Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases

Linda Troeberg, Kazunari Fushimi, Rama Khokha, Hervé Emonard, Peter Ghosh, Hideaki Nagase

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)


Degradation of the cartilage proteoglycan aggrecan is a key early event in the development of osteoarthritis. Adamalysin with thrombospondin motifs (ADAMTS) -4 and ADAMTS-5 are considered to be the main enzymes responsible for aggrecan breakdown, making them attractive drugs targets. Here we show that calcium pentosan polysulfate (CaPPS), a chemically sulfated xylanopyranose from beechwood, is a multifaceted exosite inhibitor of the aggrecanases and protects cartilage against aggrecan degradation. CaPPS interacts with the noncatalytic spacer domain of ADAMTS-4 and the cysteine-rich domain of ADAMTS-5, blocking activity against their natural substrate aggrecan with inhibitory concentration 50 values of 10-40 nM but only weakly inhibiting hydrolysis of a nonglycosylated recombinant protein substrate. In addition, CaPPS increased cartilage levels of tissue inhibitor of metalloproteinases-3 (TIMP-3), an endogenous inhibitor of ADAMTS-4 and -5. This was due to the ability of CaPPS to block endocytosis of TIMP-3 mediated by low-density lipoprotein receptor-related protein. CaPPS also increased the affinity of TIMP-3 for ADAMTS-4 and -5 by more than 100-fold, improving the efficacy of TIMP-3 as an aggrecanase inhibitor. Studies with TIMP-3-null mouse cartilage indicated that CaPPS inhibition of aggrecan degradation is TIMP-3 dependent. These unique properties make CaPPS a prototypic disease-modifying agent for osteoarthritis.

Original languageEnglish
Pages (from-to)3515-3524
Number of pages10
JournalThe FASEB Journal
Issue number10
Early online date16 Jul 2008
Publication statusPublished - 1 Oct 2008


  • ADAM Proteins/antagonists & inhibitors
  • ADAMTS4 Protein
  • ADAMTS5 Protein
  • Aggrecans/metabolism
  • Animals
  • Antirheumatic Agents/chemistry
  • Cartilage/drug effects
  • Cells, Cultured
  • Culture Media, Conditioned
  • Endocytosis/drug effects
  • Endopeptidases/metabolism
  • Enzyme Inhibitors/chemistry
  • Fagus/chemistry
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Osteoarthritis/drug therapy
  • Pentosan Sulfuric Polyester/chemistry
  • Procollagen N-Endopeptidase/antagonists & inhibitors
  • Swine
  • Tissue Inhibitor of Metalloproteinase-3/genetics

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