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(Investigative Ophthalmology and Visual Science. 2007;48:4291-4299.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0086
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The Role of Gremlin, a BMP Antagonist, and Epithelial-to-Mesenchymal Transition in Proliferative Vitreoretinopathy

Helena Lee,1 Sarah J. O'Meara,2 Colm O'Brien,1,3 and Rosemary Kane2,3

1From the Department of Ophthalmology, Mater Misericordiae Hospital, and the 2School of Medicine and Medical Science, University College Dublin, Ireland; and the 3UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland.

PURPOSE. Proliferative vitreoretinopathy (PVR), a major reason for failure of retinal detachment surgery, is characterized by the formation of scarlike tissue that contains transdifferentiated retinal pigment epithelial (RPE) cells. The scar tissue occurs in response to growth factors such as transforming growth factor (TGF)-ß and epidermal growth factor (EGF). The authors postulate that transdifferentiation of RPE cells may arise via epithelial-to-mesenchymal transition (EMT). Bone morphogenetic proteins (BMPs) are expressed in the retina and have an antiproliferative role. Gremlin is expressed in the outer retina and is a BMP antagonist. The study was conducted to establish a model of PVR by inducing EMT in the human RPE cell line ARPE-19, using TGF-ß and EGF and to establish the contribution of gremlin to EMT.

METHODS. ARPE-19 cells were cultured and stimulated with TGF-ß1, EGF, and gremlin. The expression of {alpha}-smooth muscle actin ({alpha}-SMA), vimentin, and zona occludens (ZO)-1 were examined via PCR, Western blot analysis, and immunofluorescence. Zymography was performed for matrix metalloproteinase (MMP) activity. Scratch assays were performed to assess migration.

RESULTS. A model of EMT was established in the ARPE-19 cell line. The characteristics of EMT include gain of {alpha}-SMA, loss of ZO-1, upregulation of MMP activity and enhanced migration. Gremlin plays an important role in this process, contributing to the gain of {alpha}-SMA, loss of ZO-1, and upregulation of MMP activity.

CONCLUSIONS. EMT occurs in vitro in the ARPE-19 cell line in response to the growth factors TGF-ß1 and EGF. EMT is also induced by Gremlin.






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Copyright © 2007 by the Association for Research in Vision and Ophthalmology