Tissue inhibitor of metalloproteinase 4 in aqueous humor of patients with primary open angle glaucoma, pseudoexfoliation syndrome and pseudoexfoliative glaucoma and its role in proteolysis imbalance

Background: To quantify the levels of tissue inhibitor of metalloproteinase 4 (TIMP4) and its ratios with free metalloproteinases (MMP) in the aqueous humor of patients with primary open angle glaucoma (POAG), pseudoexfoliation syndrome (PXS) and pseudoexfoliative glaucoma (PXG) and to evaluate a possible imbalance between MMPs and TIMPs in these samples. Methods: Free MMP2, MMP3, MMP9, TIMP1, TIMP2, TIMP4 concentrations and active levels of MMP2 and MMP3 were determined with immunoassay ELISA and activity assay kits in 168 aqueous samples. Results: TIMP4 was elevated in glaucoma patients(POAG: 0.95 +/- 0.49 PXG: 1.28 +/- 1.38 pg/ml. p < 0.001). POAG, PXS and PXG samples demonstrated higher MMP2, TIMP1 and TIMP2 concentrations (p < 0.001). Samples from the PXS and PXG groups had a lower total/active MMP2 ratio (p < 0.004 and p < 0.008 respectively). Stoichiometric analysis showed an overbalance of TIMPsover MMPs in both POAG & PXG groups, especially of TIMP4. Conclusion: TIMP4 elevation is a novel finding in glaucomatous eyes. A disregulation of extracellular matrix homeostasis is suggested in POAG, PXS and PXG.