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B.M. Coyle, J.M. Sivak, B.M. Stramer, M.E. Fini; Overlapping Corneal Epithelial Phenotypes Due to Deficiency in Matrix Metalloproteinase Gelatinase B (MMP-9) and Transcription Factors Smad3 and Pax6 . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3810.
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Purpose:We recently reported that the Matrix Metalloproteinase Gelatinase B (GelB; MMP-9) coordinates and effects processes involved in regeneration of the corneal and skin epithelium following injury (J. Biol. Chem., 277:2065, 2002). Smad3 is a molecule that transduces signals by TGF-beta, a cytokine that regulates gelB expression. Pax6 is an important developmental regulatory molecule that controls expression of many target genes. In vitro studies reveal that Pax6 regulates the transcriptional promoter of the GelB gene. To provide clues to the in vivo interaction between these three molecules in corneal epithelial maintenance and repair, we compared the phenotypes of GelB, Smad3, and Pax6-deficient mice. Methods:GelB and Smad3 knockout mouse lines and the small eye (sey) mouse mutant strain were used in these studies. Results:The corneas of mice lacking Smad3 are viable and show no overt developmental abnormalities. ¾th's of adult Smad3 -/- mice had a bilateral 50% reduction in corneal epithelial thickness as compared to +/- mice. Histological examination of sey mouse eyes also revealed a thinned corneal epithelium. We previously reported that corneal re-epithelialization is faster in gelB-deficient mice and skin repair has been reported to occur faster in Smad3-deficient mice. We now show that corneal re-epithelialization is also considerable faster in Sey mice. GelB was expressed at the migrating epithelial front in normal mice, but not in sey mice. Sey mice showed corneal scarring, similar to patients with aniridia, with expression of α-smooth muscle actin and stromal localization of TGF-ß2. In contrast, Smad3 -/- mice showed no stromal α-smooth muscle actin expression in stromal repair tissue following penetrating keratectomy. Conclusions:These data suggest an interaction between GelB, Smad3, and Pax6 in maintenance and regeneration of the corneal epithelium.
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