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Role of ID Proteins in BMP4 Inhibition of Profibrotic Effects of TGF-?2 in Human TM Cells.

ABSTRACT: Increased expression of TGF-?2 in primary open-angle glaucoma (POAG) aqueous humor (AH) and trabecular meshwork (TM) causes deposition of extracellular matrix (ECM) in the TM and elevated IOP. Bone morphogenetic proteins (BMPs) regulate TGF-?2-induced ECM production. The underlying mechanism for BMP4 inhibition of TGF-?2-induced fibrosis remains undetermined. Bone morphogenic protein 4 induces inhibitor of DNA binding proteins (ID1, ID3), which suppress transcription factor activities to regulate gene expression. Our study will determine whether ID1and ID3 proteins are downstream targets of BMP4, which attenuates TGF-?2 induction of ECM proteins in TM cells.Primary human TM cells were treated with BMP4, and ID1 and ID3 mRNA, and protein expression was determined by quantitative PCR (Q-PCR) and Western immunoblotting. Intracellular ID1 and ID3 protein localization was studied by immunocytochemistry. Transformed human TM cells (GTM3 cells) were transfected with ID1 or ID3 expression vectors to determine their potential inhibitory effects on TGF-?2-induced fibronectin and plasminogen activator inhibitor-I (PAI-1) protein expression.Basal expression of ID1-3 was detected in primary human TM cells. Bone morphogenic protein 4 significantly induced early expression of ID1 and ID3 mRNA (P < 0.05) and protein in primary TM cells, and a BMP receptor inhibitor blocked this induction. Overexpression of ID1 and ID3 significantly inhibited TGF-?2-induced expression of fibronectin and PAI-1 in TM cells (P < 0.01).Bone morphogenic protein 4 induced ID1 and ID3 expression suppresses TGF-?2 profibrotic activity in human TM cells. In the future, targeting specific regulators may control the TGF-?2 profibrotic effects on the TM, leading to disease modifying IOP lowering therapies.

SUBMITTER: Mody AA

PROVIDER: S-EPMC5295782 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Role of ID Proteins in BMP4 Inhibition of Profibrotic Effects of TGF-β2 in Human TM Cells.

Mody Avani A AA Wordinger Robert J RJ Clark Abbot F AF

Investigative ophthalmology & visual science 20170201 2

<h4>Purpose</h4>Increased expression of TGF-β2 in primary open-angle glaucoma (POAG) aqueous humor (AH) and trabecular meshwork (TM) causes deposition of extracellular matrix (ECM) in the TM and elevated IOP. Bone morphogenetic proteins (BMPs) regulate TGF-β2-induced ECM production. The underlying mechanism for BMP4 inhibition of TGF-β2-induced fibrosis remains undetermined. Bone morphogenic protein 4 induces inhibitor of DNA binding proteins (ID1, ID3), which suppress transcription factor activ ...[more]

PMID: 28159972

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Project description:PurposeThe effects of aqueous mediators possibly increasing the outflow resistance, transforming growth factor-β1 (TGF-β1), TGF-β2, autotaxin (ATX), and lysophosphatidic acid (LPA) on human trabecular meshwork (hTM) cells and monkey Schlemm's canal endothelial (SCE) cells were characterized and compared, and the effects of intracameral application of these mediators on intraocular (IOP) elevation were also examined.MethodsCells were treated with TGF-β1, TGF-β2, ATX, LPA, or vehicle, and mRNA and protein expression levels of α-SMA, COL1A1, fibronectin, β-catenin, and ZO-1 were examined with real-time quantitative PCR (RT-qPCR) or immunofluorescence analyses or both. The permeability of cell monolayers was measured by determining the transendothelial electrical resistance (TEER) or with the fluorescein isothiocyanate (FITC)-dextran permeability assay. IOP was evaluated in rabbit eyes after intracameral administration of the mediators.ResultsAll mediators induced upregulation of α-SMA, COL1A1, and fibronectin in hTM cells. The effect of TGF-β2 on mRNA expression of fibrotic markers was statistically significantly greater than that of TGF-β1. The effects of ATX and LPA indicated the time-dependent difference in the upregulation of α-SMA, COL1A1, and fibronectin. The TEER and FITC-dextran permeability of the SCE cells was evaluated after treatment with TGF-β1 and TGF-β2, but no statistically significant change was observed within 24 h. ATX and LPA also reduced permeability statistically significantly after 3 h and 0.5 h, respectively, and the effect of LPA was more rapid compared to that of ATX. Statistically significant IOP elevation was observed in rabbit eyes as early as 0.5-2.0 h after ATX and LPA treatment and at 24 h after treatment with TGF-β2.ConclusionsTGF-β2 and ATX and LPA regulate aqueous outflow by modulation of hTM cells and SCE cells, and differences in timing between the effects of each mediator were observed. ATX and LPA showed more rapid effects on IOP elevation than TGF-β2. It was suggested that TGF-β2 and ATX/LPA are involved in increases of IOP, but the timing and sustainability differ between mediators, and they may play specific roles in different glaucoma subtypes.

Dataset Information

Role of ID Proteins in BMP4 Inhibition of Profibrotic Effects of TGF-?2 in Human TM Cells.

Publications

Role of ID Proteins in BMP4 Inhibition of Profibrotic Effects of TGF-β2 in Human TM Cells.

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