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1From the School of Optometry, University of Waterloo, Waterloo, Ontario, Canada; the 2Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and the 3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
PURPOSE. Smad3, a mediator of TGF-ß signaling has been shown to be involved in the epithelial-to-mesenchymal transformation (EMT) of lens epithelial cells in a lens injury model. In this study, the role of Smad3 in anterior subcapsular cataract (ASC) formation was investigated in a transgenic TGF-ß/Smad3 knockout mouse model.
METHODS. TGF-ß1 transgenic mice (containing a human TGF-ß1 cDNA construct expressed under the
A-crystallin promoter) were bred with mice on a Smad3-null background to generate mice with the following genotypes: TGF-ß1/Smad3/ (null), TGF-ß1/Smad3+/, TGF-ß1/Smad3+/+, and nontransgenic/Smad3+/+. Lenses from mice of each genotype were dissected and prepared for histologic or optical analyses.
RESULTS. All transgenic TGF-ß1 lenses demonstrated subcapsular plaque formation and EMT as indicated by the expression of
-smooth muscle actin. However, the sizes of the plaques were reduced in the TGF-ß1/Smad3/ lenses, as was the level of type IV collagen deposition when compared with TGF-ß1/Smad3+/ and TGF-ß1/Smad3+/+ lenses. An increased number of apoptotic figures was also observed in the plaques of the TGF-ß1/Smad3/ lenses compared with TGF-ß1/Smad3+/+ littermates.
CONCLUSIONS. Lens-specific expression of TGF-ß1 induced ASC formation in the absence of the Smad3 signaling mediator, suggests that alternative TGF-ß-signaling pathways participate in this ocular fibrotic model.
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