FP receptor instrumental in upregulation of matrix metalloproteinase

May 7, 2007

Topical latanoprost (Xalatan, Pfizer Ophthalmics) upregulates matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, and FP receptor gene expression in the mouse sclera. These responses are critically dependent on an intact FP receptor gene, said John Crowston, MD, University of Melbourne, Center for Eye Research Australia, East Melbourne, Australia.

Topical latanoprost (Xalatan, Pfizer Ophthalmics) upregulates matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, and FP receptor gene expression in the mouse sclera. These responses are critically dependent on an intact FP receptor gene, said John Crowston, MD, University of Melbourne, Center for Eye Research Australia, East Melbourne, Australia.

"Prostaglandin alpha analogues bind the prostaglandin FP receptor and have been shown to induce long-term stable reduction of IOP in humans and primates," Dr. Crowston said. "The prostaglandins are thought to do so by increasing uveoscleral outflow, probably by reducing extracellular matrix protein and by relaxing the ciliary muscle."

He also explained that prostaglandin-mediated upregulation of MMPs has been demonstrated in cell culture models and in vivo in various animal models.

"MMPs are endopeptidases that degrade extracellular matrix, and there is evidence of this [with] in vitro cell culture models of human ciliary muscles," Dr. Crowston said. "The FP receptor is a critical component in the MMP upregulation. However, the role of the MMP receptor in MMP gene upregulation in vivo is not well understood."

Dr. Crowston and colleagues conducted a study to determine changes in MMP expression over time. Wild-type mice were treated once daily with 200 mg of topical latanoprost. Scleral and retinal tissues were harvested after 2 hours and 1, 3, and 7 days of treatment; pooled MMP mRNA was quantified and compared with untreated control eyes. To assess the role of the FP receptor, FP knockout and wild-type littermate controls were treated daily for 7 days and MMP expression was determined in the sclera and retina and compared with untreated fellow eyes.

He reported that MMP-2, MMP-3, MMP-9, and FP mRNA were upregulated in the sclera, with peak expression at day 7 of treatment. There was no upregulation of these genes in the retina. In addition, in FP receptor knockout mice, there was no increase in MMP gene expression in the sclera compared with the untreated fellow eyes. Significant increases in MMP gene expression were observed in the wild-type littermates with intact FP receptors.

"A fully intact FP receptor seems to be necessary for the latanoprost-mediated MMP-2, MMP-3, and MMP-9 upregulation in the mouse eye in vivo," Dr. Crowston concluded.