Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3

Linda Troeberg, Christopher Lazenbatt, Md Ferdous Anower-E-Khuda, Craig Freeman, Oleg Federov, Hiroko Habuchi, Osami Habuchi, Koji Kimata, Hideaki Nagase

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)


Tissue inhibitor of metalloproteinase 3 (TIMP-3) is an important regulator of extracellular matrix (ECM) turnover. TIMP-3 binds to sulfated ECM glycosaminoglycans or is endocytosed by cells via low-density lipoprotein receptor-related protein 1 (LRP-1). Here, we report that heparan sulfate (HS) and chondroitin sulfate E (CSE) selectively regulate postsecretory trafficking of TIMP-3 by inhibiting its binding to LRP-1. HS and CSE also increased TIMP-3 affinity for glycan-binding metalloproteinases, such as adamalysin-like metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), by reducing the dissociation rate constants. The sulfation pattern was crucial for these activities because monosulfated or truncated heparin had a reduced ability to bind to TIMP-3 and increase its affinity for ADAMTS-5. Therefore, sulfation of ECM glycans regulates the levels and inhibitory activity of TIMP-3 and modulates ECM turnover, and small mimicries of sulfated glycans may protect the tissue from the excess destruction seen in diseases such as osteoarthritis, cancer, and atherosclerosis.

Original languageEnglish
Pages (from-to)1300-1309
Number of pages10
JournalChemistry & Biology
Issue number10
Early online date28 Aug 2014
Publication statusPublished - 23 Oct 2014
Externally publishedYes


  • ADAM Proteins/chemistry
  • Animals
  • Cartilage, Articular/metabolism
  • Chondroitin Sulfates/chemistry
  • Endocytosis
  • Extracellular Matrix/metabolism
  • Heparan Sulfate Proteoglycans/metabolism
  • Heparitin Sulfate/chemistry
  • Humans
  • Kinetics
  • Low Density Lipoprotein Receptor-Related Protein-1/chemistry
  • Mice
  • Protein Binding
  • Tissue Inhibitor of Metalloproteinase-3/antagonists & inhibitors

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