Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases.

Journal article

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.

Authors: Troeberg, L; Fushimi, K; Khokha, R; Emonard, H; Ghosh, P

• Publication status: Published
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• Volume: 22
• Issue: 10
• Pages: 3515-3524
• Publication date: 2008-10-01
• DOI: 10.1096/fj.08-112680
• EISSN: 1530-6860
• ISSN: 0892-6638
• Language: English
• Keywords: Animals; Mice, Mutant Strains; Aggrecans; Mice; Culture Media, Conditioned; ADAM Proteins; Swine; Fagus; Enzyme Inhibitors; Tissue Inhibitor of Metalloproteinase-3; Endocytosis; Cells, Cultured; Endopeptidases; Procollagen N-Endopeptidase; Antirheumatic Agents; Pentosan Sulfuric Polyester; Cartilage; Humans; Osteoarthritis