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J.A. Rakic, V. Lambert, B. Wielockx, C. Munaut, Z. Werb, A. Baker, A. Noel, J. Foidart; Severe Inhibition of Choroidal Neovascularization in Mice With a Combined Deficiency of MMP-2 and MMP-9 Genes . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3938.
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Purpose: To evaluate the relative contribution of matrix metalloproteinases (MMPs) 2, 9 and MT1-MMP to choroidal neovascularization (CNV) such as occurring during the exudative form of age-related macular degeneration (AMD). Methods: The expression profile of different MMPs was evaluated in human and experimental choroidal neovascularization by RT-PCR. The activity of MMP-2 and MMP-9 was studied by gelatin and in situ zymography. The influence of endogenous MMP-9 and MMP-2 was explored in single (MMP-9 KO, MMP-2 KO) or double gene (MMP-2,9 KO) deficient mice with a model of laser-induced CNV. To investigate the therapeutical potential of endogenous or pharmacological MMP inhibition, the observations were extended to wild-type (WT) mice treated with adenovirus-mediated TIMP-1 or TIMP-2 transfer, with a broad spectrum (BB-94) or a selective synthetic MMP-inhibitor. Results: Both MMP-2 and MMP-9 were increasingly processed during the early stages of CNV formation, with the appearance of active forms of MMP-2 resulting from MT1-MMP overexpression. The incidence and the severity of CNV were strongly decreased in double deficient compared to single gene deficient mice or corresponding WT strains. In these MMP2,9 deficient mice, the reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Treatment of WT mice with overexpression of endogenous inhibitor TIMP-2 (delivered by adenoviral vectors) or with daily injection of a synthetic selective MMP inhibitor significantly decreased the magnitude of the pathological reaction. Conclusions: These findings suggest that MMP-2 and MMP-9 cooperate in the development of the disease and that their selective inhibition might represent an alternative strategy for the treatment of choroidal neovascularization.
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