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Gene and Protein Expression Changes in Human Trabecular Meshwork Cells Treated with Transforming Growth Factor-ß

¹From the Section on Aging and Ocular Disease, National Eye Institute, National Institutes of Health, Bethesda, Maryland; and ²Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.

PURPOSE. To determine the genomic and proteomic expression changes in human trabecular meshwork cells when they are treated with transforming growth factor (TGF)-ß.

METHODS. Human trabecular meshwork cells from five donors were cultured for 3 days with 1 ng/mL of either TGF-ß1 or -ß2. Changes in gene expression determined with gene microarrays and alterations in protein expression detected by two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) were studied in these cells after the incubation.

RESULTS. With both TGF-ßs, there was a substantial upregulation of genes that were related to secreted proteins or extracellular matrix. This result was consistent with pathologic changes observed in disease and with experiments on perfused trabecular meshwork. Several of the gene changes suggest that other signaling pathways, such as ErbB and Wnt, were altered. Changes in enzyme expression in the prostaglandin pathway indicated that the prostaglandins may have a different cellular profile in the presence of glaucoma. Two genes, osteoblast-specific factor 2 and corneal-derived transcript 6, which are highly expressed in the cells under normal conditions, were substantially upregulated with the TGF-ßs. Proteomic analysis indicated that there was increased proteolysis of vimentin with both treatments. Tropomyosin 1 was increased in both gene and protein expression, suggesting alterations of the cytoskeleton by the disease. The TGF-ß1 treatment caused more robust changes than those induced by TGF-ß2. Three genes—aldose reductase, thioredoxin reductase 1, and glucose-6-phosphate 1-dehydrogenase—were identified that were downregulated in expression. These genes had decreases in protein expression with TGF-ß1 treatment but had little change in either gene or protein expression with TGF-ß2.

CONCLUSIONS. Human trabecular meshwork cells can be subjected to increased levels of TGF-ß for several years as a result of glaucoma. The results indicate that changes in extracellular matrix as well as alterations in cytoskeletal proteins occur in these cells as a result of increased TGF-ß. These results are consistent with changes observed in the trabecular meshwork in glaucoma and suggest that at least some of the histologic alterations observed in the meshwork in glaucoma may be the result of increased TGF-ßs.

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