Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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 publication

DOI

10.1096/fj.08-112680

Type

Journal article

Journal

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Publication Date

10/2008

Volume

22

Pages

3515 - 3524

Addresses

Kennedy Institute of Rheumatology Division, Imperial College London, 65 Aspenlea Rd, Hammersmith, London, W6 8LH, UK.

Keywords

Cartilage, Cells, Cultured, Animals, Swine, Humans, Mice, Mice, Mutant Strains, Fagus, Osteoarthritis, Endopeptidases, Procollagen N-Endopeptidase, Pentosan Sulfuric Polyester, Tissue Inhibitor of Metalloproteinase-3, Antirheumatic Agents, Enzyme Inhibitors, Culture Media, Conditioned, Endocytosis, ADAM Proteins, Aggrecans, ADAMTS4 Protein, ADAMTS5 Protein