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Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases
Author(s) -
Troeberg Linda,
Fushimi Kazunari,
Khokha Rama,
Emonard Hervé,
Ghosh Peter,
Nagase Hideaki
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-112680
Subject(s) - aggrecan , aggrecanase , adamts , chemistry , cartilage , thrombospondin , disintegrin , cartilage oligomeric matrix protein , proteoglycan , microbiology and biotechnology , biochemistry , osteoarthritis , matrix metalloproteinase , pharmacology , metalloproteinase , extracellular matrix , biology , articular cartilage , medicine , anatomy , alternative medicine , pathology
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 metallo‐proteinases‐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. FASEB J. 22, 3515–3524 (2008)