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Editors Selection IGR 10-2

Basic research: Frizzled-related protein -1 and TM

Comment by Ted Acott on:

20999 Increased expression of serum amyloid a in glaucoma and its effect on intraocular pressure, Wang WH; McNatt LG; Pang IH et al., Investigative Ophthalmology and Visual Science, 2008; 49: 1916-1923

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The molecular etiology of glaucomatous elevations of intraocular pressure (IOP) remains obscure. Wang et al. (505) present an intriguing study in which they identify a component that is elevated in trabecular meshwork ™ cells from eyes with glaucoma, when compared with eyes from normal individuals. This component, secreted frizzled-related protein-1 (sFRP-1), is an antagonist of the wingless-type (Wnt) cellular signal transduction pathway. The authors then show that this signaling pathway is present and active in the TM. Similar studies have identified various other components that are differentially expressed in normal and glaucomatous TM. The strength of this study is that the authors then add sFRP-1 protein to perfused human anterior segment organ cultures, the best current model for aqueous outflow studies, and show that it decreases outflow facility. They also show that coincident with this effect it was active in Wnt signaling by measuring a decrease in -catenin, one of the downstream steps in this signal transduction. To further verify this effect, they use viral gene transfer of the sFRP-1 gene to over-express the protein in mouse eyes in vivo and show an elevation in IOP. To extend the likelihood that this gene is acting as they think, they use a drug intervention that would reverse the sFRP-1 effect on Wnt signaling to overcome the in vivo IOP elevation in the in sFRP-1 infected mouse eyes. As the authors admit, these various components have other modes of action in cells and thus, this is not an absolutely definitive study. However, the confluence of these alternative approaches provides very strong support for the hypothesis they are advancing. Although this careful and elegant study does not prove that glaucoma is actually caused via effects on this pathway and it does not explain the downstream mechanism by which it would impact IOP, this does stand out as an excellent study. The possibility that they have identified a key player in the development of glaucoma remains very likely and exciting. This is clearly a molecular system worthy of further investigation.

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