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Gene Review

ADAMTS4  -  ADAM metallopeptidase with thrombospondin...

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Disease relevance of ADAMTS4

  • CONCLUSION: CSA can inhibit IL-1-induced aggrecanase-mediated proteoglycan catabolism in articular cartilage explants maintained in culture for 4 days, thus demonstrating molecular mechanisms whereby CSA may be an effective therapy for degenerative joint disease [1].
  • OBJECTIVE: To determine the effect of cyclosporin A (CSA) on aggrecanase- and matrix metalloproteinase (MMP)-mediated catabolism of proteoglycan (aggrecan) in articular cartilage explants stimulated with interleukin-1 (IL-1) in a culture system that mimics early pathologic processes associated with arthritic disease [1].
  • Role of aggrecanase 1 in Lyme arthritis [2].
  • We have applied a seamless method of SUMO tagging and removal in order to produce a homogeneous unmodified preparation of canine IL-1beta from Escherichia coli which was found to be a potent inducer of aggrecanase activity in isolated canine articular chondroctyes [3].

High impact information on ADAMTS4


Biological context of ADAMTS4

  • Age-related changes in aggrecan glycosylation affect cleavage by aggrecanase [7].
  • Using this assay we have characterized cartilage aggrecanase with respect to assay kinetics, pH and salt optima, heat sensitivity, and stability upon storage [8].
  • Aggrecanase-mediated hydrolysis resulted in an immobilized product that reveals an N-terminal neoepitope, recognized by the specific antibody BC-3 [9].

Anatomical context of ADAMTS4


Associations of ADAMTS4 with chemical compounds

  • CONCLUSION: These studies support a central role for MT4-MMP in IL-1-induced cartilage aggrecanolysis and are consistent with the identification of p68 as the aggrecanase that cleaves within the CS2 domain, and of p53 as the aggrecanase that generates G1-NITEGE [13].
  • RESULTS: Both aggrecanase-1 and aggrecanase-2 are able to cleave bovine and human biglycan at a site within their central leucine-rich repeat regions [14].
  • Because aggrecan is highly glycosylated with chondroitin sulfate (CS) and keratan sulfate (KS), we investigated whether glycosylation affects digestion by aggrecanase at the Glu(373)-Ala(374) bond [7].
  • NH2-terminal aggrecan fragments generated by cleavage at the aggrecanase site were also detected using antisera recognizing the new COOH terminus, NITEGE, formed by cleavage at the Glu373-Ala374 bond, indicating that cleavage at this site does not require prior cleavage at the MMP site [15].
  • Aggrecanase activity was inhibited by the metalloprotease inhibitor, EDTA, while a panel of inhibitors of serine, cysteine, and aspartic proteinases had no effect, suggesting that aggrecanase is a metalloproteinase [8].

Regulatory relationships of ADAMTS4


Other interactions of ADAMTS4

  • IL-1 treatment increased mRNA abundance for ADAMTS4 ( approximately 3-fold) and ADAMTS5 ( approximately 10-fold) but this was not accompanied by a marked change in enzyme protein abundance [13].
  • RT-PCR analysis of mRNA extracted from joint capsule fibroblasts showed that these cells express both aggrecanase-1 and -2 [ADAMTS-2 (Tang) and ADAMTS-5] [10].
  • This work suggests a prominent role for aggrecanase enzymes in the degradation of aggrecan and to a lesser extent versican [17].
  • CONCLUSIONS: Our data suggest that proteoglycan and collagen degradation are regulated through different mechanisms: IL-1 beta induces the synthesis of active enzymes that degrade proteoglycans, such as 'aggrecanase', and inactive proMMPs [18].
  • RESULTS: Pretreatment with 0.5 microM Se-met prevented IL-1beta-induced MMP-1 and aggrecanase-1 expression, and reduced the cytokine inhibitory effect on type II collagen, aggrecan core protein, and TGF-beta receptor II (TGF-betaRII) mRNA levels [19].

Analytical, diagnostic and therapeutic context of ADAMTS4


  1. Cyclosporin A inhibition of aggrecanase-mediated proteoglycan catabolism in articular cartilage. Little, C.B., Hughes, C.E., Curtis, C.L., Jones, S.A., Caterson, B., Flannery, C.R. Arthritis Rheum. (2002) [Pubmed]
  2. Role of aggrecanase 1 in Lyme arthritis. Behera, A.K., Hildebrand, E., Szafranski, J., Hung, H.H., Grodzinsky, A.J., Lafyatis, R., Koch, A.E., Kalish, R., Perides, G., Steere, A.C., Hu, L.T. Arthritis Rheum. (2006) [Pubmed]
  3. Bacterial production of biologically active canine interleukin-1beta by seamless SUMO tagging and removal. Kirkpatrick, R.B., Grooms, M., Wang, F., Fenderson, H., Feild, J., Pratta, M.A., Volker, C., Scott, G., Johanson, K. Protein Expr. Purif. (2006) [Pubmed]
  4. Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury. DiMicco, M.A., Patwari, P., Siparsky, P.N., Kumar, S., Pratta, M.A., Lark, M.W., Kim, Y.J., Grodzinsky, A.J. Arthritis Rheum. (2004) [Pubmed]
  5. Mechanical compression of cartilage explants induces multiple time-dependent gene expression patterns and involves intracellular calcium and cyclic AMP. Fitzgerald, J.B., Jin, M., Dean, D., Wood, D.J., Zheng, M.H., Grodzinsky, A.J. J. Biol. Chem. (2004) [Pubmed]
  6. Induction of aggrecanase 1 (ADAM-TS4) by interleukin-1 occurs through activation of constitutively produced protein. Pratta, M.A., Scherle, P.A., Yang, G., Liu, R.Q., Newton, R.C. Arthritis Rheum. (2003) [Pubmed]
  7. Age-related changes in aggrecan glycosylation affect cleavage by aggrecanase. Pratta, M.A., Tortorella, M.D., Arner, E.C. J. Biol. Chem. (2000) [Pubmed]
  8. Generation and characterization of aggrecanase. A soluble, cartilage-derived aggrecan-degrading activity. Arner, E.C., Pratta, M.A., Trzaskos, J.M., Decicco, C.P., Tortorella, M.D. J. Biol. Chem. (1999) [Pubmed]
  9. A microplate assay specific for the enzyme aggrecanase. Miller, J.A., Liu, R.Q., Davis, G.L., Pratta, M.A., Trzaskos, J.M., Copeland, R.A. Anal. Biochem. (2003) [Pubmed]
  10. Bovine joint capsule and fibroblasts derived from joint capsule express aggrecanase activity. Ilic, M.Z., Vankemmelbeke, M.N., Holen, I., Buttle, D.J., Clem Robinson, H., Handley, C.J. Matrix Biol. (2000) [Pubmed]
  11. Intermittent compressive strain may reduce aggrecanase expression in cartilage: a study of chondrocytes in agarose gel. Mio, K., Saito, S., Tomatsu, T., Toyama, Y. Clin. Orthop. Relat. Res. (2005) [Pubmed]
  12. Alpha2-macroglobulin is a novel substrate for ADAMTS-4 and ADAMTS-5 and represents an endogenous inhibitor of these enzymes. Tortorella, M.D., Arner, E.C., Hills, R., Easton, A., Korte-Sarfaty, J., Fok, K., Wittwer, A.J., Liu, R.Q., Malfait, A.M. J. Biol. Chem. (2004) [Pubmed]
  13. Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage. Patwari, P., Gao, G., Lee, J.H., Grodzinsky, A.J., Sandy, J.D. Osteoarthr. Cartil. (2005) [Pubmed]
  14. The cleavage of biglycan by aggrecanases. Melching, L.I., Fisher, W.D., Lee, E.R., Mort, J.S., Roughley, P.J. Osteoarthr. Cartil. (2006) [Pubmed]
  15. The interglobular domain of cartilage aggrecan is cleaved by hemorrhagic metalloproteinase HT-d (atrolysin C) at the matrix metalloproteinase and aggrecanase sites. Tortorella, M.D., Pratta, M.A., Fox, J.W., Arner, E.C. J. Biol. Chem. (1998) [Pubmed]
  16. Chondrocyte-mediated catabolism of aggrecan: evidence for a glycosylphosphatidylinositol-linked protein in the aggrecanase response to interleukin-1 or retinoic acid. Sandy, J.D., Thompson, V., Verscharen, C., Gamett, D. Arch. Biochem. Biophys. (1999) [Pubmed]
  17. Characterisation of proteoglycans and their catabolic products in tendon and explant cultures of tendon. Samiric, T., Ilic, M.Z., Handley, C.J. Matrix Biol. (2004) [Pubmed]
  18. Matrix degradation by chondrocytes cultured in alginate: IL-1 beta induces proteoglycan degradation and proMMP synthesis but does not result in collagen degradation. Beekman, B., Verzijl, N., de Roos, J.A., TeKoppele, J.M. Osteoarthr. Cartil. (1998) [Pubmed]
  19. Comparative effects of 2 antioxidants, selenomethionine and epigallocatechin-gallate, on catabolic and anabolic gene expression of articular chondrocytes. Andriamanalijaona, R., Kypriotou, M., Baugé, C., Renard, E., Legendre, F., Raoudi, M., Boumediene, K., Gatto, H., Monginoux, P., Pujol, J.P. J. Rheumatol. (2005) [Pubmed]
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