title: Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases.
abstract: 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.
authors.affiliation: Kennedy Institute of Rheumatology Division, Imperial College London, 65 Aspenlea Rd, Hammersmith, London, W6 8LH, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Troeberg
authors.forename: Kazunari
authors.initials: K
authors.lastname: Fushimi
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.forename: Hervé
authors.initials: H
authors.lastname: Emonard
authors.forename: Peter
authors.initials: P
authors.lastname: Ghosh
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D053674:Aggrecans / Q000378:metabolism*; D000818:Animals; D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology*; D002356:Cartilage / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004705:Endocytosis / Q000187:drug effects; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D029964:Fagus / Q000737:chemistry; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D010003:Osteoarthritis / Q000188:drug therapy / Q000201:enzymology; D010426:Pentosan Sulfuric Polyester / Q000737:chemistry / Q000494:pharmacology*; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013552:Swine; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism
chemical_list: D053674:Aggrecans; D018501:Antirheumatic Agents; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D019717:Tissue Inhibitor of Metalloproteinase-3; D010426:Pentosan Sulfuric Polyester; D010450:Endopeptidases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse; C083641:aggrecanase