Tissue inhibitor of metalloproteinase-3 differentially binds to components of Bruch's membrane

Dick, A. D.; Majid, Mohammed A.; Smith, Valerie A.; Matthews, Fiona; Newby, A. C.

Abstract

Background: Sorsby's fundus dystrophy (SFD) is caused by mutations in tissue inhibitor of metalloproteinase (TIMP)-3 and, with the exception of early onset, is similar to age-related macular degeneration. The pathological features of this condition relate to the accumulation of TIMP-3 in Bruch's membrane. Aims: To compare the extracellular membrane-binding characteristics of wild-type and four SFD-mutant TIMP-3s. Methods: COS-7 cells were transfected with wild-type, Ser-181, Gly-167, Ser-156 and Tyr-168 SFD-mutant TIMP-3 cDNA. The TIMP-3 proteins subsequently synthesised were harvested, analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis, semiquantified by EUSA and used in binding assays on the basis of the retention of the wild-type and SFD-mutant TIMP-3 proteins by components of Bruch's membrane. Results: SFD-mutant TIMP-3s could not be distinguished from wild-type TIMP-3 by the extents to which they aggregated or adhered to type-i collagen, type-IV collagen, fibronectin, laminin, elastin, chondroitin sulphates A, B and C, and heparin sulphate. Of these macromolecules, the wild-type and SFD-mutant TIMP-3s exhibited greatest affinity for elastin and laminin. Conclusion: The similarity in the physical and extracellular membrane-binding characteristics of wild-type and SFD-mutant TIMP-3s indicates that these properties are not responsible for the difference in timing of onset of SFD and age-related macular degeneration.

• Journal Article Type: Article
• Publication Date: Oct 1, 2006
• Journal: British Journal of Ophthalmology
• Print ISSN: 0007-1161
• Electronic ISSN: 1468-2079
• Publisher: BMJ Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 90
• Issue: 10
• Pages: 1310-1315
• DOI: https://doi.org/10.1136/bjo.2006.097246
• Keywords: tissue inhibitor, Bruch's membrane
• Public URL: https://uwe-repository.worktribe.com/output/1036315
• Publisher URL: http://dx.doi.org/10.1136/bjo.2006.097246