Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases

Troeberg, Linda, Fushimi, Kazunari, Khokha, Rama, Emonard, Hervé, Ghosh, Peter and Nagase, Hideaki (2008) Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. The FASEB Journal, 22 (10). pp. 3515-3524. ISSN 0892-6638

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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.

Item Type: Article
Uncontrolled Keywords: antagonists & inhibitors,adamts4 protein,adamts5 protein,metabolism,animals,chemistry,drug effects,cells, cultured,culture media, conditioned,drug effects,metabolism,chemistry,chemistry,humans,mice,mice, mutant strains,drug therapy,chemistry,antagonists & inhibitors,swine,genetics
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 09 Jan 2019 12:30
Last Modified: 22 Apr 2020 07:22
URI: https://ueaeprints.uea.ac.uk/id/eprint/69506
DOI: 10.1096/fj.08-112680

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