ADAMTS-8 exhibits aggrecanase activity and is expressed in human articular cartilage.
Members of the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family share common structural features including a disintegrin domain, a zinc metalloprotease domain, and at least one thrombospondin motif. Aberrant expression of several of these proteins has led to an understanding of their role in human disease; however, a link to function for many has not yet been made. One such uncharacterized family member, ADAMTS-8, shares significant protein sequence homology with a subgroup of ADAMTSs that includes ADAMTS-1, ADAMTS-4, ADAMTS-5, and ADAMTS-15. Each of these proteases has been shown to cleave 'aggrecanase-susceptible' site(s) within the extracellular matrix (ECM) proteoglycan aggrecan, and ADAMTS-4 and ADAMTS-5 have been postulated to play a role in the depletion of articular cartilage in osteoarthritic disease. Based on sequence relationships, in the present study we examined the ability of ADAMTS-8 to exhibit 'aggrecanase' activity. A neoepitope monoclonal antibody (MAb; AGG-C1; anti-NITEGE373) was developed and used to demonstrate the ability of ADAMTS-8 to cleave aggrecan at the aggrecanase-susceptible Glu373-Ala374 peptide bond. In addition, expression analyses demonstrated the presence of ADAMTS-8 mRNA transcripts in normal and osteoarthritic human cartilage.
Collins-Racie
Lisa A
LA
Department of Discovery Medicine, Wyeth Research, Cambridge, MA 02140, USA. lracie@wyeth.com
Flannery
Carl R
CR
Zeng
Weilan
W
Corcoran
Chris
C
Annis-Freeman
Bethany
B
Agostino
Michael J
MJ
Arai
Maya
M
DiBlasio-Smith
Elizabeth
E
Dorner
Andrew J
AJ
Georgiadis
Katy E
KE
Jin
Macy
M
Tan
Xiang-Yang
XY
Morris
Elisabeth A
EA
LaVallie
Edward R
ER
D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; D053674:Aggrecans; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015153:Blotting, Western; D016466:CHO Cells; D002358:Cartilage, Articular / Q000201:enzymology*; D006224:Cricetinae; D003412:Cricetulus; D010450:Endopeptidases / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type; D008666:Metalloendopeptidases / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution
D053674:Aggrecans; D000911:Antibodies, Monoclonal; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D011509:Proteoglycans; D012333:RNA, Messenger; D010450:Endopeptidases; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human; D008666:Metalloendopeptidases; C083641:aggrecanase