TY - JOUR T1 - Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3). JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.109397 SP - mol.117.109397 AU - Anastasios Chanalaris AU - Christine Doherty AU - Brian D Marsden AU - Gabriel Bambridge AU - Stephen P Wren AU - Hideaki Nagase AU - Linda Troeberg Y1 - 2017/01/01 UR - http://molpharm.aspetjournals.org/content/early/2017/08/10/mol.117.109397.abstract N2 - 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. ER -