Fogarasi, Marton and Janssen, Andreas and Weber, Bernhard H. F. and Stoehr, Heidi (2008) Molecular dissection of TIMP3 mutation S156C associated with Sorsby fundus dystrophy. MATRIX BIOLOGY, 27 (5). pp. 381-392. ISSN 0945-053X,
Full text not available from this repository. (Request a copy)Abstract
Sorsby fundus dystrophy (SFD) is an autosomal dominant macular degeneration of late onset. A key feature of the disease is the thickening of Bruch's membrane, an ECM structure located between the RPE and the choroid. SFD is caused by mutations in the gene encoding the ECM-associated tissue inhibitor of metalloproteases-3 (TIMP3). We have recently generated two Timp3 gene-targeted mouse lines, one deficient for the murine gene (Timp3(-/-)) and one carrying an SFD-related S156C mutation. Based on extracts and cell cultures derived from tissues of these animals we now evaluated TIMP3 functionality and its contribution to SFD. We show that the activity levels of TIMP3 target proteases including TACE, ADAMTS4/5 and aggrecan-cleaving MMPs are similar in Timp3(S156/+) and Timp(3S156C/S156C) mice when compared to controls. In Timp3(-/-) mice, a significant enhancement of enzyme activity was observed for TACE but not for ADAMTS4/5 and MMPs indicating a compensatory effect of other inhibitors regulating the latter two groups of proteases. Fibrin bead assays show that angiogenesis in Timp(3S156/+) and Timp(3S156C/S156C) mice is not altered whereas increased formation of capillary tubes was observed in Timp3(-/-) animals over controls. Rescue experiments using recombinant proteins demonstrate that the inhibitory activities of TIMP3 towards TACE and aggrecan-cleaving MMPs as well as the anti-angiogenic properties of TIMP3 are not impaired by SFD mutation S156C. We finally demonstrate that wild-type and S156C-TIMP3 proteins block the binding of VEGF to its receptor VEGFR2 to a similar extent. Taken together, this study shows that S156C-TIMP3 retains its known functional properties suggesting that causes other than an imbalance in protease or angiogenic activities represent the primary molecular defect underlying SFD. (c) 2008 Elsevier B.V./International Society of Matrix Biology. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | COMPLEMENT FACTOR-H; PIGMENT EPITHELIAL-CELLS; UNUSUAL CLINICAL-FEATURES; TISSUE INHIBITOR; METALLOPROTEINASES-3 TIMP3; MACULAR DEGENERATION; EXTRACELLULAR-MATRIX; AGE; ANGIOGENESIS; EXPRESSION; Sorsby fundus dystrophy; tissue inhibitor of metalloproteases-3 (TIMP3); Timp3 gene-targeted mice; protease activity; angiogenesis |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Oct 2020 13:18 |
| Last Modified: | 29 Oct 2020 13:18 |
| URI: | https://pred.uni-regensburg.de/id/eprint/30831 |
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