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 ORCID: https://orcid.org/0000-0003-0939-4651 (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
Related URLs:	https://ora.ox.ac.uk/objects/uuid:5101fa...
Depositing User:	LivePure Connector
Date Deposited:	04 Jan 2019 12:30
Last Modified:	21 Oct 2022 21:32
URI:	https://ueaeprints.uea.ac.uk/id/eprint/69437
DOI:	10.1124/mol.117.109397

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