Inactivation of tissue inhibitor of metalloproteinases by neutrophil elastase and other serine proteinases

Okada, Yasunori; Watanabe, Shôji; Nakanishi, Isao; Kishi, Jun; Hayakawa, Taro; Watorek, W; Travis, James; Nagase, Hideaki

doi:10.1016/0014-5793(88)80817-2

Cited by 182 publications

(100 citation statements)

References 26 publications

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“…Thus, the balance between the activities of TIMPs and active metalloproteinases is probably a critical factor in the control of connective tissue remodelling in both health and disease, and a change of this balance in favour of active metalloproteinases may be an important determinant in the disease process. Although the inactivation of TIMPs by either reactive oxygen species or proteinases has not been demonstrated in vivo, the potentiation of metalloproteinase activity through inactivation of TIMP-1 by neutrophil elastase has been shown in vitro [12]. In this study, we have demonstrated a mechanism by which oxidative stress might potentiate metalloproteinase activity by TIMPs inactivation.…”

Section: Introductionmentioning

confidence: 66%

“…TIMP-1 is often co-expressed with metalloproteinases from connective tissue cells [22,23]. Okada et al demonstrated the proteolytic inactivation of TIMP-1 by neutrophil elastase [12] and suggested that neutrophils, which infiltrate inflammatory sites, may contribute to TIMP-1 inactivation. The lack of inhibitory capacity of the natural inhibitor of neutrophil elastase, ct-l-proteinase inhibitor, at inflammatory sites has been described [24].…”

Section: Discussionmentioning

confidence: 99%

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Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

Frears¹,

Zhang²,

Blake³

et al. 1996

FEBS Letters

161

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Peroxynitrite (ONOO-) has recently been implicated in connective tissue destruction in vivo. We have studied the effect of ONOO-on the activity of tissue inhibitor of metalloprotelnase-1 (TIMP-1) in vitro. The inactivation of TIMP-1 by ONOO-was dose dependent with 50 ~tM ONOOreducing the inhibitory activity of TIMP-1 towards gelatiuase-A by 50%. High concentrations of ONOO-(500 ~tM-5 mM) caused protein fragmentation whilst lower concentrations (< 250 ~tM) inactivated TIMP-1 without altering the molecular weight. Inactivation could be blocked by ONOO scavengers but not by hydroxyl radical scavengers. Our results show that ONOO-is capable of inactivating TIMP-1, a process which could potentiate metalloproteinase-mediated tissue breakdown.

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Section: Introductionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

Frears¹,

Zhang²,

Blake³

et al. 1996

FEBS Letters

161

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“…The present study, however, indicates that neutrophil elastase and cathepsin G are also good activators of proMMP-3. Tissue inhibitor of metalloproteinases (TIMP), a specific inhibitor of MMPs, is destroyed completely by neutrophil elastase and partially by cathepsin G, but not by plasmin [21]. Taken together, both elastase and cathepsin G which can be supplied from neutrophils infiltrated in rheumatoid joint cavity [22] may play important roles in regulation of MMP-3 activity by both activation of the zymogen and inactivation of TIMP.…”

Section: Resultsmentioning

confidence: 99%

Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 (‘gelatinase’) by human neutrophil elastase and cathepsin G

1989

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The ability of human neutrophil elastase and cathepsin G to activate matrix metalloproteinase 3 (MMP‐3 = stromelysin) and MMP‐2 (‘gelatinase’) purified from human rheumatoid synovial fibroblasts in culture was examined. The zymogen of MMP‐3 (proMMP‐3) was activated to full activity with elastase and cathepsin G by limited proteolysis of the molecule into two active forms of M r ∼ 45000 and M r ∼ 25000. In contrast, proMMP‐2 was not activated at all by these neutrophil serine proteinases, although it was degraded into small fragments. These data suggest that neutrophil elastase and cathepsin G may play an important role in the activation of proMMP‐3 in vivo in various inflammatory conditions, but proMMP‐2 may be activated in different ways.

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“…The final product was homogeneous on SDS/PAGE. The concentration of TIMP was determined by titration with the known amount of MMP-3 (stromelysin) which binds to TIMP in 1:1 stoichiometry (Okada et al, 1988b).…”

Section: Purification Of Timpmentioning

confidence: 99%

Purification and characterization of matrix metalloproteinase 9 from U937 monocytic leukaemia and HT1080 fibrosarcoma cells

Morodomi

Osuga

Sasaguri

et al. 1992

Biochemical Journal

185

126

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603The precursor of matrix metalloproteinase 9 (proMMP-9), also known as '92 kDa progelatinase/type IV procollagenase', was purified from the conditioned medium of U937 monocytic leukaemia and HT1080 fibrosarcoma cell lines stimulated with phorbol 12-myristate 13-acetate. ProMMP-9 in these culture media is non-covalently complexed with the 29 kDa tissue inhibitor of metalloproteinases (TIMP), but free proMMP-9 was separated from the TIMP-proMMP-9 complex by chromatography on Green A Dyematrex gel. The final product was homogeneous on SDS/PAGE, with a molecular mass of 88 kDa without reduction and 92 kDa with reduction. Treatment of proMMP-9 with 4-aminophenylmercuric acetate converted the 88 kDa precursor into 80 kDa and 68 kDa forms. Gelatin-containing zymographic analysis showed zones of lysis associated with all three species. However, only the 68 kDa species was shown to be catalytically active by its ability to bind to a2-macroglobulin. In the presence of an equimolar amount of TIMP, only the 80 kDa species was generated by treatment with 4-aminophenylmercuric acetate, but no enzyme activity was detected. This indicates that TIMP binds to the 80 kDa intermediate and inhibits the generation of the active 68 kDa species. Eight endopeptidases (trypsin, chymotrypsin, plasmin, plasma kallikrein, thrombin, cathepsin G, neutrophil elastase and thermolysin) were tested for their ability to activate proMMP-9. Of them, trypsin was the most effective activator of proMMP-9. Only partial activation (10-30%) was observed with plasmin, cathepsin G and chymotrypsin. The active forms generated by trypsin were identified as 80 kDa, 74 kDa and 66 kDa by their abilities to bind to a2-macroglobulin. In the presence of an equimolar amount of TIMP, proMMP-9 was also converted into the same molecular-mass species by trypsin, but they were not proteolytically active. This suggests activated MMP-9 is inhibited by TIMP. Activated MMP-9 digested gelatin, type-V collagen, reduced carboxymethylated transferrin and, to a lesser extent, type-IV collagen and laminin A chain. The specific activity against gelatin was estimated to be 15000 units/mg (1 unit = 1 ,ug of gelatin degraded/min at 37°C) by titration with a2-macroglobulin. Comparative studies on digestion of gelatin and collagen types IV and V by MMP-9 and MMP-2 indicated that both enzymes degrade these substrates into similar fragments. However, the susceptibilities of laminin, fibronectin and reduced carboxymethylated transferrin to these two MMPs were sufficiently different to indicate differences in substrate specificities between these two closely related proteinases.

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Inactivation of tissue inhibitor of metalloproteinases by neutrophil elastase and other serine proteinases

Cited by 182 publications

References 26 publications

Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 (‘gelatinase’) by human neutrophil elastase and cathepsin G

Purification and characterization of matrix metalloproteinase 9 from U937 monocytic leukaemia and HT1080 fibrosarcoma cells

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