Proprotein convertase activation of aggrecanases in cartilage in situ.
Proteolytic degradation of the major cartilage macromolecules, aggrecan and type II collagen, is a key pathological event in osteoarthritis (OA). ADAMTS-4 and ADAMTS-5, the primary aggrecanases capable of cartilage aggrecan cleavage, are synthesized as latent enzymes and require prodomain removal for activity. The N-termini of the mature proteases suggest that activation involves a proprotein convertase, but the specific family member responsible for aggrecanase activation in cartilage in situ has not been identified. Here we describe purification of a proprotein convertase activity from human OA cartilage. Through biochemical characterization and the use of siRNA, PACE4 was identified as a proprotein convertase responsible for activation of aggrecanases in osteoarthritic and cytokine-stimulated cartilage. Posttranslational activation of ADAMTS-4 and ADAMTS-5 was observed in the extracellular milieu of cartilage, resulting in aggrecan degradation. These findings suggest that PACE4 represents a novel target for the development of OA therapeutics.
Malfait
Anne-Marie
AM
Pfizer Global Research and Development, 700 Chesterfield Parkway-AA3E, Chesterfield, St. Louis, MO 63017, USA. anne-marie.malfait@pfizer.com
Arner
Elizabeth C
EC
Song
Ruo-Hua
RH
Alston
James T
JT
Markosyan
Stella
S
Staten
Nicholas
N
Yang
Zhiyong
Z
Griggs
David W
DW
Tortorella
Micky D
MD
D051722:ADAM Proteins / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000368:Aged; D000369:Aged, 80 and over; D002356:Cartilage / Q000201:enzymology* / Q000378:metabolism; D010450:Endopeptidases / Q000737:chemistry*; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D008954:Models, Biological; D010003:Osteoarthritis / Q000378:metabolism; D011348:Procollagen N-Endopeptidase / Q000378:metabolism; D043484:Proprotein Convertases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012697:Serine Endopeptidases / Q000378:metabolism*
D010450:Endopeptidases; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C083641:aggrecanase