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R.J. Wordinger, D. Fleenor, P. Hellberg, I.–H. Pang, T. Tovar, G. Zode, J. Fuller, A. Clark; Opposing Effects of TGF–beta2, BMP–4, and Gremlin on Fibronectin Production in the Human Trabecular Meshwork: Role for Gremlin in Glaucoma . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1844.
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Primary open–angle glaucoma (POAG) is the second leading cause of irreversible blindness in the world and the primary risk factor for the disease is elevated intraocular pressure (IOP). Elevated IOP is due to increased aqueous humor outflow resistance and is associated with a number of morphological and biochemical changes in the trabecular meshwork (TM). Glaucoma patients have elevated levels of TGF–ß2 in their aqueous humor, and TGFb has been shown to increase extracellular matrix (ECM) production in the TM. The bone morphogenetic protein (BMP) signaling pathway can modify TGF–ß signaling in several different tissues.
We used ELISA and immunohistochemistry to demonstrate that the human TM synthesized and secreted BMP–2, BMP–4, and BMP–5 as well as expressed BMPRI and BMPRII.
TM cells responded to exogenous BMP–4 by phosphorylating Smad signaling proteins. Cultured human TM cells treated with TGF–ß2 significantly increased fibronectin (FN) levels, and BMP–4 blocked this FN induction. Since alterations in BMP signaling may be involved in glaucoma pathogenesis, we profiled the expression of BMP family genes in normal and glaucomatous TM cells, and found significant elevation of BMP antagonist gremlin mRNA and protein levels in glaucomatous TM cells. Gremlin blocked the negative effect of BMP–4 on TGF–ß–induction of fibronectin, and gremlin added to the medium of ex vivo perfusion cultured human eye anterior segments caused the glaucoma phenotype of elevated IOP.
These results are consistent with the hypothesis that in POAG, elevated Gremlin expression by TM cells inhibits BMP–4 antagonism of TGF–ß2 leading to increased ECM deposition and elevated IOP.
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