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From the Departments of Ophthalmology* and Pathology, Wakayama Medical University, Wakayama, Japan; the Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; the Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida; and the Department of Ophthalmology,|| University of Cincinnati Medical Center, Cincinnati, Ohio
Lens epithelial cells undergo epithelial-mesenchymal transition (EMT) after injury as in cataract extraction, leading to fibrosis of the lens capsule. Fibrosis of the anterior capsule can be modeled in the mouse by capsular injury in the lens, which results in EMT of the lens epithelium and subsequent deposition of extracellular matrix without contamination of other cell types from outside the lens. We have previously shown that signaling via Smad3, a key signal-transducing element downstream of transforming growth factor (TGF)-ß and activin receptors, is activated in lens epithelial cells by 12 hours after injury and that this Smad3 activation is blocked by administration of a TGF-ß2-neutralizing antibody in mice. We now show that EMT of primary lens epithelial cells in vitro depends on TGF-ß expression and that injury-induced EMT in vivo depends, more specifically, on signaling via Smad3. Loss of Smad3 in mice blocks both morphological changes of lens epithelium to a mesenchymal phenotype and expression of the EMT markers snail, 
-smooth muscle actin, lumican, and type I collagen in response to injury in vivo or to exposure to exogenous TGF-ß in organ culture. The results suggest that blocking the Smad3 pathway might be beneficial in inhibiting capsular fibrosis after injury and/or surgery.
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