MMP-2 and MMP-9 synergize in promoting choroidal neovascularization.
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.
Lambert
Vincent
V
Laboratory of Tumor and Development Biology, University of Liège, Belgium.
Wielockx
Ben
B
Munaut
Carine
C
Galopin
Catherine
C
Jost
Maud
M
Itoh
Takeshi
T
Werb
Zena
Z
Baker
Andrew
A
Libert
Claude
C
Krell
Hans-Willi
HW
Foidart
Jean-Michel
JM
Noël
Agnès
A
Rakic
Jean-Marie
JM
D000818:Animals; D002829:Choroid / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology; D020256:Choroidal Neovascularization / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D005786:Gene Expression Regulation; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011480:Protease Inhibitors / Q000494:pharmacology
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D005337:Fibrin; D005340:Fibrinogen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9