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R. Fuchshofer, U. Welge–Lussen, E. Tamm; BMP7, a Natural Antagonist of TGF–beta 2 in Human Trabecular Meshwork Cells . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3698.
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Purpose: Aqueous humor of patients with primary open angle glaucoma (POAG) contains elevated amounts of transforming growth factor (TGF)–beta 2. Treatment of cultured trabecular meshwork (TM) cells with TGF–beta 2 causes an accumulation of extracellular matrix (ECM) by increasing the expression of ECM proteins and by inhibiting the activation of matrix metalloproteinases (MMP). In anterior segment organ cultures, treatment with TGF–beta 2 causes an increase in outflow resistance. Fibrogenic TGF–beta signaling is largely mediated through Smad pathways, which are also used by bone morphogenetic protein (BMP) 7, a member of the TGF–beta superfamily. We investigated, if BMP7 signaling antagonizes fibrogenic effects of TGF–beta on trabecular meshwork cells in vitro. Methods: Cultured TM cells from 3 human donors were treated with 300pM BMP7, 300pM TGF–beta 2, or a combination of both for 72 hours. The expression of fibronectin, collagen types I, III and IV, connective tissue growth factor (CTGF), plasminogen activator inhibitor (PAI) –1 and MMP–2 were quantified by western and northern blot analysis. Results: Treatment with TGF–beta 2 induced the expression of collagen type IV, fibronectin, CTGF, and increased the basal levels of PAI–1 a protein that inhibits activation of MMPs. In contrast, all these effects were inhibited when BMP7 was added in combination with TGF–beta 2. BMP7 alone had no effects. Treatment with BMP7, TGF–beta 2, or the combination of both had no effect on the expression of collagen type I and III. Conclusions: BMP7 strongly antagonizes those effects of TGF–beta on cultured TM cells that cause an accumulation of ECM compounds. These findings indicate that BMP7 is a natural antagonist to TGF–beta 2 signaling in the outflow pathways in vivo. Pharmacologic modulation of BMP7 signalling might be used for therapy of POAG.
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