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首页> 外文期刊>Journal of Clinical Medicine >Bone Morphogenetic Protein (BMP)4 But Not BMP2 Disrupts the Barrier Integrity of Retinal Pigment Epithelia and Induces Their Migration: A Potential Role in Neovascular Age-Related Macular Degeneration
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Bone Morphogenetic Protein (BMP)4 But Not BMP2 Disrupts the Barrier Integrity of Retinal Pigment Epithelia and Induces Their Migration: A Potential Role in Neovascular Age-Related Macular Degeneration

机译：骨形态发生蛋白（BMP）4但不是BMP2扰乱了视网膜色素上皮的阻隔完整性，并诱导其迁移：在新生血管时代相关黄斑变性中的潜在作用

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Disruption of retinal pigment epithelial (RPE) barrier integrity and RPE migration are hallmark features in neovascular age-related macular degeneration (nAMD), but the underlying causes and pathophysiology are not completely well-defined. Herein, we aimed to evaluate the effect of bone morphogenetic proteins (BMPs) on the barrier function and migration of RPE. In particular, we investigated the role of BMP2 and BMP4 in these processes as our analysis of RNA-sequencing (seq) data from human donor eyes demonstrated that they are highly differentially expressed BMP members in macular RPE/choroid versus macular retina. We used electrical cell-substrate impedance sensing (ECIS) system to monitor precisely in real time the barrier integrity and migration of ARPE-19 after treatment with various concentrations of BMP2 or BMP4. Immunofluorescence was also used to assess the changes in the expression and the organization of the key tight junction protein, zona occludens (ZO)-1, in ARPE-19 cells under BMP2 or BMP4 treatment. This was followed by measuring the activity of matrix metalloproteinases (MMPs). Finally, RNA-seq and ELISA were used to determine the local and circulating levels of BMP2 and BMP4 in retinas and serum samples from nAMD donors. Our ECIS results showed that BMP4 but not BMP2 decreased the transcellular electrical resistance (TER) of ARPE-19 and increased their migration in comparison with control (vehicle-treated cells). Furthermore, immunofluorescence showed a disorganization of ZO-1 in BMP4-treated ARPE-19 not in BMP2-treated cells or vehicle-treated controls. This effect of BMP4 was associated with significant increases in the activity of MMPs, specifically MMP2. Lastly, these results were corroborated by additional findings that circulating but not local BMP4 levels were significantly higher in nAMD donor samples compared to controls. Collectively, our results demonstrated unreported effects of BMP4 on inducing RPE dysfunction and suggest that BMP4 but not BMP2 may represent a potential therapeutic target in nAMD.
机译：视网膜色素上皮（RPE）阻隔完整性和RPE迁移的破坏是新生血管年龄相关性黄斑变性（NAMD）的标志特征，但潜在的原因和病理生理学并不完全明确定义。在此，我们旨在评估骨形态发生蛋白（BMPS）对RPE屏障函数和迁移的影响。特别地，我们研究了BMP2和BMP4在这些过程中的作用，因为我们对人类供体眼的RNA测序（SEQ）数据的分析证明它们是黄斑/脉络膜的高度差异表达的BMP成员，而脉络膜与黄斑视网膜。我们使用电池 - 基板阻抗感测（ECIS）系统在用各种浓度的BMP2或BMP4治疗后，实时监测ARPE-19的阻挡完整性和迁移。免疫荧光还用于评估BMP2或BMP4处理下ARPE-19细胞中的表达和关键紧密结蛋白，ZONA闭塞蛋白（ZO）-1的组织的变化。然后测量基质金属蛋白酶（MMPs）的活性。最后，RNA-SEQ和ELISA用于测定来自Namd供体的视黄色和血清样品中BMP2和BMP4的局部和循环水平。我们的ECIS结果表明，BMP4但不是BMP2降低了ARPE-19的介性电阻（TER），并与对照（车辆处理的细胞）相比增加了它们的迁移。此外，免疫荧光显示在BMP4处理的ARPE-19中的ZO-1中的毒杂化在BMP2处理的细胞或载体处理的对照中。 BMP4的这种效果与MMP的活性的显着增加有关，特别是MMP2。最后，通过另外的结果证实了这些结果，与对照组相比，Namd供体样品中的循环但不是局部BMP4水平显着高。集体，我们的结果表明BMP4对诱导RPE功能障碍的未报告效果，并表明BMP4但不是BMP2可以代表NAMD中的潜在治疗目标。

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