Abstract
Proliferative vitreoretinopathy (PVR), a serious vision-threatening complication of retinal detachment (RD), is characterized by the formation of contractile fibrotic membranes, in which epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a major event. Recent studies suggest an important role of bone morphogenetic protein 4 (BMP4) in the suppression of fibrosis. In this study, we aimed to investigate the role of BMP4 in the pathological process of PVR, particularly in the EMT of RPE cells. We found that BMP4 and its receptors were co-labelled with cytokeratin and α-SMA positive cells within the PVR membrane. Moreover, the mRNA and protein expression levels of BMP4 were decreased whereas BMP4 receptors ALK2, ALK3 and ALK6 were increased during TGF-β-induced EMT in primary RPE cells. Exogenous BMP4 inhibited TGF-β-induced epithelial marker down-regulation, as well as mesenchymal marker up-regulation at both the mRNA and protein levels in RPE cells. In addition, BMP4 treatment attenuated the TGF-β-induced gel contraction, cell migration and Smad2/3 phosphorylation. However, knockdown of endogenous BMP4 stimulated changes in EMT markers. Our results confirm the hypothesis that BMP4 might inhibit TGF-β-mediated EMT in RPE cells via the Smad2/3 pathway and suppress contraction. This might represent a potential treatment for PVR.
Highlights
Double-labelled bone morphogenetic protein 4 (BMP4), ALK2, ALK3 or ALK6 with cytokeratin or α-SMA is shown on human Proliferative vitreoretinopathy (PVR) membranes
To investigate whether BMP4 is involved in the pathogenesis of PVR, we first used immunofluorecense confocal microscopy to examine the expression of BMP4 and its receptors ALK2, ALK3 and ALK6 within the ERM from PVR patients
As retinal pigment epithelium (RPE) cells are the only epithelial cells present within ERM4, it is expected that many BMP4, ALK2, ALK3 or ALK6-positive cells are derived from RPE or transdifferentiated cells
Summary
Double-labelled BMP4 (red, the fourth line), ALK2 (red, the first line), ALK3 (red, the second line) or ALK6 (red, the third line) with cytokeratin or α-SMA (green) is shown on human PVR membranes. TGF-βand BMPs act through two similar classes of receptors known as type I (TβRI, BMPR-I) and type II (TβRII, BMPR- II) receptors. TGF-βand BMPs counter-regulate each other and share similar downstream canonical sma and mothers against decapentaplegic (Smad) signalling pathways or non-canonical signalling pathways[26]. They keep the balance of normal biological activities. We look forward to developing a new drug for the treatment of PVR
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