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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 J

Publication Date

10/2008

Volume

22

Pages

3515 - 3524

Keywords

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