Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3

Chanalaris, Anastasios, Doherty, Christine, Marsden, Brian D, Bambridge, Gabriel, Wren, Stephen P, Nagase, Hideaki and Troeberg, Linda (2017) Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3. Molecular Pharmacology, 92 (4). pp. 459-468. ISSN 0026-895X

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    Abstract

    Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases (TIMP)-3, through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1). We discovered that suramin (C51H40N6O23S6) bound to TIMP-3 with a KD value of 1.9 ± 0.2 nM and inhibited its endocytosis via LRP1, thus increasing extracellular levels of TIMP-3 and inhibiting cartilage degradation by the TIMP-3 target enzyme, adamalysin-like metalloproteinase with thrombospondin motifs 5. NF279 (8,8'-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt), a structural analog of suramin, has an increased affinity for TIMP-3 and increased ability to inhibit TIMP-3 endocytosis and protect cartilage. Suramin is thus a promising scaffold for the development of novel therapeutics to increase TIMP-3 levels and inhibit cartilage degradation in osteoarthritis.

    Item Type: Article
    Additional Information: Copyright © 2017 by The Author(s).
    Uncontrolled Keywords: animals,drug effects,cell line, tumor,drug effects,dose-response relationship, drug,drug effects,hek293 cells,humans,organ culture techniques,drug therapy,physiology,pharmacology,swine,metabolism
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    Depositing User: LivePure Connector
    Date Deposited: 04 Jan 2019 12:30
    Last Modified: 08 Jan 2019 17:30
    URI: https://ueaeprints.uea.ac.uk/id/eprint/69437
    DOI: 10.1124/mol.117.109397

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