Lens-specific expression of TGF-β induces anterior subcapsular cataract formation in the absence of Smad3

Abstract

PURPOSE. Smad3, a mediator of TGF-β 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-β/Smad3 knockout mouse model. METHODS. TGF-β1 transgenic mice (containing a human TGF-β1 cDNA construct expressed under the αA-crystallin promoter) were bred with mice on a Smad3-null background to generate mice with the following genotypes: TGF-β1/Smad3-/- (null), TGF-β1/Smad3+/-, TGF-β1/Smad3+/+, and nontransgenic/ Smad3+/+. Lenses from mice of each genotype were dissected and prepared for histologic or optical analyses. RESULTS. All transgenic TGF-β1 lenses demonstrated subcapsular plaque formation and EMT as indicated by the expression of α-smooth muscle actin. However, the sizes of the plaques were reduced in the TGF-β1/Smad3-/- lenses, as was the level of type IV collagen deposition when compared with TGF-β1/Smad3 +/- and TGF-β1/Smad3+/+ lenses. An increased number of apoptotic figures was also observed in the plaques of the TGF-β1/Smad3-/- lenses compared with TGF-β1/Smad3 -/- littermates. CONCLUSIONS. Lens-specific expression of TGF-β1 induced ASC formation in the absence of the Smad3 signaling mediator, suggests that alternative TGF-β-signaling pathways participate in this ocular fibrotic model. Copyright © Association for Research in Vision and Ophthalmology.