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A. F. Clark, L. G. McNatt, P. E. Hellberg, J. C. Millar, J. S. Rubin, I.-H. Pang, W.-H. Wang; A Functional WNT Signaling Pathway in the Trabecular Meshwork That Regulates Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1142. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To compare gene expression between normal and glaucomatous trabecular meshwork (TM) in order to identify novel signaling pathways involved in regulating intraocular pressure (IOP).
Gene expression was compared using total RNA isolated from normal (n=6) and glaucomatous (n=6) cultured human TM cells. Differential gene expression was confirmed using QPCR. Western immunoblot and ELISA were used to determine protein differences. The effect of altered gene/protein expression on IOP was determined using perfusion cultured human anterior segments and viral expression vector transduction of mouse eyes.
Expression of the WNT signaling inhibitor sFRP1 was elevated in glaucomatous TM cells (5-fold increase in mRNA, p<0.01; 50% increase in protein, p<0.05). Human TM cells express various components of the WNT signaling system, including WNTs 2b, 5a, 5b and FZD 1,2,6,7. Increased sFRP1 caused decreased levels of the WNT signaling intermediate ß-catenin in the TM of perfusion cultured eyes (p<0.05) as well as in cultured TM cells. Recombinant sFRP1 significantly decreased the aqueous outflow facility in perfusion cultured human eyes (40-60% decrease, n=4, p<0.05). Transduction of mouse eyes with Ad5.sFRP1 significantly elevated IOP (2-fold increase, p<0.05). There was a positive correlation between anterior segment sFRP1 expression and level of IOP elevation (r2=0.81).
The TM contains a functional WNT signaling pathway. Perturbation of the WNT signaling pathway by the WNT inhibitor sFRP1 leads to elevated IOP, which may play a role in glaucoma pathogenesis.
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