Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arterial microfibrils contain a 128 Kd collagenase and pepsin resistant glycoprotein (GP 128) essential for their ability to induce platelet aggregation. A previous report (Fauvel F. et al, (1984) Biochem. Biophys. Res. Comm., 123, 114-120) showed that GP 128 and thrombospondin (TSP) synthetized by endothelial cells each inhibited the aggregation of platelets by microfibrils and not by collagen. We used a monospecific antiplatelet TSP IgG in an immunoblotting assay for the identification of a TSP-like structure in untreated, collagenase-treated and pepsin-treated arterial microfibrils. The only constituent recognized in the three samples of microfibrils was GP 128. Fab fragments of this IgG provoked a dose dependent inhibition of the microfibril induced platelet aggregation (50% inhibition with 0.25 mg, 100% inhibition with 1 mg); in contrast, they did not affect collagen induced aggregation. The results indicate that a glycoprotein constituent with a thrombospondin-like antigenicity is involved in the thrombogenic properties of arterial microfibrils.
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PMID:Immunochemical identification of a thrombospondin-like structure in an arterial microfibrillar extract. 283 11

C-terminal truncation of ADAMTS-4 from the p68 form to the p53 form is required for activation of its capacity to cleave the Glu(373)-Ala(374) interglobular domain bond of aggrecan. In transfected human chondrosarcoma cells, this process is not autoproteolytic because the same products form with an inactive mutant of ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin-like motif 4) and truncation is completely blocked by tissue inhibitor of metalloproteinase-1. Instead, activation can be mediated by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase (MT4-MMP, MMP-17) because co-transfection with the active form of MT4-MMP markedly enhanced activation, whereas an inactive mutant of MT4-MMP was ineffective. Treatment of co-transfected cells with phosphatidylinositol-specific phospholipase C liberated the complex of MT4-MMP and p68 ADAMTS4 from the cell membrane, but the p53 ADAMTS4 remained associated. Specific glycosaminoglycan lyase digestions, followed by product analyses using fluorescence-assisted carbohydrate electrophoresis and immunoprecipitation experiments, showed that the p53 form is associated with syndecan-1 through both chondroitin sulfate and heparan sulfate. We conclude that ADAMTS-4 activation in this cell system involves the coordinated activity of both glycosylphosphatidyl inositol-anchored MT4-MMP and the proteoglycan form of syndecan-1 on the cell surface.
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PMID:ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. 1470 64

Osteoarthritis (OA) is a progressive disease of cartilage degradation that significantly impacts quality of life. There are currently no effective treatments and, while a large number of potential therapeutic targets exist, most have not been validated in vivo. The range of OA models in the mouse has dramatically expanded in the last decade, beyond spontaneous models, to include genetically modified transgenic, knockout (KO) and knock-in (KI) mice that can develop premature cartilage degeneration reminiscent of OA. In addition, instability models of OA, either induced by intra-articular (IA) collagenase or surgery, are providing a set of tools to assist in the identification of disease-modifying OA drug (DMOAD) targets. These models are now vital tools to dissect the pathways essential to the pathogenesis of OA. Two targets, ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs)-5 and IL-1beta (interleukin-1 beta), have been validated in the surgical destabilization of the medial meniscus model (DMM) in KO mice. Other potential targets evaluated in instability models, either showed no disease modification or a worsening of disease, suggesting that those targets have no role, a protective role or that other, more destructive enzymes etc., can overcompensate. Development of small molecule or protein antagonist inhibitors of therapeutic targets require many years to bring to clinical trials and often confront potency and safety issues which impede successful progress. Validation, or confirmation of therapeutic targets in vivo is most clearly and efficiently obtained by using KO studies, than by creating potent and selective DMOADs to multiple potential targets. While the results in the mouse will not always transpose to the human condition, the track record of mouse knockouts corresponding to the human phenotype have been excellent. These results indicate that the evaluation of genetically modified mice will become increasingly important as we unravel the genes contributing to OA.
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PMID:In vivo osteoarthritis target validation utilizing genetically-modified mice. 1730 14