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

• RESULTS: ADAMTS-4, but not ADAMTS-5, was induced in human chondrocytes infected with B burgdorferi [2].
• The active forms of ADAMTS-4 were increased in synovial fluid samples from patients with active Lyme arthritis and were elevated in the joints of mice infected with B burgdorferi [2].
• The effects of medium supplementation with inhibitors of biosynthesis (cycloheximide), of matrix metalloproteinase (MMP) activity (CGS 27023A or GM 6001), and of aggrecanase activity (SB 703704) on GAG release after injury were assessed [4].
• Transcription levels of matrix metalloproteinases-3, -9, and -13, aggrecanase-1, and the matrix protease regulator cyclooxygenase-2 increased with the duration of 50% compression 2-16-fold by 24 h [5].
• OBJECTIVE: To study the production of aggrecanase 1 (ADAM-TS4) in monolayer chondrocytes, capsular fibroblasts, and cartilage [6].

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

• Cyclosporin A inhibition of aggrecanase-mediated proteoglycan catabolism in articular cartilage [1].
• Fibroblast cultures were established from explant cultures of joint capsule and when these cells were exposed to aggrecan, cleavage of the core protein of aggrecan at the aggrecanase sites was observed [10].
• Intermittent compressive strain may reduce aggrecanase expression in cartilage: a study of chondrocytes in agarose gel [11].
• Finally, the use of the anti-neoepitope antibodies to detect aggrecanase-generated alpha(2)M-fragments in synovial fluid was investigated and found to be uninformative [12].
• Sensitivity to known matrix metalloproteinase inhibitors as well as to the endogenous tissue inhibitor of metalloproteinases, TIMP-1, further support the notion that aggrecanase is a metalloproteinase potentially related to the ADAM family or MMP family of proteases previously implicated in the catabolism of the extracellular matrix [8].

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

• Moreover, phosphatidylinositol-specific phospholipase C (PIPLC) treatment of rat cells markedly inhibited the aggrecanase response to IL-1b and RA [16].

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

• Amino-terminal sequence analysis of the resulting aggrecan core protein fragments revealed that the core protein was cleaved at five specific sites attributed to glutamyl endopeptidases referred to as aggrecanase activity [10].
• ADAM-TS4 production was evaluated by immunofluorescence or by Western blot analysis [6].
• Aggrecanase activity was measured in cells grown on an immobilized peptide substrate, and peptide cleavage was monitored by enzyme-linked immunosorbent assay [6].

References