on Matrix Metalloproteinase-2 Activation in Cultured Human Trabecular Meshwork Cells
Invest. Ophthalmol. Vis. Sci., May 1, 2007; 48(5): 2105 - 2114.
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