Discovery of a new signaling pathway that regulates IOP

Researchers have discovered elevated expression of sFRP1 (secreted frizzled related protein), a WNT signaling inhibitor, in glaucomatous trabecular meshwork (TM) cells. They also observed that the TM has a functional signaling pathway in which elevated sFRP1 decreased outflow facility, according to one researcher.

"This validates a new signaling pathway in the TM that regulates IOP," said Abbot F. Clark, senior director of glaucoma research, Alcon Laboratories, Fort Worth, TX.

Gene expression was compared using total RNA isolated from 6 normal and 6 glaucomatous cultured TM cells. After differential gene expression was confirmed, the effect of altered expression on IOP was determined using perfusion cultured human anterior segments and viral expression vector transduction of mouse eyes.

A four- to five-fold increase in the expression of sFRP1 was found in the glaucomatous TM cells. This was confirmed at the protein level.

"We are hypothesizing that sFRP1 blocks WNT signaling, and that leads to an increase in IOP," Dr. Clark said.

An apparent correlation also was found between sFRP1 expression and the signaling mediator beta-catenin. High levels of sFRP1 were associated with low levels of beta-catenin, and the inverse was also observed.

Looking for the effects of this expression, Dr. Clark and colleagues found a statistically significant decrease in outflow facility in perfusion cultured human eyes. Those eyes that received sFRP1 also had lower levels of beta-catenin.