Aggrecanase - A target for the design of inhibitors of cartilage degradation

被引:45
作者
Arner, EC [1 ]
Pratta, MA [1 ]
Decicco, CP [1 ]
Xue, CB [1 ]
Newton, RC [1 ]
Trzaskos, JM [1 ]
Magolda, RL [1 ]
Tortorella, MD [1 ]
机构
[1] Dupont Pharmaceut Co, Expt Stn E400 4239, Wilmington, DE 19880 USA
来源
INHIBITION OF MATRIX METALLOPROTEINASES: THERAPEUTIC APPLICATIONS | 1999年 / 878卷
关键词
D O I
10.1111/j.1749-6632.1999.tb07676.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Asn(341)-Phe(342), where the matrix metalloproteinases (MMPs) have been shown to clip; and the other, between Glu(373)-Ala(374), 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.
引用
收藏
页码:92 / 107
页数:16
相关论文
共 31 条
[1]   Cytokine-induced cartilage proteoglycan degradation is mediated by aggrecanase [J].
Arner, EC ;
Hughes, CE ;
Decicco, CP ;
Caterson, B ;
Tortorella, MD .
OSTEOARTHRITIS AND CARTILAGE, 1998, 6 (03) :214-228
[2]   Generation and characterization of aggrecanase - A soluble, cartilage-derived aggrecan-degrading activity [J].
Arner, EC ;
Pratta, MA ;
Trzaskos, JM ;
Decicco, CP ;
Tortorella, MD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (10) :6594-6601
[3]   MODULATION OF INTERLEUKIN-1-INDUCED ALTERATIONS IN CARTILAGE PROTEOGLYCAN METABOLISM BY ACTIVATION OF PROTEIN-KINASE-C [J].
ARNER, EC ;
PRATTA, MA .
ARTHRITIS AND RHEUMATISM, 1991, 34 (08) :1006-1013
[4]   A DIRECT SPECTROPHOTOMETRIC MICRO-ASSAY FOR SULFATED GLYCOSAMINOGLYCANS IN CARTILAGE CULTURES [J].
FARNDALE, RW ;
SAYERS, CA ;
BARRETT, AJ .
CONNECTIVE TISSUE RESEARCH, 1982, 9 (04) :247-248
[5]  
FLANNERY CR, 1992, J BIOL CHEM, V267, P1008
[6]   DEVELOPMENT OF A CLEAVAGE-SITE-SPECIFIC MONOCLONAL-ANTIBODY FOR DETECTING METALLOPROTEINASE-DERIVED AGGRECAN FRAGMENTS - DETECTION OF FRAGMENTS IN HUMAN SYNOVIAL-FLUIDS [J].
FOSANG, AJ ;
LAST, K ;
GARDINER, P ;
JACKSON, DC ;
BROWN, L .
BIOCHEMICAL JOURNAL, 1995, 310 :337-343
[7]  
FOSANG AJ, 1992, J BIOL CHEM, V267, P19470
[8]   FIBROBLAST AND NEUTROPHIL COLLAGENASES CLEAVE AT 2 SITES IN THE CARTILAGE AGGRECAN INTERGLOBULAR DOMAIN [J].
FOSANG, AJ ;
LAST, K ;
KNAUPER, V ;
NEAME, PJ ;
MURPHY, G ;
HARDINGHAM, TE ;
TSCHESCHE, H ;
HAMILTON, JA .
BIOCHEMICAL JOURNAL, 1993, 295 :273-276
[9]   Degradation of cartilage aggrecan by collagenase-3 (MMP-13) [J].
Fosang, AJ ;
Last, K ;
Knauper, V ;
Murphy, G ;
Neame, PJ .
FEBS LETTERS, 1996, 380 (1-2) :17-20
[10]  
HUANG JJ, 1987, MOL BIOL MED, V4, P169