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Retinal Pigment Epithelium Protection from Oxidant-Mediated Loss of MMP-2 Activation Requires Both MMP-14 and TIMP-2

¹From the Vascular Biology Institute, Department of Medicine, Miller School of Medicine University of Miami, Miami, Florida; the ²Laboratory of Cell and Cancer Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and the ³Duke Center for Macular Degeneration, Duke University Eye Center, Durham, North Carolina.

PURPOSE. Eyes with age-related macular degeneration (AMD) demonstrate accumulation of specific deposits and extracellular matrix (ECM) molecules under the retinal pigment epithelium (RPE). Metalloproteinases (MMP) are crucial regulators of basement membrane and ECM turnover. Accordingly, loss of RPE MMP activity most likely leads to excessive accumulation of collagen and other ECM, a potential mechanism for formation of deposits. A prior study showed that MMP-2 activity, but not pro-MMP-2 protein, decreases after RPE oxidative injury, indicating that oxidant injury disrupts the enzymatic cleavage of pro-MMP-2. Activation of MMP-2 requires the formation of a tri-molecular complex of pro-MMP-2, MMP-14, and tissue inhibitor of metalloproteinases (TIMP)-2. Therefore, a study was conducted to investigate the impact of oxidant injury on the interaction between these three molecules.

METHODS. Human GFP-RPE cells were oxidant injured by transient exposure to H₂O₂ and myeloperoxidase, and the time course of recovery determined. Supernatants and cell lysates were collected for analysis of MMP-2, MMP-14, and TIMP-2 activity, mRNA and protein expression. In some studies, overexpression with either MMP-14 or TIMP-2 was performed to revert the cells to a preinjury phenotype.

RESULTS. Transient injury resulted in a decrease of both MMP-14 and TIMP-2 activity and protein. Overexpression of each single molecule failed to prevent the injury-induced decrease of MMP-2 activity. In contrast, overexpression of MMP-14 together with the addition of exogenous TIMP-2 prevented the reduction of MMP-2 activation.

CONCLUSIONS. Loss of MMP-2 activity after oxidant injury is caused by the downregulation of MMP-14 and TIMP-2. Overexpression of either MMP-14 or TIMP-2 alone before oxidant injury is not enough to prevent loss of MMP-2 activity. All three components of the tri-molecular complex must be present to preserve normal MMP-2 activity after oxidant injury.

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				O. Alcazar, S. W. Cousins, and M. E. Marin-Castano MMP-14 and TIMP-2 Overexpression Protects against Hydroquinone-Induced Oxidant Injury in RPE: Implications for Extracellular Matrix Turnover Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5662 - 5670. [Abstract] [Full Text] [PDF]