title: Latanoprost induces matrix metalloproteinase-1 expression in human nonpigmented ciliary epithelial cells through a cyclooxygenase-2-dependent mechanism.
abstract: Prostaglandins (PGs) have been implicated in the regulation of intraocular pressure (IOP) by facilitating the remodeling of tissues involved in aqueous humor outflow. A contribution of cyclooxygenase-2 (COX-2)-dependent PGs to this process was emphasized by a recent study showing an impaired COX-2 expression in the nonpigmented ciliary epithelium (NPE) of patients with primary open-angle glaucoma. With the use of human NPE cells (ODM-2), the present study therefore investigated the effect of the antiglaucomatous drug latanoprost (PGF2alpha analog) on the expression of COX-2 and its association with the induction of matrix metalloproteinases (MMPs). In NPE cells, latanoprost led to a concentration- and time-dependent increase of COX-2 mRNA levels. Up-regulation of COX-2 expression was accompanied by phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK and was abrogated by specific inhibitors of both pathways. PGE2 formation by latanoprost was abolished by the selective COX-2 inhibitor NS-398 and by the F-prostaglandin receptor antagonist AL-8810. Moreover, latanoprost led to a delayed up-regulation of MMP-1 mRNA, whereas the expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 remained unchanged. Latanoprost-induced MMP-1 mRNA and protein expression was abolished by NS-398 and by COX-2-silencing small-interfering RNA. In line with this finding, MMP-1 expression was also induced by PGE2, a major COX-2 product. As a whole, our results show that MMP-1 expression by latanoprost requires prior up-regulation of COX-2. Induction of COX-2- and subsequent MMP-1 expression in the NPE may represent a potential mechanism underlying the IOP-lowering and antiglaucomatous action of latanoprost.
authors.affiliation: Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany. hinz@pharmakologie.uni-erlangen.de
authors.forename: Burkhard
authors.initials: B
authors.lastname: Hinz
authors.forename: Susanne
authors.initials: S
authors.lastname: Rösch
authors.forename: Robert
authors.initials: R
authors.lastname: Ramer
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Tamm
authors.forename: Kay
authors.initials: K
authors.lastname: Brune
mesh_terms: D001082:Aqueous Humor / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002461:Cell Line, Transformed; D002924:Ciliary Body / Q000166:cytology*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007429:Intraocular Pressure; D000077338:Latanoprost; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D014162:Transfection
chemical_list: D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011461:Prostaglandins F, Synthetic; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D000077338:Latanoprost; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone