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T. Tovar, A. F. Clark, R. J. Wordinger; Effects of TGF-β2, BMPs-2/5/7, and Gremlin on Fibronectin in Human Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3209.
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Transforming growth factor beta 2 (TGF-β2) has been implicated in the development of elevated intraocular pressure in primary open-angle glaucoma (POAG). Glaucoma patients have increased levels of TGF-β2 in their aqueous humor, and TGF-β2 increases extracellular matrix (ECM) proteins such as fibronectin (FN) in trabecular meshwork (TM) cells. Bone morphogenetic protein 4 (BMP4) inhibits TGF-β2 induction of FN, which is reversed by the BMP antagonist gremlin. The purpose of the present study was to investigate whether other members of the BMP family, BMPs 2, 5, and 7 have the same antagonistic effect on TGF-β2 induction of fibronectin expression in human trabecular meshwork cells.
Primary human TM cell strains were treated with TGF-β2 (5ng/ml), BMPs 2, 4, 5, or 7 (10ng/ml), gremlin (1ug/ml), or a combinations of TGF-β2, BMPs, and/or gremlin for 48 hours. The effects of TGF-β2, BMPs, and gremlin on FN expression were determined by western immunoblotting.
Exogenous TGF-β2 increased TM cell FN levels, and BMP-2, BMP-4 and BMP-7, but not BMP-5 blocked this fibronectin induction. The BMP antagonist gremlin blocked the negative effects of BMP-2, BMP-4 and BMP-7 and enhanced FN expression.
TGF-β2 induction of ECM (e.g. fibronectin) deposition may be responsible for the elevated intraocular pressure in POAG. The human trabecular meshwork modulates TGF-β2 effects on the ECM with BMPs. However, this modulatory effect is opposed by gremlin, which blocks the negative action of BMP-2, BMP-4 and BMP-7 and leads to increased expression of ECM. The pharmacological modulation of gremlin may provide a novel therapeutic target in glaucoma.
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