Aggrecanase. A target for the design of inhibitors of cartilage degradation.
In arthritic diseases there is a gradual erosion of cartilage that leads to a loss of joint function. Aggrecan, which provides cartilage with its properties of compressibility and elasticity, is the first matrix component to undergo measurable loss in arthritis. This loss of aggrecan appears to be due to an increased rate of degradation, that can be attributed to proteolytic cleavage of the core protein within the interglobular domain (IGD). Two major sites of cleavage have been identified within the IGD. One, between the amino acids Asn341-Phe342, where the matrix metalloproteinases (MMPs) have been shown to clip; and the other, between Glu373-Ala374, which is attributed to a novel protease, "aggrecanase." We have generated aggrecanase in conditioned media from IL-1-stimulated bovine nasal cartilage and have used an enzymatic assay to evaluate this proteinase activity. In these studies we follow the generation of aggrecanase and MMPs in response to IL-1 in this system and examine the contribution of these enzymes in aggrecan degredation. Our data suggest that aggrecanase is a key enzyme in cartilage aggrecan degradation that represents a novel target for cartilage protection therapy in arthritis.
Arner
E C
EC
Inflammatory Diseases Research and Chemical and Physical Sciences, DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400, USA. Elizabeth.C.Arner@dupontpharma.com
Pratta
M A
MA
Decicco
C P
CP
Xue
C B
CB
Newton
R C
RC
Trzaskos
J M
JM
Magolda
R L
RL
Tortorella
M D
MD
D000818:Animals; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology*; D002417:Cattle; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D007700:Kinetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D009300:Nasal Septum; D009924:Organ Culture Techniques; D013997:Time Factors
D007375:Interleukin-1; D010450:Endopeptidases; D008666:Metalloendopeptidases; C030895:caseinase; D019278:Matrix Metalloproteinase 3; C083641:aggrecanase