Will the real aggrecanase(s) step up: evaluating the criteria that define aggrecanase activity in osteoarthritis.
Loss of aggrecan from articular cartilage is an early and critical event in the pathogenesis of osteoarthritis (OA) and is enzymatically mediated by aggrecanase activity. Since the discovery of aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), both members of the "a disintegrin and metalloproteinase with thrombospondin motif" family of proteinases, other members of the family have been reported to have aggrecanase activity, as currently defined, including ADAMTS-1, -8, -9, -15 and -16. Understanding whether these other ADAMTS members are in fact genuine in vivo aggrecanases will be important for the development of therapeutic agents that aim to block aggrecan degradation. The goal of this review is to look at the current definition of "aggrecanase activity", and define its strengths, weaknesses and suitability for determining which ADAMTS, are aggrecanases that participate in aggrecan catabolism in OA. In addition, we propose a more comprehensive definition of aggrecanase activity, based on 6 criteria that encompass both biochemical and biological characteristics of the endogenous aggrecanase activity detected in vitro and in vivo. Finally, using these criteria, we propose which ADAMTSs should be classified as aggrecanases and therefore be considered as drug targets for the development of chondroprotective OA treatments.
Tortorella
M D
MD
Pfizer Global Research and Development, 700 Chesterfield Parkway, St. Louis MO 60013, USA. micky.d.tortorella@pfizer.com
Malfait
A M
AM
D000818:Animals; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D010003:Osteoarthritis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010802:Phylogeny; D011480:Protease Inhibitors / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology
D011480:Protease Inhibitors; D010450:Endopeptidases; C083641:aggrecanase