Tissue inhibitors of metalloproteinases

The enzymatic activity of these potentially harmful enzymes is tightly controlled. Once transcribed into protein, MMPs are expressed as inactive zymogens and require distinct activation processes to convert them into active enzymes. After secretion, MMP-activity is regulated by the noncovalent binding of tissue inhibitors of metalloproteinases ( TIMPs) as shown in Fig. 2 for MMP-2 and TIMP-2. Four TIMPs have been identified so far TIMP-1, TIMP-2, TIMP-3, and TIMP-4. All known MMPs can be inhibited by at least one of the four known TIMPs. Nevertheless, individual differences with regard to bond strength and thus the magnitude of inhibition of a particular MMP do exist. 

Morgunova E, Tuuttila A, Bergmann U et al (2002) Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc Natl Acad Sci USA 99 7414—7419... 

The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP-9) can form complexes with TIMPs when the enzymes are in the latent form. 

Plasminogen activator Plasminogen activator inhibitor-1 Tissue inhibitor of metalloproteinase... 

THP-1 Human monocytic leukaemia Thy 1+ Murine T cell antigen t.i.d. Ter in die (three times a day) TIL Tumour-infiltrating lymphocytes UMP Tissue inhibitors of metalloproteinase... 

TIMP-1, TIMP-2 Tissue inhibitors of metalloproteinases 1 and 2 Ha Thymus leukaemia antigen TLC TTiin-layer chromatt raphy TLCK Tosyl-lysyl-CHiCl TLP Tumour-like proliferation Tm T memory... 

Moreau M, Brocheriou I, Petit L, Ninio E, Chapman MJ, Rouis M. Interleukin-8 mediates downregulation of tissue inhibitor of metalloproteinase-1 expression in cholesterol-loaded human macrophages relevance to stability of atherosclerotic plaque. Circulation 1999 99(3) 420-426. 

Fukuda Y, Ishizaki M, Kudoh S, Kitaichi M, Yamanaka N. Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases. Lab Invest 1998 78(6) 687-698. 

Burger, D. et al., Imbalance between interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon direct contact with stimulated T lymphocytes Involvement of membrane-associated cytokines, Arthr. Rheum., 41, 1748, 1998. 

A1. Alvarez, O. A., Carmichael, D. F., and DeClerck, Y. A., Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J. Natl. Cancer Inst. 82, 589-595 (1990). 

KI3. Kossakouska, A. E., Urbanski, S. J., Huchcroft, S. A., and Edwards, R. R., Relationship between clinical aggressiveness of large cell immunoblastic lymphomas and expression of 92 kDa gelatinase (type IV collagenase) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Oncol. Res. 4, 233-240 (1992). 

TIMP Tissue inhibitor of metalloproteinase family. E(M) 0(0) 1(1) 1BR9... 

George, S.J., C.T. Lloyd, G.D. Angehni,A.C. Newby, and A.H. Baker, Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3. Circulation, 2000.101(3) 296-304. 

The MMPs are secreted as inactive proenzymes, which are activated by proteolytic cleavage. Once activated they are subject to control by tissue inhibitors of metalloproteinases (TIMPs). It is the imbalance between the active enzymes and the TIMPs that leads to destructive tissue degradation that potent directed pharmaceuticals can overcome. These enzymes have been the target of... 

Murphy G, Willenbrock F, Ward RV, Cockett MI, Eaton D, Docherty AJP. The C-terminal domain of 72 kDa gelatinase A is not required for catalysis, but is essential for membrane activation and modulates interactions with tissue inhibitors of metalloproteinase. J. Biochem. 1992 328 637-641. 

Kwak HJ, Park MJ, Cho H, Park CM, Moon SI, Lee HC, Park IC, Kim MS, Rhee CH, Hong SI. 2006. Transforming growth factor-betal induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Spl in human fibrosarcoma cells. Mol Cancer Res 4 209-220. 

Matrix Metal loproteinases, Tissue Inhibitors of Metalloproteinases... 

Another possible strategy that, to our knowledge, has not been studied is to increase the concentration or effect of matrix metalloproteinases, compounds that are responsible for controlled, ongoing degradation of collagen. One such method would be to block tissue inhibitors of metalloproteinases (TIMPs). Such a method would have... 

Ulrich D, Hrynyschyn K, Pallua N. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in sera and tissue of patients with Dupuytren s disease. Plastic and Reconstructive Surgery 2003, 112, 1279-1286. 

Antithrombotic effects Decreased matrix metalloproteinases Increased tissue inhibitor of metalloproteinase 1 Increased collagen and fewer inflammatory cells in atherosclerotic plaque Reduced tissue factor expression and thrombin generation... 

Abbreviations CEL, cellulose DXM, dexamethasone EIPA, ethylisopropylamiloride FIB, fibrin MR methylprednisolone NA, not available Neo-R, neointima reduction PC, phosphorylcholine PCL, polycaprolactone PFM-P75, polyfluoroalkoxyphosphazene PLLA(PLA), poly-L-lactic acid POP, polyorganophosphazene PU, polyurethane Q-DL, Quanam drug eluting stent Q-M, Quanam metal stent SNR sodium nitroprusside TIMP, tissue inhibitors of metalloproteinase. 

Johnson TW, Wu YX, Herdeg C, et al, Stent-based delivery of tissue inhibitor of metalloproteinase-3 adenovirus inhibits neointimal formation in porcine coronary arteries. Arterioscler Thromb Vase Biol 2005 25(4) 754-759. 

The MMPs are a family of zinc-dependent neutral endopep-tidases that share structural domains but differ in substrate specificity, cellular sources, and inductivity (Table I). All the MMPs are important for remodeling of the extra cellular matrix and share the following functional features (/) they degrade extracellular matrix components, including fibronectin, collagen, elastin, proteoglycans, and laminin, (//) they are secreted in a latent proform and require activation for proteolytic activity, (///) they contain zinc at their active site and need calcium for stability, (/V) they function at neutral pH, and (v) they are inhibited by specific tissue inhibitors of metalloproteinases (TIMPs). 

Lamoreaux, W. J., Fitzgerald, M. E., Reiner, A., Hasty, K. A., and Charles, S. T. 1998. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc. Res. 55 29-42. 

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