title: Selective inhibition of ADAMTS-1, -4 and -5 by catechin gallate esters.
abstract: Three mammalian ADAMTS enzymes, ADAMTS-1, -4 and -5, are known to cleave aggrecan at certain glutamyl bonds and are considered to be largely responsible for cartilage aggrecan catabolism observed during the development of arthritis. We have previously reported that certain catechins, polyphenolic compounds found in highest concentration in green tea (Camellia sinensis), are capable of inhibiting cartilage aggrecan breakdown in an in vitro model of cartilage degradation. We have now cloned and expressed recombinant human ADAMTS-1, -4 and -5 and report here that the catechin gallate esters found in green tea potently inhibit the aggrecan-degrading activity of these enzymes, with submicromolar IC50 values. Moreover, the concentration needed for total inhibition of these members of the ADAMTS group is approximately two orders of magnitude lower than that which is needed to partially inhibit collagenase or ADAM-10 activity. Catechin gallate esters therefore provide selective inhibition of certain members of the ADAMTS group of enzymes and could constitute an important nutritional aid in the prevention of arthritis as well as being part of an effective therapy in the treatment of joint disease and other pathologies involving the action of these enzymes.
authors.affiliation: Division of Genomic Medicine, University of Sheffield Medical School, Sheffield Children's Hospital, Stephenson Wing, D-Floor, UK.
authors.forename: Mireille N
authors.initials: MN
authors.lastname: Vankemmelbeke
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Jones
authors.forename: Cyprianne
authors.initials: C
authors.lastname: Fowles
authors.forename: Mirna Z
authors.initials: MZ
authors.lastname: Ilic
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Handley
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Day
authors.forename: C Graham
authors.initials: CG
authors.lastname: Knight
authors.forename: John S
authors.initials: JS
authors.lastname: Mort
authors.forename: David J
authors.initials: DJ
authors.lastname: Buttle
mesh_terms: D051722:ADAM Proteins; D000072197:ADAM10 Protein; D000071097:ADAMTS1 Protein; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D015153:Blotting, Western; D002392:Catechin / Q000031:analogs & derivatives* / Q000378:metabolism*; D002417:Cattle; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019483:Disintegrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004952:Esters / Q000378:metabolism*; D005822:Genetic Vectors; D006801:Humans; D020128:Inhibitory Concentration 50; D007313:Insecta; D008565:Membrane Proteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D011348:Procollagen N-Endopeptidase; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D013662:Tea
chemical_list: D017077:Culture Media, Conditioned; D019483:Disintegrins; D004791:Enzyme Inhibitors; D004952:Esters; D008565:Membrane Proteins; D011994:Recombinant Proteins; D013662:Tea; C417939:catechin gallate; D002392:Catechin; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; C103778:ADAM 10 protein, Bos taurus; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000071121:ADAMTS4 Protein; C083641:aggrecanase