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J. Xu, S. He, C. Spee, S. J. Ryan, D. R. Hinton; TNF- Induced MMP-9 Expression is Regulated by BMP-4 in Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4100.
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Matrix metalloproteinase-9 (MMP-9) has been shown to play an important role in the pathogenesis of choroidal neovascularization (CNV), and its expression is regulated by inflammatory cytokines. Our previous work indicated that there was less severe laser-induced CNV in transgenic mice overexpressing bone morphogenetic protein-4 (BMP-4) in retinal pigment epithelium (RPE). We hypothesize that overexpressed BMP-4 could modulate CNV formation by inhibiting MMP-9 expression. The goal of the current study was to determine whether BMP-4 regulates MMP-9 expression induced by tumor necrosis factor -α (TNF-α) in RPE cells in vitro, and in laser-induced CNV mouse model.
Confluent primary human fetal RPE cells were pretreated with or without BMP-4 (50ng/ml) and then stimulated with TNF-α (10ng/ml) for 24 hours. MMP-9 secretion was studied using gelatin zymography assay from concentrated culture supernatants. Laser-induced CNV in mice was produced by diode green laser (150 mW, 0.05 s, 75 µm) photocoagulation in both eyes of each mouse. One week after laser treatment, retinal sections from C57BL/6 wild-type mice and transgenic mice overexpressing BMP-4 in RPE were used to detect MMP-9 expression by immunostaining. MMP-9 expression was also determined by western blot and zymography with protein extracts from murine posterior eye cups.
Resting primary fetal RPE cells did not secrete MMP-9. Stimulation with TNF-α induced MMP-9 secretion, and pretreatment with BMP-4 reduced MMP-9 expression induced by TNF-α. Immunostaining and western blots showed less MMP-9 expression in CNV lesions in mice overexpressing BMP-4 compared with C57BL/6 wild-type mice.
BMP-4 inhibited MMP-9 expression induced by TNF-α in human fetal RPE cells in vitro. The increased MMP-9 expression in laser-induced CNV mouse model was also down-regulated in mice overexpressing BMP-4. BMP-4 might modulate CNV formation by regulating MMP-9 expression in the laser-induced CNV mouse model.
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