GROWTH-FACTOR AND CYTOKINE MODULATION OF TRABECULAR MESHWORK MATRIX METALLOPROTEINASE AND TIMP EXPRESSION

Purpose. We hypothesize that regulated trabecular extracellular matrix (ECM) turnover, initiated by the matrix metalloproteinases, is critic al for the maintenance of normal aqueous humor outflow rates. However, very little is known about the regulation of trabecular ECM turnover. To identify candidate trabecular regulators, we evaluated the effects of several growth factors and cytokines on trabecular matrix metallop roteinase and TIMP expression. Methods. Porcine trabecular meshwork ce lls were treated with several doses of a variety of growth and cytokin es and culture media was analyzed after 24, 48 and 72 h. Zymograms wer e used to evaluate stromelysin, gelatinase A and B activity levels, wh ile immunoblots of Western transfers were used to evaluate stromelysin , collagenase, TIMP-1 and TIMP-2 protein levels. Results. A phorbol mi togen (TPA), TNF alpha and beta, interleukin-1 alpha and PDGF BE stimu late gelatinase B, stromelysin, interstitial collagenase and TIMP-1 ex pression, while having negligible effects on gelatinase A expression, TIMP-2 levels are reduced by TNF but not affected by the other treatme nts. Acidic and basic FGF, IL-1 beta, TGF beta and PDGF AB produce sim ilar but smaller effects, while HGF, VEGF, EGF, KGF and LIF produce sm all to moderate elevations in stromelysin with minimal other responses . PDGF AA, gamma INF oncostatin-M and endothelin-1 produce negligible changes in these proteinases and inhibitors. Conclusions. In addition to providing potential ways to modulate trabecular metalloproteinase a nd TIMP levels, the responsiveness of these cells to some of these gro wth factors and cytokines suggests possible roles in normal or pathoge nic trabecular cell regulation and some may affect aqueous humor outfl ow.