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MMP-2 and MMP-9 synergize in promoting choroidal neovascularization
Vincent Lambert1, Ben Wielockx, Carine Munaut
1Laboratory of Tumor and Development Biology, University of Liège, Belgium.
Abstract:
Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but their precise role and potential interactions remain unclear. To address the question of MMP-2 and MMP-9 functions, mice deficient in the expression of MMP-2 (MMP-2 KO), MMP-9 (MMP-9 KO), and both MMP-2 and MMP-9 (MMP-2,9 KO) with their corresponding wild-type mice (WT) underwent CNV induction by laser-induced rupture of the Bruch's membrane. Both the incidence and the severity of CNV were strongly attenuated in double deficient compared with single gene deficient mice or corresponding WT controls. The reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Furthermore, overexpression of the endogenous MMP inhibitors TIMP-1 or TIMP-2 (delivered by adenoviral vectors) in WT mice or daily injection of a synthetic and gelatinase selective MMP inhibitor (Ro 26-2853) significantly decreased the pathological reaction. These findings suggest that MMP-2 and MMP-9 may cooperate in the development of AMD and that their selective inhibition represents an alternative strategy for the treatment of choroidal neovascularization.
Insights
Matrix metalloproteinase 2 (MMP-2) and MMP-9 play a cooperative role in choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). Inhibiting these enzymes significantly reduces pathological neovascularization, suggesting a therapeutic target.
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Matrix metalloproteinase 2 (MMP-2) and MMP-9 are elevated in choroidal neovascularization (CNV), a key feature of exudative age-related macular degeneration (AMD).
- The specific roles and interactions of MMP-2 and MMP-9 in AMD pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the functional roles and potential cooperation of MMP-2 and MMP-9 in the development of CNV.
- To evaluate the therapeutic potential of inhibiting MMP-2 and MMP-9 in a mouse model of CNV.
Main Methods:
- Generation and characterization of mice deficient in MMP-2, MMP-9, or both (MMP-2,9 KO) alongside wild-type (WT) controls.
- Induction of CNV via laser-induced rupture of the Bruch's membrane in these mouse models.
- Assessment of CNV incidence and severity, along with fibrinogen/fibrin accumulation.
- Pharmacological inhibition of MMPs using TIMP-1, TIMP-2, or a selective MMP inhibitor (Ro 26-2853) in WT mice.
Main Results:
- Mice deficient in both MMP-2 and MMP-9 (MMP-2,9 KO) exhibited significantly attenuated CNV incidence and severity compared to single-deficient or WT mice.
- Reduced neovascularization in double-deficient mice was associated with increased fibrinogen/fibrin accumulation.
- Overexpression of TIMP-1 or TIMP-2, and administration of the MMP inhibitor Ro 26-2853, markedly decreased the pathological CNV response in WT mice.
Conclusions:
- MMP-2 and MMP-9 appear to cooperate in promoting choroidal neovascularization during AMD.
- Selective inhibition of MMP-2 and MMP-9 presents a promising therapeutic strategy for treating CNV in AMD.