Expression of Sorsby's fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis.
Sorsby's fundus dystrophy (SFD) is an autosomal dominant degenerative disease of the macula caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP-3) gene. Choroidal neovascularization is a hallmark of this disease, which closely resembles the exudative form of age-related macular degeneration. However, the mechanism by which TIMP-3 mutations induce the disease phenotype in SFD remains unknown. To address this question we established human retinal pigment epithelial cell lines expressing wild type or S156C (Ser(156) changed to cysteine) mutant TIMP-3. S156C TIMP-3 had reduced matrix metalloproteinase (MMP) inhibitory activity in retinal pigment epithelial cells and resulted in increased secretion and activation of gelatinase A and B. The conditioned medium from these cells induced angiogenesis in "in vivo" chick chorioallantoic membrane assays that could be reversed with recombinant wild type TIMP-3. Our data indicate that the choroidal neovascularization in SFD may be a result of increased MMP activity, which could lead to the stimulation of angiogenesis. These results also suggest the potential therapeutic use of TIMP-3 or synthetic MMP inhibitors in this disease.
Qi
Jian Hua
JH
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Ebrahem
Quteba
Q
Yeow
Karen
K
Edwards
Dylan R
DR
Fox
Paul L
PL
Anand-Apte
Bela
B
D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D002642:Chick Embryo; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry; D004338:Drug Combinations; D004847:Epithelial Cells / Q000378:metabolism*; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D007797:Laminin / Q000494:pharmacology; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009154:Mutation; D018919:Neovascularization, Physiologic; D010641:Phenotype; D010857:Pigment Epithelium of Eye / Q000166:cytology* / Q000378:metabolism; D011509:Proteoglycans / Q000494:pharmacology; D012160:Retina / Q000166:cytology*; D012694:Serine / Q000737:chemistry; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D004338:Drug Combinations; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D011509:Proteoglycans; D019717:Tissue Inhibitor of Metalloproteinase-3; C059485:matrigel; D012694:Serine; D003094:Collagen; D003545:Cysteine