title: Role of retinal pigment epithelial cell β-catenin signaling in experimental proliferative vitreoretinopathy.
abstract: Proliferative vitreoretinopathy is caused by the contraction of fibrotic membranes on the epiretinal surface of the neurosensory retina, resulting in a traction retinal detachment and loss of visual acuity. Retinal pigment epithelial (RPE) cells play an important role in formation of such fibrotic, contractile membranes. We investigated the role of Wnt/β-catenin signaling, a pathway implicated in several fibrotic diseases, in RPE cells in proliferative vitreoretinopathy. In vitro culture of swine RPE sheets resulted in nuclear translocation of β-catenin in dedifferentiated RPE cells. FH535, a specific inhibitor of β-catenin signaling, reduced the outgrowth of cultured RPE sheets and prevented dedifferentiated RPE cell proliferation and migration. It also inhibited formation of contractile membranes by dedifferentiated RPE cells on collagen I matrices. Expression and function of the β-catenin signaling target connexin-43 were down-regulated by FH535, and functional blockade of connexins with carbenoxolone also prevented the in vitro formation of fibrotic, contractile membranes. Intravitreal injection of FH535 in swine also inhibited formation of dense, contractile membranes on the epiretinal surface and prevented development of traction retinal detachment. These findings demonstrate that β-catenin signaling is involved in formation of contractile membranes by dedifferentiated RPE cells and suggest that adjunctive treatment targeting this pathway could be useful in preventing proliferative vitreoretinopathy.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Umazume
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Tsukahara
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky.
authors.forename: Lanhsin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Fernandez de Castro
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky.
authors.forename: Kevin
authors.initials: K
authors.lastname: McDonald
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Kaplan
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky. Electronic address: shigeo.tamiya@louisville.edu.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Tamiya
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism; D055724:Electrophysiological Phenomena / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D034421:Sus scrofa; D018630:Vitreoretinopathy, Proliferative / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D018031:Connexin 43; C575430:FH535; D013449:Sulfonamides; D051176:beta Catenin