Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage.
Osteoarthritis is a degenerative joint disorder characterized by breakdown of articular cartilage. Degradation of aggrecan, which together with type II collagen provides cartilage with its unique characteristics of compressibility and elasticity, is an early and sustained feature of osteoarthritis. The present work was set up to identify the enzyme(s) responsible for aggrecan breakdown in osteoarthritis. We found that the two cartilage aggrecanases, ADAM-TS4 and ADAM-TS5, are present in osteoarthritic cartilage and that they are responsible for aggrecan degradation without the participation of matrix metalloproteinases. This is based on 1) neoepitopes found on aggrecan fragments in osteoarthritis (OA) cartilage explants in vitro, 2) aggrecan fragments detected in synovial fluid of OA patients, 3) the observation that an aggrecanase inhibitor, BB-16, blocked aggrecan degradation in OA cartilage in vitro, whereas the matrix metalloproteinase inhibitor XS309 did not, and 4) the presence of mRNA and protein for ADAM-TS4 and ADAM-TS5 in OA cartilage. These results suggest that ADAM-TS4 and ADAM-TS5 represent a potential target for the treatment of osteoarthritis.
Malfait
Anne-Marie
AM
Imperial College School of Medicine, London W6 8LH, United Kingdom. anne-marie.malfait@pharmacia.com
Liu
Rui-Qin
RQ
Ijiri
Kosei
K
Komiya
Setsuro
S
Tortorella
Micky D
MD
D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D053674:Aggrecans; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002356:Cartilage / Q000201:enzymology* / Q000378:metabolism; D002417:Cattle; D002586:Cesium / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000939:Epitopes; D016326:Extracellular Matrix Proteins; D006801:Humans; D007700:Kinetics; D037181:Lectins, C-Type; D008666:Metalloendopeptidases / Q000737:chemistry*; D008969:Molecular Sequence Data; D010003:Osteoarthritis / Q000628:therapy; D011348:Procollagen N-Endopeptidase; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013582:Synovial Fluid / Q000378:metabolism; D013997:Time Factors
D053674:Aggrecans; D002712:Chlorides; D004791:Enzyme Inhibitors; D000939:Epitopes; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D011509:Proteoglycans; D012333:RNA, Messenger; D002586:Cesium; D010450:Endopeptidases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C083641:aggrecanase; C028019:cesium chloride