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 1 Correspondence: Kennedy Institute of Rheumatology Division, Imperial College London, 65 Aspenlea Rd, Hammersmith, London, W6 8LH, UK. E-mail: h.nagase@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
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Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases
Troeberg, Linda; Fushimi, Kazunari; Khokha, Rama; Emonard, Hervé; Ghosh, Peter; Nagase, Hideaki
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, Volume 22 (10): 3515
Fed of American Socs for Experimental Biology – Oct 1, 2008
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