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J.-X. Ma, K. Park, K. Lee, T. Zhou, B. Zhang; Blocking Wnt Signaling, a Unifying Mechanism for the Anti-Angiogenic, Anti-Inflammatory and Anti-Fibrogenic Effect Of Pedf. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5094.
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We have recently shown that Wnt signaling plays a key pathogenic role in diabetic retinopathy and AMD. Pigment epithelium-derived factor (PEDF) has displayed anti-angiogenic, anti-inflammatory and anti-fibrogenic activities. The purpose of this study is to identify a unifying mechanism responsible for the broad beneficial effects of PEDF.
PEDF transgenic (PEDF-Tg) mice were generated using a human PEDF cDNA under the control of the beta-actin promoter. The oxygen-induce retinopathy (OIR) and VLDLR-/- mice are used as retinal neovascularization (NV) models. The Wnt pathway activation was evaluated by Western blot analysis of beta-catenin and phosphorylated LRP6, and TOPFLASH promoter activity assay. Binding of PEDF to LRP6 was determined by ligand-receptor binding assay and co-precipitation analysis.
Intravitreal injection of PEDF protein suppressed Wnt signaling in the retinas of the OIR and VLDLR-/- models. Over-expression of PEDF in PEDF-Tg mice attenuated the Wnt pathway activation in the OIR model, while PEDF-/- mice with OIR showed exacerbated activation of the Wnt pathway, compared to the Wt mice with OIR. Silencing PEDF by siRNA alone resulted in activation of Wnt signaling. PEDF bound to LRP6, a Wnt co-receptor, with a high affinity and blocked the Wnt signaling induced by a Wnt ligand. Co-precipitation assay showed that PEDF specifically bound to LRP6 at the E1E2 domain. Binding of PEDF to LRP6 blocked the LRP6 and the frizzled receptor dimerization induced by a Wnt ligand.
PEDF is a potent inhibitor of the Wnt pathway. As the Wnt pathway regulates angiogenesis, inflammation and fibrosis, blocking Wnt signaling represents a unifying mechanism for the broad activities of PEDF. Decreased ocular levels of PEDF are responsible, at least in part, for the Wnt signaling activation in diabetic retinopathy and AMD.
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