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V. E. Lorenc, P. F. Barcelona, S. G. Ortiz, G. G. Chiabrando, M. C. Sánchez; Insulin-Like Growth Factor 1 (IGF-1) Modulate Migratory Capacity of Glial Muller Cells Through the Activation of Metalloproteinase-2 (MMP-2). Invest. Ophthalmol. Vis. Sci. 2010;51(13):5760.
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IGF-1 has an active participation during the normal retinal vascular development of the retina as well as in the pathogenesis of retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Glial Müller cells (MC) are known to be involved in these diseases by producing Vascular Endothelial Growth Factor (VEGF) and secreting MMPs that participate in the extracellular proteolysis during neovascularization. However, at present, is not well elucidated the function of IGF-1 during this process. In this work we evaluate the effect of IGF-1 on the regulation of MMPs and on the migratory capacity of an immortalized human Müller cells line, MIO-M1.
The human MIO-M1 was cultured in presence of 10 nM IGF-1 for different times (4, 6 and 8 h). The effect of IGF-1 on MMPs activity was evaluated in MC supernatants by zymography. The expression level of MT1-MMP and MMP-2 was analyzed by Western blot (WB) analysis. Cell migration was evaluated on collagen or laminin-coated surface using time-lapse video microscopy. The IGF-1 induced signalling pathways were evaluated by WB.
By zymography we observed that IGF-1 increased pro-MMP-2 activity, whereas MMP-2 activity decreased with stimulus times. By WB we observed that, under IGF-1 stimulus, MMP-2 increased in MC extracts and decreased in MC supernatants. IGF-1 also produced an activation of the MAPK-ERK1/2 y PI3K/Akt pathway, indicating that these transduction events may be mediated by IGF-1 receptors. MT1-MMP protein was decreased in the IGF-1 stimulated cells. This MMPs regulation was also accompanied by an increase of cell motility on the collagen or laminin-coated surfaces.
The present study demonstrates that IGF-1 regulates the proteolytic activity of MMP-2 produced by MIO-M1 cells increasing their migratory capacity in a way that seems to be associated with IGF-1R expressed in these cells.
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