Tissue inhibitors of matrix metalloproteinases

Although much has been learned ftom in vitro assays, we do not yet fully understand the predominant migratory mechanisms used by cancer cells in vivo. It is important that any molecular mediators (or their inhibitors) identified in one assay are tested in complementary assays and validated in appropriate in vivo models before they can be assumed to play a significant role in invasion and metastasis. There are several examples where a molecule can have either positive or negative regulatory roles in key cellular functions depending on the cellular/microenvironmental context (e.g., tissue inhibitors of matrix metalloproteinases TIMPs (12)). Thus, care needs to be taken to avoid undesirable activities or, as in the example of some angiogenic inhibitors, compensatory mechanisms that result in adverse events (13). 

Dollery CM, Humphries SE, McClelland A, et al. Expression of tissue inhibitor of matrix metalloproteinases I by use of an... 

Nusgens, B.V. et al., Topically applied vitamin C enhances the mRNA level of collagens I and III, their processing enzymes and tissue inhibitor of matrix metalloproteinase 1 in the human dermis, J. Invest. Dermatol., 116, 853, 2001. 

Matrix metalloproteinases Require zinc for catalysis Model extracellular matrix components regulated by TIMPs (tissue inhibitors of matrix metalloproteinases)... 

Cell movement within the extracellular matrix requires remodeling of the various components of the matrix. This is accomplished by a variety of matrix metal-loproteinases (MMPs) and regulators of the MMPs, tissue inhibitors of matrix metalloproteinases (TIMPs). Dysregulation of this delicate balance of the regulators of cell movement allows cancer cells to travel to other parts of the body (metastasize) as well as to spread locally to contiguous tissues. 

Recently, part of the mechanism for eye growth in myopia has been determined. Induction of myopia leads to decreased glycosaminoglycan synthesis, increased levels of matrix metalloproteinase-2, and decreased amounts of tissue inhibitor of matrix metalloproteinase-2 in the fibrous sclera of both chicks and tree shrews (65,66), while transforming growth factor (TGF)-p-2 regulates the visual eye growth in the final steps (67). 

K8. Komorowski, J., Pasieka, Z., Jankiewicz-Wika, J., and Stepien, H., Matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases and angiogenic cytokines in peripheral blood of patients with thyroid cancer. Thyroid 12,655-662 (2002). 

M4. Manicourt, D. H., Fujimoto, N., Obata, K., and Thonar, E. J., Levels of circulating collagenase, stromelysin-1, and tissue inhibitor of matrix metalloproteinases 1 in patients with rheumatoid arthritis. Relationship to serum levels of antigenic keratan sulfate and systemic parameters of inflammation. Arthritis Rheum. 38, 1031-1039... 

Oberg, A., Hoyhtya, M., Tavelin, B., Stenling, R., and Lindmark, G., Limited value of preoperative serum analyses of matrix metalloproteinases (MMP-2, MMP-9) and tissue inhibitors of matrix metalloproteinases (TIMP-1, TIMP-2) in colorectal cancer. Anticancer Res. 20, 1085-1091 (2000). 

P3. Peress, N., Perillo, E., and Zucker, S., Localization of tissue inhibitor of matrix metalloproteinases in Alzheimer s disease and normal brain. J. Neuropath. Exper. Neurol. 54, 16-22 (1995). 

Y7. Yoshikawa, T., Tissue inhibitor of matrix metalloproteinase-1 in the plasma of patients with gastric carcinoma. A possible marker for serosal invasion and metastasis. Cancer 86, 1929-1935 (1999). 

Y9. Yukawa, N., Yoshikawa, T., Akaike, M., et al. Plasma concentration of tissue inhibitor of matrix metalloproteinase 1 in patients with colorectal carcinoma. Br. J. Surg. 88, 1596-1601 (2001). 

Shan et al. found two significantly inhibited tumor invasions and metastasis in CRC cell lines HT29 and SW480 in vivo (0-80 mg/kg/day for 4 weeks). The results revealed that Tan-IIA showed the activity by reducing levels of urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMP)-2 and MMP-9 and by increasing levels of tissue inhibitor of matrix metalloproteinase protein (TIMP)-l... 

Tan H Heywood D, Ralph GS et al (2003) Tissue inhibitor of matrix metalloproteinase 1 inhibits excitotoxic cell death in neurons. Mol Cell Neurosci 22 98-106... 

The functions of the extracellular matrix are manifold (1.) stabilization of the tissue and organ structure, (2.) structural linkage of cells, (3.) transmission of information between the various types of cells within the tissue and the extracellular milieu, (4.) adhesion or migration of cells, and (5.) influence on the development and differentiation of cells and their polarity. In fibrogenesis, collagen fibres build the framework in which the other components of the extracellular matrix are embedded. In line with this wide scop>e of functions, the extracellular matrix is not only organ-sp>ecific as regards its architecture, but it also displays variations at different locations within the liver, e.g. in Disse s space, in the periportal fields and within the acinus zones. The extracellular matrix is a dynamic structure, i. e. there is a constant equilibrium between build-up (by matrix-metalloproteinases = MMP) and break-down (by tissue inhibitors of matrix metaUoproteinases = TIMP). 

Ninety percent of cancer deaths are caused by metastatic rather than primary tumors. Define metastasis. Explain the rationale for the following new cancer treatments (a) batima-stat, an inhibitor of matrix metalloproteinases and of the plasminogen activator receptor, (b) antibodies that block the function of integrins, integral membrane proteins that mediate attachment of cells to the basal laminae and extracellular matrices of various tissues, and (c) bisphosphonate, which inhibits the function of bone-digesting osteoclasts. 

Herman MP, Sukhova GK, Kisiel W, et al. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis. J Clin Invest 2001 107 1117-1126. 

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. 

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. 

Expression of matrix metalloproteinases (MMPs) and their inhibitors is an important function of the RPE, particularly with respect to the maintenance of appropriate permeability of the Bruch s membrane (Ahir et al., 2002). This function can be tested in vitro (Marin-Castano et al., 2006). For example, it has been shown that the expression of MMP-2, TIPM-2s (tissue inhibitor of MMP-2), and type IV collagen by cultured ARPE-19 cells is affected by repetitive exposures to nonlethal oxidant injury with hydroquinone (Marin-Castano et al., 2006). Oxidative stress decreases MMP-2 activity and increases collagen type IV accumulation. 

K4. Khokha, R., and Denhardt, D. T., Matrix metalloproteinases and tissue inhibitors of metal-loproteinases A review of their role in tumorigenesis and tissue invasion. Invasion Metastasis 9, 391-405 (1989). 

Hickey M, Higham J, Sullivan M, Miles L, Fraser IS. Endometrial bleeding in hormone replacement therapy users preliminary findings regarding the role of matrix metalloproteinase 9 (MMP-9) and tissue inhibitors of MMPs. Fertil Steril 2001 75(2) 288-96. 

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... 

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