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

Anastasios Chanalaris, Christine Doherty, Brian D Marsden, Gabriel Bambridge, Stephen P Wren, Hideaki Nagase, Linda Troeberg

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
8 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)459-468
Number of pages10
JournalMolecular Pharmacology
Volume92
Issue number4
Early online date5 Sep 2017
DOIs
Publication statusPublished - 1 Oct 2017
Externally publishedYes

Keywords

  • Animals
  • Cartilage/drug effects
  • Cell Line, Tumor
  • Chondrocytes/drug effects
  • Dose-Response Relationship, Drug
  • Extracellular Space/drug effects
  • HEK293 Cells
  • Humans
  • Organ Culture Techniques
  • Osteoarthritis/drug therapy
  • Protein Binding/physiology
  • Suramin/pharmacology
  • Swine
  • Tissue Inhibitor of Metalloproteinase-3/metabolism

Cite this