Effects of Antiglaucoma Drops on MMP and TIMP Balance in Conjunctival and Subconjunctival Tissue

Abstract

To study the effects of antiglaucoma drugs on metabolism within the extracellular matrix (ECM) of the ocular surface, including corneal, conjunctival, and subconjunctival tissue. Several antiglaucoma drugs--including beta-blockers, alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative-were topically administrated to rat eyes daily for 2 weeks or were incubated with human corneal cells or human fibroblasts for 72 hours. Thereafter, expression and enzymatic activity of the matrix metalloproteinases (MMPs), a group of enzymes proteolyzing ECM and their inhibitors, called tissue inhibitors of metalloproteinase (TIMPs), were evaluated. Quantitative RT-PCR revealed significantly upregulated and downregulated expression of MMPs and TIMPs, respectively, in rat conjunctival and subconjunctival tissue on the administration of alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative, suggesting that these drugs may enhance ECM degradation. However, in contrast, beta-blocker administration caused reverse effects--that is, upregulation and downregulation of TIMPs and MMPs, respectively. Enzymatic activity of MMPs in rat conjunctival and subconjunctival tissue analyzed by biochemical assay and zymography was markedly enhanced on the administration of alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative, but not of beta-blockers. Similar effects of these antiglaucoma drugs were observed in cultured human corneal cells and human fibroblast cells. The present experimental observations suggest that some alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative stimulate ECM degradation of ocular surface tissue by modulating the balance between MMPs and TIMPs.