title: Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 in the retinal pigment epithelium and interphotoreceptor matrix: vectorial secretion and regulation.
abstract: Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play an essential role in both normal and pathological extracellular matrix degradation, and a TIMP has been associated with at least one type of retinal degeneration. We have studied expression of MMP-2 and TIMP-1 by zymography, immunocytochemistry, and immunoblotting in the retinal pigment epithelium (RPE) from normal, aged and diseased retinas. MMPs and TIMPs were found in the rat RPE, interphotoreceptor matrix (IPM), and in media conditioned by human and rat RPE in culture. In other polarized cells. MMPs and TIMP-2 are secreted vectorially towards the basal lamina. In the RPE, however, MMP-2 and TIMP-1 were secreted preferentially from the apical surface, the surface bordering the IPM. These findings provide new evidence that MMPs and TIMPs could play a role in the turnover of IPM components. Cell homogenates and conditioned media from RPE isolated from mutant Royal College of Surgeons (RCS) rats with inherited retinal dystrophy had similar amounts of MMP-2 and TIMP-1 as those from congenic control rats. The secretion of MMP-2 and TIMP-1 from RPE cell cultures isolated from young and aged human donors varied widely. However, with increasing cell passage number, secretion of MMPs and TIMPs from human RPE increased dramatically. Also, growing human RPE on bovine corneal endothelial cell-generated extracellular matrix instead of plastic reduced the secretion of both MMPs and TIMPs. These data suggest that the integrity of Bruch's membrane may serve to regulate RPE functions in MMP and TIMP secretion and that extracellular matrices contain signals that regulate MMP and TIMP synthesis and/or secretion by the RPE.
authors.affiliation: Department of Anatomy, University of California, San Francisco 94143-0730, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Padgett
authors.forename: G M
authors.initials: GM
authors.lastname: Lui
authors.forename: Z
authors.initials: Z
authors.lastname: Werb
authors.forename: M M
authors.initials: MM
authors.lastname: LaVail
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002675:Child, Preschool; D004591:Electrophoresis, Polyacrylamide Gel; D018093:Gelatinases / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000378:metabolism*; D010857:Pigment Epithelium of Eye / Q000201:enzymology / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000201:enzymology*; D019714:Tissue Inhibitor of Metalloproteinases
chemical_list: D006023:Glycoproteins; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2