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Danhong Zhu, Jing Xu, Xuemei Deng, Jamie Hsiung, Stephen Ryan, David Hinton; AMD-like phenotypes in transgenic mice over-expressing BMP4 in RPE. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4589.
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BMP4 mediates oxidative stress-induced senescence of retinal pigment epithelial (RPE) cells in vitro. To determine whether BMP4 plays a role in the initiation and development of age-related macular degeneration (AMD) in vivo, we generated a transgenic mouse model that specifically over-expressed BMP4 in RPE and analyzed the phenotypes in aged transgenic mice (Tg).
The DNA construct, mouse BMP4 cDNA regulated by the human VMD2 gene promotor, was micro-injected into fertilized mouse oocytes to generate transgenic mice. We analyzed the phenotype of Tg and age-matched wild-type (Wt) mice in 18- to 24-month-old mice. Real time PCR, immunohistology, transmission electron microscopy and fluorescein angiography (FA) were used to analyze the phenotype of this transgenic mouse model and age- matched controls.
This BMP4 over-expressing mouse accumulated remarkable amounts of oxidized lipid in RPE and on Bruch’s membrane (BM). This suggests that over-expressed BMP4 induces oxidative stress of RPE which might lead to subsequent AMD phenotypes, including RPE atrophy and thickened BM. RPE in Tg mice showed decreased height, hypo- or hyper-pigmentation, disorganized basal infoldings and cellular lipid vesicles. Some Tg mice eventually developed choroidal neovascularization (CNV) with fluorescein leakage on FA, isolectin B4 positive staining on flat mounted posterior eye cups and CNV-like lesions by histology. These changes were not seen in aged -matched controls.
The BMP4 over-expressing mice mimic the pathological process of AMD and may be a good model for studying AMD. Our work suggests that a dysregulated growth factor, BMP4, may be involved in the pathogenesis of AMD.
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