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R. Fuchshofer, K. Ramsey, D. Stephan, P. Russell, U. Welge-Lussen, E. Tamm; Changes in Gene Expression in Human Trabecular Meshwork Cells After Treatment With BMP-7 and/or TGF-beta2. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2057.
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Transforming growth factor (TGF)-ß2 is found in higher amounts than normal in the aqueous humor of patients with POAG. In vitro, TGF-ß2 causes an accumulation of extracellular matrix in the human trabecular meshwork (HTM) and an increase in TM outflow resistance. In a previous study, we showed that bone morphogenetic protein (BMP)-7 signaling antagonizes the effects of TGF-ß2 on HTM cells. The purpose of the present study was to determine in vitro genomic expression changes in HTM cells after long term treatment with TGF-ß2, BMP-7 and combined TGF-ß/BMP7.
RNA was isolated from HTM cells after 72 h treatment with 300 pM TGF-ß2, 300 pM BMP-7, or combined TGF-ß/BMP7. Changes in gene expression were determined by hybridization of gene microarrays, and confirmed by real-time RT-PCR and western blotting.
Several distinct changes in the expression of signaling molecules were observed. The expression of Smad-7, an inhibitory Smad of the TGF-ß pathway was upregulated by TGF-ß2 treatment. The upregulation was considerably increased the biological function and interaction of both growth factors in the HTM and their following treatment with BMP-7 alone and the combination of TGF-ß/BMP7. The expression of gremlin, a member of the DAN family of BMP antagonists, which is highly conserved through evolution, showed a significant downregulation after BMP-7 and the combined TGF-ß/BMP7 treatment, but was not changed after treatment with TGF-ß2 alone. BMP-7 and the combined TGF-ß/BMP7 treatment caused a substantial downregulation of CDC42bpb, a downstream effector of CDC42 in cytoskeletal reorganization, whereas CDC42bpb was increased after TGF-ß2 treatment. TGF-ß2 showed an increase in VEGF expression, which was slightly downregulated by the combined TGF-ß/BMP7 treatment. BMP-7 alone had no effect on the expression of VEGF.
Treatment of HTM with TGF-ß2, BMP-7, or TGF-ß/BMP7 causes distinct changes in HTM gene expression. The identification and functional analysis of differentially expressed genes will facilitate our understanding of the biological function and interaction of both growth factors in the HTM and their roles in POAG.
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