Tissue inhibitor of metalloproteinases TIMPs

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. 

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. 

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... 

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... 

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). 

Korczak B, Dennis JW (1993) Inhibition of AG inked oligosaccharide processing in tumor cells is associated with enhanced tissue inhibitor of metalloproteinases (TIMP) gene expression. Int J Cancer 53 634-639... 

Ito, A., Sato, T., Iga, T., and Mori, Y. Tumor necrosis factor bifunctionally regulates matrix metalloproteinases and tissue inhibitor of metalloproteinases (TIMP) production by human fibroblasts. FEBS Lett. 269, 93-95 (1990). 

MEASUREMENT OF MATRIX METALLOPROTEINASES (MMPS) AND TISSUE INHIBITORS OF METALLOPROTEINASES (TIMP) IN BLOOD AND URINE POTENTIAL CLINICAL APPLICATIONS... 

The Tissue Inhibitors of MetalloProteinases (TIMP-1, -2, -3, and -4) make up a family of homologous MMP inhibitors widely distributed in tissues (N2). TIMP concentrations in extracellular fluids and tissues generally far exceed the concentration of MMPs, thereby limiting the proteolytic activity of circulating MMPs. In contrast to the inhibitory role of other TIMPs, low concentration of TIMP-2 actually enhances MTl-MMP induced activation of MMP-2 by forming a triplex on the cell surface (S3). In addition, TIMPs have been shown to have growth promoting and inhibitory activities whieh are independent of their MMP inhibitory funetion (S5). As noted with... 

Z3. Zucker, S., Hymowitiz, M., Conner, C., et al. Measurement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in blood and tissues. Ann. New York Acad. Sci. 878, 212-227 (1999). 

Z5. Zucker, S., Lysik, R. M., DiMassimo, B. I., et al. Plasma assay of gelatinase B Tissue inhibitor of metalloproteinase (TIMP) complexes in cancer. Cancer 76, 700-708 (1995). 

Bourboulia, D. and Stetler-Stevenson, W. G. (2010). Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) Positive and negative regulators in tumor cell adhesion. Semin. Cancer Biol, pp. 161-168, Elsevier. 

Immunologic Although chloroquine has been used successfully in the treatment of systemic lupus erythematosus, its exact mechanism of action is not known. Matrix metalloproteinases (MMPs) may play a role in the immune response and tissue damage that occur in autoimmune skin diseases. The effects of chloroquine for 3 months on serum MMP activities and tissue inhibitors of metalloproteinases (TIMPs) have been studied in 25 patients with SLE and in 25 sex- and age-matched controls [4 ]. Before treatment, MMP activities were significantly much higher in the patients with SLE, as were TIMP concentrations. After chloroquine treatment, the MMP activities fell significantly while TIMP concentrations increased... 

MMP-9 is preferentially expressed in UIP (46). The concentrations of MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) are more increased in BAL fluid of patients with OP than in those with UIP (47). These data suggest that an imbalance between MMPs and TIMPs may play a role in the connective tissue remodeling of OP. Laminin-5, a glycoprotein involved in cell attachment, migration, proliferation, differentiation, and apoptosis expressed in epithelial cells of wound healing, is also expressed in regenerating epithelial cells in OP and UIP (48). 

The tissue-destructive potential of neutrophil-derived enzymes are countered by powerful plasma antiproteinases. These include ai-proteinase inhibitor, a2-macroglobulin, leukoproteinase inhibitor, plasminogen activator inhibitor (PAI-1), and tissue inhibitor of metalloproteinases (TIMPs) (4). Together, these inhibitors create an antiprotease shield in both plasma and in interstitial fluids. There is growing evidence that this antiprotease shield can be overwhelmed by the over exuberant neutrophil response in chronic wounds. 

Denhardt DT, Feng B, Edwards et al (1993) Tissue inhibitor of metalloproteinases (TIMP) structure, control of expression and biological functions. Pharmacol Ther 59 329-341... 

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