Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky.
Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky.
Am J Pathol. 2014 May;184(5):1419-28. doi: 10.1016/j.ajpath.2014.01.022. Epub 2014 Mar 18.
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.
增殖性玻璃体视网膜病变是由神经感觉视网膜的视网膜表面上的纤维性膜收缩引起的，导致牵引性视网膜脱离和视力丧失。视网膜色素上皮 (RPE) 细胞在这种纤维性、收缩性膜的形成中起着重要作用。我们研究了 Wnt/β-连环蛋白信号通路在增殖性玻璃体视网膜病变中的 RPE 细胞中的作用，该通路涉及几种纤维化疾病。猪 RPE 片的体外培养导致去分化的 RPE 细胞中β-连环蛋白的核易位。FH535 是β-连环蛋白信号通路的特异性抑制剂，可减少培养的 RPE 片的生长，并防止去分化的 RPE 细胞增殖和迁移。它还抑制了去分化的 RPE 细胞在胶原 I 基质上形成收缩性膜。β-连环蛋白信号通路的靶标连接蛋白-43 的表达和功能被 FH535 下调，用 carbenoxolone 阻断连接蛋白的功能也可防止体外形成纤维性、收缩性膜。FH535 在猪的玻璃体内注射也抑制了视网膜表面纤维性、收缩性膜的形成，并防止了牵引性视网膜脱离的发展。这些发现表明，β-连环蛋白信号通路参与了去分化的 RPE 细胞收缩性膜的形成，并表明针对该途径的辅助治疗可能有助于预防增殖性玻璃体视网膜病变。
