title: Microvesicles shed by oligodendroglioma cells and rheumatoid synovial fibroblasts contain aggrecanase activity.
abstract: Membrane microvesicle shedding is an active process and occurs in viable cells with no signs of apoptosis or necrosis. We report here that microvesicles shed by oligodendroglioma cells contain an 'aggrecanase' activity, cleaving aggrecan at sites previously identified as targets for adamalysin metalloproteinases with disintegrin and thrombospondin domains (ADAMTSs). Degradation was inhibited by EDTA, the metalloproteinase inhibitor GM6001 and by tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. This inhibitor profile indicates that the shed microvesicles contain aggrecanolytic ADAMTS(s) or related TIMP-3-sensitive metalloproteinase(s). The oligodendroglioma cells were shown to express the three most active aggrecanases, namely Adamts1, Adamts4 and Adamts5, suggesting that one or more of these enzymes may be responsible for the microvesicle activity. Microvesicles shed by rheumatoid synovial fibroblasts similarly degraded aggrecan in a TIMP-3-sensitive manner. Our findings raise the novel possibility that microvesicles may assist oligodendroglioma and rheumatoid synovial fibroblasts to invade through aggrecan-rich extracellular matrices.
authors.affiliation: Dipartimento di Biomedicina sperimentale e Neuroscienze cliniche, via del Vespro 129, 90127 Palermo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lo Cicero
authors.forename: Iwona
authors.initials: I
authors.lastname: Majkowska
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Italia
authors.initials: I
authors.lastname: Di Liegro
authors.forename: Linda
authors.initials: L
authors.lastname: Troeberg
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071116:ADAMTS5 Protein; D053674:Aggrecans / Q000378:metabolism; D002468:Cell Physiological Phenomena; D022162:Cytoplasmic Vesicles / Q000201:enzymology* / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D009837:Oligodendroglioma / Q000201:enzymology*; D059748:Proteolysis; D011994:Recombinant Proteins / Q000378:metabolism; D012213:Rheumatic Fever / Q000473:pathology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000494:pharmacology
chemical_list: D053674:Aggrecans; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011994:Recombinant Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3; D010450:Endopeptidases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; C083641:aggrecanase