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K. Han, J.-H. Chang, D. Azar; MT1-MMP Modulates the Expression of FGF Receptor and VEGF in Mouse Corneal Fibroblast Cell Lines. Invest. Ophthalmol. Vis. Sci. 2010;51(13):69.
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To evaluate the pro-angiogenic role of stromal fibroblast-derived MT1-MMP in mouse corneal fibroblasts.
Immortalized MT1-MMP knockout and knock-in corneal fibroblast cell lines were generated. Levels of ERK, phospho-ERK proteins and activated Ras were examined by western blot analysis in WT, MT1-MMP KO and MT1-MMP KI corneal fibroblast cells. Expression levels of the tyrosine kinase receptors FGFR-1 and -2, VEGFR-1 and EGFR were quantitated by real-time PCR. The VEGF protein expression level was determined by western blotting and immunohistochemistry in the corneal fibroblast cell lines. The VEGF mRNA expression levels were measured in the absence and presence of ERK and Ras inhibitors in bFGF-stimulated corneal fibroblast cell lines by real-time PCR.
VEGF expression and ERK activation were significantly diminished in bFGF stimulated MT1-MMP knockout mouse corneal fibroblasts when compared to that of wildtype fibroblasts. Diminished FGFR-1 and EGF receptor expression was demonstrated in MT1-MMP knockout cells (KO) cells. MT1-MMP- and bFGF-mediated VEGF expression is prevented by ERK and Ras inhibitors in WT corneal fibroblasts. The transcription factor HIF-1α, was activated by bFGF on MT1-MMP wildtype (WT) and MT-MMP knock-in (KI), but not in MT1-MMP knockout (KO) fibroblasts.
MT1-MMP modulates the activity of bFGF-induced signaling molecules ERK and Ras in corneal fibroblasts. Transcription factor HIF-1α may play a role in MT1-MMP- and bFGF-induced VEGF expression in corneal fibroblasts. In this study, we demonstrated that MT1-MMP potentiates bFGF-induced VEGF expression, likely by modulating the bFGF signal transduction pathway.
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