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Timp3  -  tissue inhibitor of metalloproteinase 3

Mus musculus

Synonyms: Metalloproteinase inhibitor 3, Sun, TIMP-3, Timp-3, Tissue inhibitor of metalloproteinases 3
 
 
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Disease relevance of Timp3

  • We have used retroviral-mediated gene delivery to effect sustained autocrine expression of TIMP-3 in murine neuroblastoma and melanoma tumor cells in order to further examine the ability of TIMPs to inhibit angiogenesis in vivo [1].
  • In contrast, MMP-7 and TIMP-3 mRNAs are markedly decreased in obesity [2].
  • Thus, in inflammatory joint disease TIMP-3 likely dampens the inflammatory response of TNF-alpha by reducing ADAM17 activity [3].
  • In conclusion, exposing TIMP-3 null animals to sepsis rapidly enhances the phenotypic abnormalities of these mice, due to increased MMP activity induced by CLP [4].
  • Timp-3(-/-) mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB) [5].
 

High impact information on Timp3

  • Mice deficient in the metalloprotease inhibitor TIMP3, which inhibits the tumor-necrosis factor alpha (TNF-alpha)-converting enzyme (TACE, also called ADAM17), have elevated levels of TNF and severe inflammation in the liver [6].
  • Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity [7].
  • In this issue of the JCI, Sun et al. report findings in adenosine deaminase-deficient mice that suggest the occurrence of anti-inflammatory actions of adenosine in the lung, mediated through A(1) adenosine receptors on macrophages [8].
  • We have developed a mouse line deficient for tissue inhibitor of metalloproteinases-3 (TIMP-3), the only TIMP known to reside within the ECM [9].
  • Unscheduled activation of gelatinase-A was evident by zymography and correlated with earlier fragmentation of fibronectin in Timp-3(-/-) mammary [10].
 

Chemical compound and disease context of Timp3

 

Biological context of Timp3

 

Anatomical context of Timp3

 

Associations of Timp3 with chemical compounds

  • We propose that in the natural ovulatory process, TIMP-1 is probably a factor that regulates corpus luteum regression while TIMP-3 is important in maintaining the structural integrity of the corpus luteum [16].
  • RESULTS: Articular cartilage from Timp3-knockout animals (ages > or =6 months) showed reduced Safranin O staining and an increase in ...VDIPEN content compared with cartilage from heterozygous and wild-type animals [17].
  • A major difference in vitro was the stimulation of expression of TIMP-3 by dexamethasone which inhibits EGF- and PMA-induced TIMP-1 transcription [18].
  • The differential display (DD) was employed to identify the gene(s) responsible for 1,10-phenanthroline (OP)-induced apoptosis in murine tumor cells (Sun, Y., Bian, J., Wang, Y. and Jacobs, C. (1997) Oncogene 14, 385-393 [1]) [19].
  • On the basis of 5-azacytidine reversal, the mechanism for this down-regulation appears to involve changes in the methylation state of the TIMP-3 promoter [20].
 

Enzymatic interactions of Timp3

 

Regulatory relationships of Timp3

  • Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha [7].
  • Transcripts encoding TIMP-3 were detected from day 6.0-7.0 in the maternal decidua immediately adjacent to embryonic cells expressing MMP-9 [22].
  • Recently, the prohormone convertase SPC-6 has been found to be co-expressed in embryo-proximal decidua in association with TIMP-3 [23].
 

Other interactions of Timp3

  • Similar results were obtained using mouse lungs of different developmental stages, with the addition that in mouse lung, TIMP-2 and TIMP-3 were upregulated as lung development progressed [24].
  • At the time of tooth eruption, Timp-3 was expressed in most dental epithelial cells except secretory ameloblasts, and gelatinase B was intensely expressed in osteoclasts in the jaw bone [25].
  • Compared to wild-type animals, Timp3-/- mice showed a dramatic increase in the initial inflammatory response to intra-articular antigen injection, and serum TNF-alpha levels were greatly elevated in the Timp3-/- animals after immunization [3].
  • TNF shedding is mediated by TNF-alpha converting enzyme, which is selectively inhibited by the tissue inhibitor of metalloproteinase 3 (TIMP3) [12].
  • Expression of MMP-2, -3, -9, -12, and -13 and of TIMP-1 and -2 mRNA rapidly increased at the onset of egg laying in infected mice, while TIMP-3 was unchanged [26].
 

Analytical, diagnostic and therapeutic context of Timp3

  • To determine the relative importance of this inhibitor in joint pathology, wild-type and Timp3-/- mice were immunized with methylated bovine serum albumin followed by arthritis induction by intra-articular injection of the same antigen [3].
  • In addition, retinal tissue removed from control (without NV) and experimental animals (with NV) was analyzed for the expression of TIMP-1, TIMP-2, and TIMP-3 mRNA and protein using RT-PCR and Western blot analysis [27].
  • Microarray analysis revealed tissue inhibitors of metalloproteinases [TIMP-1 and TIMP-3] were significantly under expressed in VDR KO mice as compared to WT mice which was further validated by RT-PCR [28].
  • Mouse tissue inhibitor of metalloproteinases-3 (mTIMP-3), a gene specifically not expressed in neoplastic JB6 cells, have been isolated recently through the use of the mRNA differential display technique (Sun, Y., Hegamyer, G., and Colburn, N. H. (1994) Cancer Res. 54, 1139-1144) [29].
  • The objectives of this study were to determine the effects of a septic lung stress induced by cecal ligation and perforation (CLP) on lung function, structure, pulmonary surfactant, and inflammation in TIMP-3 null mice [4].

References

  1. Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model. Spurbeck, W.W., Ng, C.Y., Strom, T.S., Vanin, E.F., Davidoff, A.M. Blood (2002) [Pubmed]
  2. Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. Chavey, C., Mari, B., Monthouel, M.N., Bonnafous, S., Anglard, P., Van Obberghen, E., Tartare-Deckert, S. J. Biol. Chem. (2003) [Pubmed]
  3. Lack of tissue inhibitor of metalloproteinases-3 results in an enhanced inflammatory response in antigen-induced arthritis. Mahmoodi, M., Sahebjam, S., Smookler, D., Khokha, R., Mort, J.S. Am. J. Pathol. (2005) [Pubmed]
  4. Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response to sepsis. Martin, E.L., Moyer, B.Z., Pape, M.C., Starcher, B., Leco, K.J., Veldhuizen, R.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
  5. Combination of tumor necrosis factor-alpha ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice. Kassiri, Z., Oudit, G.Y., Sanchez, O., Dawood, F., Mohammed, F.F., Nuttall, R.K., Edwards, D.R., Liu, P.P., Backx, P.H., Khokha, R. Circ. Res. (2005) [Pubmed]
  6. TIMP3 checks inflammation. Black, R.A. Nat. Genet. (2004) [Pubmed]
  7. Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. Federici, M., Hribal, M.L., Menghini, R., Kanno, H., Marchetti, V., Porzio, O., Sunnarborg, S.W., Rizza, S., Serino, M., Cunsolo, V., Lauro, D., Mauriello, A., Smookler, D.S., Sbraccia, P., Sesti, G., Lee, D.C., Khokha, R., Accili, D., Lauro, R. J. Clin. Invest. (2005) [Pubmed]
  8. A1 antagonism in asthma: better than coffee? Tilley, S.L., Boucher, R.C. J. Clin. Invest. (2005) [Pubmed]
  9. Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). Leco, K.J., Waterhouse, P., Sanchez, O.H., Gowing, K.L., Poole, A.R., Wakeham, A., Mak, T.W., Khokha, R. J. Clin. Invest. (2001) [Pubmed]
  10. Accelerated apoptosis in the Timp-3-deficient mammary gland. Fata, J.E., Leco, K.J., Voura, E.B., Yu, H.Y., Waterhouse, P., Murphy, G., Moorehead, R.A., Khokha, R. J. Clin. Invest. (2001) [Pubmed]
  11. Differential response of TIMP-3 null mice to the lung insults of sepsis, mechanical ventilation, and hyperoxia. Martin, E.L., McCaig, L.A., Moyer, B.Z., Pape, M.C., Leco, K.J., Lewis, J.F., Veldhuizen, R.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  12. Tissue inhibitor of metalloproteinase 3 regulates TNF-dependent systemic inflammation. Smookler, D.S., Mohammed, F.F., Kassiri, Z., Duncan, G.S., Mak, T.W., Khokha, R. J. Immunol. (2006) [Pubmed]
  13. Cell and agonist-specific regulation of genes for matrix metalloproteinases and their tissue inhibitors by primary glial cells. Crocker, S.J., Milner, R., Pham-Mitchell, N., Campbell, I.L. J. Neurochem. (2006) [Pubmed]
  14. Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP-3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10. Apte, S.S., Hayashi, K., Seldin, M.F., Mattei, M.G., Hayashi, M., Olsen, B.R. Dev. Dyn. (1994) [Pubmed]
  15. Differential regulation of TIMP-1, -2, and -3 mRNA and protein expressions during mouse incisor development. Yoshiba, N., Yoshiba, K., Stoetzel, C., Perrin-Schmitt, F., Cam, Y., Ruch, J.V., Hosoya, A., Ozawa, H., Lesot, H. Cell Tissue Res. (2006) [Pubmed]
  16. Temporal and spatial expression of tissue inhibitors of metalloproteinases during the natural ovulatory cycle of the mouse. Inderdeo, D.S., Edwards, D.R., Han, V.K., Khokha, R. Biol. Reprod. (1996) [Pubmed]
  17. Increased collagen and aggrecan degradation with age in the joints of Timp3(-/-) mice. Sahebjam, S., Khokha, R., Mort, J.S. Arthritis Rheum. (2007) [Pubmed]
  18. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. Leco, K.J., Khokha, R., Pavloff, N., Hawkes, S.P., Edwards, D.R. J. Biol. Chem. (1994) [Pubmed]
  19. Induction of glutathione synthetase by 1,10-phenanthroline. Sun, Y. FEBS Lett. (1997) [Pubmed]
  20. Specific methylation events contribute to the transcriptional repression of the mouse tissue inhibitor of metalloproteinases-3 gene in neoplastic cells. Pennie, W.D., Hegamyer, G.A., Young, M.R., Colburn, N.H. Cell Growth Differ. (1999) [Pubmed]
  21. Metalloproteinase axes increase beta-catenin signaling in primary mouse mammary epithelial cells lacking TIMP3. Hojilla, C.V., Kim, I., Kassiri, Z., Fata, J.E., Fang, H., Khokha, R. J. Cell. Sci. (2007) [Pubmed]
  22. Tissue inhibitor of metalloproteinases-3 is the major metalloproteinase inhibitor in the decidualizing murine uterus. Leco, K.J., Edwards, D.R., Schultz, G.A. Mol. Reprod. Dev. (1996) [Pubmed]
  23. Subtilisin proprotein convertase-6 expression in the mouse uterus during implantation and artificially induced decidualization. Wong, B.S., Liu, S., Schultz, G.A., Rancourt, D.E. Mol. Reprod. Dev. (2002) [Pubmed]
  24. Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development. Ryu, J., Vicencio, A.G., Yeager, M.E., Kashgarian, M., Haddad, G.G., Eickelberg, O. Thromb. Haemost. (2005) [Pubmed]
  25. Timp-1, -2 and -3 show coexpression with gelatinases A and B during mouse tooth morphogenesis. Sahlberg, C., Reponen, P., Tryggvason, K., Thesleff, I. Eur. J. Oral Sci. (1999) [Pubmed]
  26. Regulation of hepatic fibrosis and extracellular matrix genes by the th response: new insight into the role of tissue inhibitors of matrix metalloproteinases. Vaillant, B., Chiaramonte, M.G., Cheever, A.W., Soloway, P.D., Wynn, T.A. J. Immunol. (2001) [Pubmed]
  27. The balance between proteinases and inhibitors in a murine model of proliferative retinopathy. Majka, S., McGuire, P., Colombo, S., Das, A. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  28. Heart extracellular matrix gene expression profile in the vitamin D receptor knockout mice. Rahman, A., Hershey, S., Ahmed, S., Nibbelink, K., Simpson, R.U. J. Steroid Biochem. Mol. Biol. (2007) [Pubmed]
  29. Molecular cloning of mouse tissue inhibitor of metalloproteinases-3 and its promoter. Specific lack of expression in neoplastic JB6 cells may reflect altered gene methylation. Sun, Y., Hegamyer, G., Kim, H., Sithanandam, K., Li, H., Watts, R., Colburn, N.H. J. Biol. Chem. (1995) [Pubmed]
 
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