Abstract
ADAMTS4 (aggrecanase-1) is considered to play a key role in the degradation of aggrecan in arthritides. The inhibitory activity of tissue inhibitors of metalloproteinases (TIMPs) to ADAMTS4 was examined in an assay using aggrecan substrate. Among the four TIMPs, TIMP-3 inhibited the activity most efficiently with an IC(50) value of 7.9 nM, which was at least 44-fold lower than that of TIMP-1 (350 nM) and TIMP-2 (420 nM) and >250-fold less than that of TIMP-4 (2 microM for 35% inhibition). These results suggest that TIMP-3 is a potent inhibitor against the aggrecanase activity of ADAMTS4 in vivo.
MeSH terms
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ADAM Proteins
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ADAMTS4 Protein
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Aggrecans
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Extracellular Matrix Proteins*
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Humans
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Inhibitory Concentration 50
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Lectins, C-Type
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Metalloendopeptidases / antagonists & inhibitors*
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Metalloendopeptidases / metabolism
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Procollagen N-Endopeptidase
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Protein Processing, Post-Translational
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Proteoglycans / chemistry
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Proteoglycans / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Tissue Inhibitor of Metalloproteinase-1 / pharmacology
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Tissue Inhibitor of Metalloproteinase-2 / pharmacology
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Tissue Inhibitor of Metalloproteinase-3 / pharmacology
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Tissue Inhibitor of Metalloproteinase-4
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Tissue Inhibitor of Metalloproteinases / pharmacology*
Substances
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Aggrecans
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Extracellular Matrix Proteins
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Lectins, C-Type
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Peptide Fragments
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Proteoglycans
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Recombinant Proteins
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Tissue Inhibitor of Metalloproteinase-1
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Tissue Inhibitor of Metalloproteinase-3
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Tissue Inhibitor of Metalloproteinases
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Tissue Inhibitor of Metalloproteinase-2
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ADAM Proteins
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Metalloendopeptidases
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Procollagen N-Endopeptidase
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ADAMTS4 Protein
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ADAMTS4 protein, human