Cytokine-induced cartilage proteoglycan degradation is mediated by aggrecanase
Osteoarthritis and CartilagePublished 1 May 1998Open access
Elizabeth C. Arner, Clare Hughes, Carl P. Decicco, Bruce Caterson, Micky D. Tortorella
Citations138
SJR quartileQ1
SJR score2.33
SNIP2.06
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TL;DR
The data suggest that 'aggrecanase' is primarily responsible for proteoglycan cleavage in these experimental systems and that this protease has properties in common with metalloproteases including members of the MMP and ADAM family.
Abstract
Our data suggest that 'aggrecanase' is primarily responsible for proteoglycan cleavage in these experimental systems and that this protease has properties in common with metalloproteases including members of the MMP and ADAM family. Inhibition of 'aggrecanase' may have utility in preventing cartilage loss in arthritis.
Keywords
MedicineBiochemistry, Genetics and Molecular Biology
NatureCleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4
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NatureA metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells
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The results should facilitate the development of therapeutically useful inhibitors of TNF-α release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.
NatureCloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α
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Connective Tissue ResearchA Direct Spectrophotometric Microassay for Sulfated Glycosaminoglycans in Cartilage Cultures
1,353 Citations1982Richard W. Farndale, C A Sayers +1 more
A rapid spectrophotometric procedure is described for the estimation of sulfated glycosaminoglycans in cartilage cultures that is substantially free from interference, is sensitive to less than 1 microgram (4 micrograms/ml) of chondroitin sulfate, and provides a simple alternative to the traditional methods for gly cosaminoglycan determinations.
Journal of Bone and Joint SurgeryBiochemical and Metabolic Abnormalities in Articular Cartilage from Osteo-Arthritic Human Hips
851 Citations1970Henry J. Mankin, Louis Lippiello
Articular cartilage of the proximal end of the femur from patients with osteo-arthritis and "normal" controls with fractures of neck of femur was obtained at the time of surgical replacement of the Femoral head.
Journal of Biological ChemistryProteinpolysaccharide Complex from Bovine Nasal Cartilage
667 Citations1969Vincent Hascall, Stanley W. Sajdera
Reduction and alkylation of isolated proteoglycan subunit and of the glycoprotein fraction suggest that disulfide bonds in both are required for aggregation, but that those in the former are more sensitive to reduction.
Journal of Clinical InvestigationAggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints.
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Both neoepitopes were also detected by immunohistochemistry in articular cartilage from patients undergoing joint replacement for osteoarthritis, rheumatoid arthritis, and in Cartilage from adults with no known joint disease.
Arthritis & RheumatismThe structure of aggrecan fragments in human synovial fluid. evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis
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The consistent pattern of fragments seen on SDS-PAGE and the single predominant N-terminal sequence suggest a common degradative mechanism of aggrecan in these different joint conditions, which appear to have important implications with regard to the development of therapies to protect cartilage from degradation in patients with joint disease.
Journal of Clinical InvestigationThe structure of aggrecan fragments in human synovial fluid. Evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain.
416 Citations1992John D. Sandy, Carl R. Flannery +2 more
It is concluded that the release of aggrecan fragments from articular cartilage into the synovial fluid seen at all stages of human osteoarthritis is promoted by the action of a normal cartilage proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain.
FEBS LettersDegradation of cartilage aggrecan by collagenase‐3 (MMP‐13)
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The results show that MMP‐13 cleaves aggrecan in the IGD at the same site (PEN341‐FFG..) identified for other members of the MMP family, and also at a novel site ..VKP384‐VFE.. not previously observed for other proteinases.
Journal of Biological ChemistryThe interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B.
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Investigation on aggrecan the major proteoglycan of cartilage shows that in spite of a high keratan sulfate content the interglobular domain provides important sites for cleavage by different proteinases, including several members of the matrix metalloproteinase family.
Journal of Biological ChemistryCatabolism of aggrecan in cartilage explants. Identification of a major cleavage site within the interglobular domain
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Results indicate that catabolism of aggrecan in cartilage explants involves proteolytic cleavage within a conserved region of the interglobular domain and that this results in the separation of the G1 domain from the remainder of the molecule.
Journal of Biological ChemistryIdentification of a stromelysin cleavage site within the interglobular domain of human aggrecan. Evidence for proteolysis at this site in vivo in human articular cartilage.
272 Citations1992Carl R. Flannery, Michael W. Lark +1 more
Results clearly indicate that stromelysin cleaves the Asn341-Phe342 bond of human aggrecan in situ.
Biochemical JournalMonoclonal antibodies that specifically recognize neoepitope sequences generated by ‘aggrecanase’ and matrix metalloproteinase cleavage of aggrecan: application to catabolism <i>in situ</i> and <i>in vitro</i>
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PubMedTetracyclines inhibit human synovial collagenase in vivo and in vitro.
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This work has shown that addition of minocycline or a chemically modified tetracycline to synovial culture media in vitro profoundly inhibited collagenase activity in patients with rheumatoid arthritis.
Journal of Biological ChemistryCell-mediated Catabolism of Aggrecan
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The accumulation of G1 domain with a COOH-terminal of Glu shows that such aggrecanase-mediated cleavage can occur independent of the cleavage of the Asn-Phe bond by matrix metalloproteinases.
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Biochemical Journal<i>N</i>-terminal sequence of proteoglycan fragments isolated from medium of interleukin-1-treated articular-cartilage cultures. Putative site(s) of enzymic cleavage
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124 Citations1989Elizabeth C. Arner, Michael A. Pratta
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Biochemical JournalNeutrophil collagenase (MMP-8) cleaves at the aggrecanase site E373–A374 in the interglobular domain of cartilage aggrecan
119 Citations1994Amanda Fosang, Karena Last +7 more
Native and recombinant neutrophil collagenase (MMP-8) was shown to cleave at the E373-A374 'aggrecanase' site in the interglobular domain of aggrecan, suggesting that a metalloproteinase cleaved at the aggre canase site in situ.
Biochemical JournalA tissue-culture model of cartilage breakdown in rheumatoid arthritis. Quantitative aspects of proteoglycan release
108 Citations1979James J. Steinberg, Clement B. Sledge +2 more
Journal of Biological ChemistryMonoclonal antibodies recognizing protease-generated neoepitopes from cartilage proteoglycan degradation. Application to studies of human link protein cleavage by stromelysin.
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Journal of Biological ChemistryAnalysis of the catabolism of aggrecan in cartilage explants by quantitation of peptides from the three globular domains
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Results suggest that catabolism of aggrecan in articular cartilage involves a specific proteolysis of the core protein at a site which is within the interglobular domain and NH2-terminal to the sequence LPGG.
Journal of Biological ChemistryCleavage of Native Cartilage Aggrecan by Neutrophil Collagenase (MMP-8) Is Distinct from Endogenous Cleavage by Aggrecanase
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Data suggest that MMP-8 does not represent cartilage aggrecanase, and indicates that preferential cleavage occurs at a different site.
Journal of Biological ChemistryUtilization of a Recombinant Substrate rAgg1 to Study the Biochemical Properties of Aggrecanase in Cell Culture Systems
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Arthritis & RheumatismModulation of interleukin‐1–induced alterations in cartilage proteoglycan metabolism by activation of protein kinase C
31 Citations1991Elizabeth C. Arner, Michael A. Pratta
It is suggested that activation of PKC in chondrocytes may play a role in modulating the action of IL-1 on proteoglycan metabolism and prostaglandin production are mediated by an intracellular signal distinct from PKC.
Arthritis & RheumatismEffects of tenidap on the progression of osteoarthritic lesions in a canine experimental model. Suppression of metalloprotease and interleukin‐1 activity
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PubMedAnti-inflammatory drugs and their effects on cartilage synthesis and renal function.
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Exogenous administration of specific PGs may be able to minimize the deleterious actions of NSAIDs, and it is interesting to note that misoprostol on its own also stimulates GAG synthesis in explants of human osteoarthritic cartilage whilst exerting no apparent effect on healthy cartilage with a normal GAG turnover.
PubMedHigh-level expression in Escherichia coli of a soluble and fully active recombinant interleukin-1 beta.
23 Citations1987Huang Jj, Newton Rc +7 more
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Journal of Orthopaedic Research®In vivo effects of naproxen on composition, proteoglycan metabolism, and matrix metalloproteinase activities in canine articular cartilage
23 Citations1993Anthony Ratcliffee, Walid Azzo +4 more
It is indicated that in vivo treatment with naproxen has the capacity to modulate catabolic activities in articular cartilage.
Annals of the Rheumatic DiseasesEffect of tenidap on cartilage integrity in vitro.
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It seems possible that tenidap may be useful in decreasing the deleterious action of cytokines such as IL-1 on cartilage integrity during arthritic disease and in stimulating chondrocyte repair processes.
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Inflammation ResearchEffect of antiinflammatory drugs on human interleukin-1-induced cartilage degradation
17 Citations1987Elizabeth C. Arner, L. R. Darnell +4 more
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Journal of Pharmacy and PharmacologyEffect of naproxen sodium on the net synthesis of glycosaminoglycans and protein by normal canine articular cartilage in-vitro
12 Citations1990Kenneth D. Brandt, Marjorie Albrecht
The effects of the non‐steroidal anti‐inflammatory drug, naproxen sodium, on the metabolism of normal canine articular cartilage has been examined and it is suggested that it had no direct effect on the integrity of the extracellular matrix.
Biochemical JournalIsothiazolones interfere with normal matrix metalloproteinase activation and inhibit cartilage proteoglycan degradation
11 Citations1996Elizabeth C. Arner, Michael A. Pratta +5 more
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PubMedThe levels of collagenase, tissue inhibitor of metalloproteinases-1 (TIMP-1), collagenase approximately TIMP-1 complexes and glycosaminoglycan (GAG) in sequential samples of synovial fluid aspirated from patients with osteoarthritis.
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These immunoassays give valuable information on the levels of collagenase and TIMP-1 in individual patients with time and may help to determine the mechanisms controlling the turnover of cartilage collagen in different arthritides.
The Journal of Clinical PharmacologyThe Effect of Naproxen and Interleukin‐1 on Proteoglycan Catabolism and on Neutral Metalloproteinase Activity in Normal Articular Cartilage <i>In Vitro</i>
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