MATRIX METALLOPROTEINASES AND METALLOPROTEINASE INHIBITORS IN CHOROIDAL NEOVASCULAR MEMBRANES

PURPOSE. Matrix metalloproteinases (MMP) are a family of extracellular matrix degrading enzymes associated with the development of neovascul arization. To investigate the possible role of these enzymes in choroi dal neovascularization, the mRNA expression of MMPs and tissue inhibit ors of metalloproteinases (TIMPs) were analyzed in subfoveal fibrovasc ular membranes from patients with age-related macular degeneration (AM D). METHODS. Surgically removed subfoveal fibrovascular membranes from five eyes were analyzed for the expression of MMP and TIMP mRNA. In s itu hybridization antisense and sense riboprobes were generated using DNA complementary to human collagenase (MMP-1), 72 kDa gelatinase (MMP -2), stromelysin (MMP-3), 92-kDa gelatinase (MMP-3), TIMP-1, TIMP-2, a nd TIMP-3. Vascular endothelial cells were detected using immunostaini ng for von Willebrand factor. RESULTS. MMP-2 and MMP-9 mRNA were detec ted in all specimens. Most of the membranes also expressed TIMP-1 and TIMP-3 mRNA, and two of the membranes expressed TIMP-2 mRNA. MMP-2, TI MP-1, and TIMP-2 mRNA had a similar overall distribution that was rela tively uniform within the vascularized membrane stroma. MMP-2 expressi on appeared to be localized mainly to the vascular endothelial cells, whereas TIMP-1 and TIMP-3 were detected in other cell types such as fi broblastlike cells. MMP-9 expression was distinctly expressed by cells at the margins of the membranes and often in proximity to a thickened Bruch's membrane-like layer under the retinal pigment epithelial cell s. TIMP-3 mRNA was strongly expressed within the retinal pigment epith elial cell layer and also in the stroma of one membrane. None of the m embranes showed detectable MMP-1 or MMP-3 expression. CONCLUSIONS. The results support a role for MMPs in the development of choroidal neova scularization in AMD. The localization of MMP-2 and MMP-9 to the areas of new vessel formation and to the enveloping Bruch's-like membrane, respectively, suggests that MMP-2 and MMP-3 may be cooperatively invol ved in the progressive growth of choroidal neovascular membranes in AM D.