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This Article Full Text Full Text (PDF) All Versions of this Article: fj.08-112680v1 22/10/3515    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Troeberg, L. Articles by Nagase, H. PubMed PubMed Citation Articles by Troeberg, L. Articles by Nagase, H.

Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases

Linda Troeberg^*, Kazunari Fushimi^*, Rama Khokha, Hervé Emonard, Peter Ghosh and Hideaki Nagase^*,1

^* Kennedy Institute of Rheumatology Division, Imperial College London, London, UK;

Ontario Cancer Research, University of Toronto, Toronto, Ontario, Canada;

University of Reims Champagne-Ardenne, Faculty of Medicine, Reims, France; and

Institute of Nutraceutical Research, Sydney, Australia

¹Correspondence: Kennedy Institute of Rheumatology Division, Imperial College London, 65 Aspenlea Rd, Hammersmith, London, W6 8LH, UK. E-mail: h.nagase{at}imperial.ac.uk

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.—Troeberg, L., Fushimi, K., Khokha, R., Emonard, H., Ghosh, P., Nagase, H. Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases.

Key Words: ADAMTS • LRP • osteoarthritis • cartilage destruction • proteoglycan