Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3)

Journal article

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 3 (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 with thrombospondin motifs 5 (ADAMTS-5). NF279, a structural analogue of suramin, has 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.

Authors: Chanalaris, A; Doherty, C; Marsden, B; Bambridge, G; Wren, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Pharmacology and Experimental Therapeutics
• Journal: Molecular Pharmacology
• Volume: 92
• Issue: 4
• Pages: 459-468
• Publication date: 2017-09-05
• Acceptance date: 2017-08-01
• DOI: 10.1124/mol.117.109397
• EISSN: 1521-0111
• ISSN: 0026-895X
• Keywords: tissue engineering; matrix metalloproteinases (MMPs)