title: Calcium pentosan polysulfate directly inhibits enzymatic activity of ADAMTS4 (aggrecanase-1) in osteoarthritic chondrocytes.
abstract: Aggrecanases that include ADAMTS1, 4, 5, 8, 9 and 15 are considered to play key roles in aggrecan degradation in osteoarthritic cartilage. Here we demonstrate that calcium pentosan polysulfate (CaPPS) directly inhibits the aggrecanase activity of ADAMTS4 without affecting the mRNA expression of the ADAMTS species in interleukin-1alpha-stimulated osteoarthritic chondrocytes. Synthetic peptides corresponding to specific regions of the thrombospondin type 1 repeat, cysteine-rich or spacer domain of ADAMTS4 inhibit the binding to immobilized CaPPS. These data suggest that CaPPS could function as chondroprotective agent for the treatment of osteoarthritis by inhibition of ADAMTS4 through interaction with the C-terminal ancillary domain.
authors.affiliation: Department of Pathology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takizawa
authors.forename: Taku
authors.initials: T
authors.lastname: Yatabe
authors.forename: Aiko
authors.initials: A
authors.lastname: Okada
authors.forename: Miyuki
authors.initials: M
authors.lastname: Chijiiwa
authors.forename: Satsuki
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Peter
authors.initials: P
authors.lastname: Ghosh
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000071121:ADAMTS4 Protein; D019902:Chondrocytes / Q000201:enzymology*; D019610:Cytoprotection; D006801:Humans; D053582:Interleukin-1alpha / Q000494:pharmacology; D010003:Osteoarthritis / Q000201:enzymology*; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D053582:Interleukin-1alpha; D010455:Peptides; D011480:Protease Inhibitors; D012333:RNA, Messenger; D010426:Pentosan Sulfuric Polyester; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human