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Gene Review

Timp2  -  TIMP metallopeptidase inhibitor 2

Rattus norvegicus

Synonyms: Metalloproteinase inhibitor 2, TIMP-2, Timp-2, Tissue inhibitor of metalloproteinases 2
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Disease relevance of Timp2

  • We investigate the effect of modified synthetic small interfering RNA (siRNA) targeting TIMP-2 in rat model of liver fibrosis [1].
  • Furthermore, portal hypertension was also ameliorated after treatment with siRNA targeting TIMP-2 [1].
  • CONCLUSIONS: The changes of MMP-2 and TIMP-2 expressions in kidney tissues of diabetes rats may contribute to the occurrence and progression of diabetic nephropathy [2].
  • CONCLUSION: Our findings indicate that long-term increases of gelatinolytic activity of active MMP-2 cause continuous disorganization of type IV collagen in basement membranes during progressive atrophy of pancreatic gland in oleic acid-induced pancreatitis, and that MT1-MMP and TIMP-2 work as activating factors during proMMP-2 activation [3].
  • Ribonuclease protection analysis of liver RNA extracted at each recovery time point demonstrated a rapid decrease in expression of the collagenase inhibitors TIMP-1 and TIMP-2, whereas collagenase mRNA expression remained at levels comparable to peak fibrosis [4].

High impact information on Timp2

  • Growth activity was unlikely due to TIMP-2 inhibition of matrix metalloproteinases because ilomastat, a synthetic inhibitor of these enzymes, had no mesenchymal growth action [5].
  • Hence, the mesenchyme synchronizes its own growth with ureteric morphogenesis by stimulating the secretion of TIMP-2 from the ureteric bud [5].
  • During the first month after injury, we found that the expression of two proteinase inhibitors (plasminogen activator inhibitor type 1 [PAI-1] and tissue inhibitor of metalloproteinases-2 [TIMP-2]) was modulated [6].
  • TIMP-2 protein was increased in the intima compared with the media and adventitia at day 7 after injury [6].
  • The levels of collagen, collagen alpha1(I) gene expression, TIMP-2 content, and smooth muscle actin-positive cells were as in the control rats [7].

Chemical compound and disease context of Timp2


Biological context of Timp2


Anatomical context of Timp2

  • However, AII-treated mesangial cells did show an increase in the amount of tissue inhibitor of metalloproteinase-2 (Timp2) immunoreactive protein secreted into the medium [14].
  • Rats administered siRNA targeting TIMP-2 showed promotion of ECM degradation, reduction in activated hepatic stellate cells and enhancement of hepatocyte regeneration [1].
  • At 12 h after hCG, luteinizing granulosa cells expressed TIMP-1 and TIMP-3 mRNA, but TIMP-2 mRNA was at levels equivalent to the background [15].
  • There were no significant differences in tissue inhibitor of metalloproteinase (TIMP-1 or TIMP-2) activity by reverse zymography in small renal arteries [16].
  • In situ hybridization showed that on day 1-4 of pregnancy, both MMP-2 and TIMP-2 mRNAs were evidently localized in the basal stromal cells [17].

Associations of Timp2 with chemical compounds


Regulatory relationships of Timp2

  • Our data suggest that FSH stimulation of TIMP-2 expression may be regulated independently to that of TIMP-1 [21].
  • Following FTS treatment, the MMP-2 and MMP-9-induced collagenolytic activity and TIMP-2 expression, were increased in FTS-compared to PBS-treated rats [22].
  • Investigation of this layer in every resorption area by gelatin histozymography and TIMP-2 histochemistry demonstrates the presence of an MMP whose histozymographic activity is inhibited by such a low dose of the inhibitor CT1746 as to identify it as gelatinase A or B [23].

Other interactions of Timp2

  • TIMP-1 and TIMP-2 were constitutively expressed, and only TIMP-1 displayed a moderate increase with hyperoxia [18].
  • TIMP-2 and TIMP-3 transcripts become detectable on day 10 and remained stable afterwards [24].
  • Gelatinase A (MMP-2) was maximally increased at 5 days, and TIMP-2 was highest at 5 days [25].
  • MMP-13 active form was elevated during the first 2 weeks post-MI while TIMP-1 and TIMP-2 protein levels were not significantly elevated until 2 weeks post-MI [26].
  • In addition, secretion of plasminogen activators into the medium was unchanged after irradiation, while secretion of Timp2 increased [27].

Analytical, diagnostic and therapeutic context of Timp2


  1. Modified synthetic siRNA targeting tissue inhibitor of metalloproteinase-2 inhibits hepatic fibrogenesis in rats. Hu, Y.B., Li, D.G., Lu, H.M. The journal of gene medicine (2007) [Pubmed]
  2. Effects of benazepril on renal function and kidney expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in diabetic rats. Sun, S.Z., Wang, Y., Li, Q., Tian, Y.J., Liu, M.H., Yu, Y.H. Chin. Med. J. (2006) [Pubmed]
  3. Long-term overexpression of membrane type-1 matrix metalloproteinase and matrix metalloproteinase-2 in oleic acid-induced pancreatitis in rats. Yamaguchi, T., Nakamura, H., Kihara, Y., Taguchi, M., Yoshikawa, H., Otsuki, M. Pancreas (2002) [Pubmed]
  4. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. Iredale, J.P., Benyon, R.C., Pickering, J., McCullen, M., Northrop, M., Pawley, S., Hovell, C., Arthur, M.J. J. Clin. Invest. (1998) [Pubmed]
  5. Tissue inhibitor of metalloproteinase-2 stimulates mesenchymal growth and regulates epithelial branching during morphogenesis of the rat metanephros. Barasch, J., Yang, J., Qiao, J., Tempst, P., Erdjument-Bromage, H., Leung, W., Oliver, J.A. J. Clin. Invest. (1999) [Pubmed]
  6. Plasminogen activator inhibitor type 1 and tissue inhibitor of metalloproteinases-2 increase after arterial injury in rats. Hasenstab, D., Forough, R., Clowes, A.W. Circ. Res. (1997) [Pubmed]
  7. Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats. Bruck, R., Genina, O., Aeed, H., Alexiev, R., Nagler, A., Avni, Y., Pines, M. Hepatology (2001) [Pubmed]
  8. Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression is regulated by multiple neural differentiation signals. Jaworski, D.M., Pérez-Martínez, L. J. Neurochem. (2006) [Pubmed]
  9. Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis. Arthur, M.J., Mann, D.A., Iredale, J.P. J. Gastroenterol. Hepatol. (1998) [Pubmed]
  10. Coordinated elevation of membrane type 1-matrix metalloproteinase and matrix metalloproteinase-2 expression in rat uterus during postpartum involution. Manase, K., Endo, T., Chida, M., Nagasawa, K., Honnma, H., Yamazaki, K., Kitajima, Y., Goto, T., Kanaya, M., Hayashi, T., Mitaka, T., Saito, T. Reprod. Biol. Endocrinol. (2006) [Pubmed]
  11. Expression of gelatinases A and B, and TIMPs 1 and 2 during corneal wound healing. Ye, H.Q., Azar, D.T. Invest. Ophthalmol. Vis. Sci. (1998) [Pubmed]
  12. Cellular localization of tissue inhibitors of metalloproteinases in the rat ovary throughout pseudopregnancy. Curry, T.E., Wheeler, S.E. Biol. Reprod. (2002) [Pubmed]
  13. Purification and sequence analysis of two rat tissue inhibitors of metalloproteinases. Roswit, W.T., McCourt, D.W., Partridge, N.C., Jeffrey, J.J. Arch. Biochem. Biophys. (1992) [Pubmed]
  14. Angiotensin II-induced modulation of rat mesangial cell phenotype. Zhang, X., O'Malley, Y., Robbins, M.E. Radiat. Res. (1999) [Pubmed]
  15. Cellular localization of gelatinases and tissue inhibitors of metalloproteinases during follicular growth, ovulation, and early luteal formation in the rat. Curry, T.E., Song, L., Wheeler, S.E. Biol. Reprod. (2001) [Pubmed]
  16. Matrix metalloproteinase-2 activity, protein, mRNA, and tissue inhibitors in small arteries from pregnant and relaxin-treated nonpregnant rats. Jeyabalan, A., Kerchner, L.J., Fisher, M.C., McGuane, J.T., Doty, K.D., Conrad, K.P. J. Appl. Physiol. (2006) [Pubmed]
  17. Expression of matrix metalloproteinase -2, -9 and tissue inhibitors of metalloproteinase -1, -2, -3 mRNAs in rat uterus during early pregnancy. Zhao, Y.G., Xiao, A.Z., Cao, X.M., Zhu, C. Mol. Reprod. Dev. (2002) [Pubmed]
  18. Gelatinases A and B are up-regulated in rat lungs by subacute hyperoxia: pathogenetic implications. Pardo, A., Barrios, R., Maldonado, V., Meléndez, J., Pérez, J., Ruiz, V., Segura-Valdez, L., Sznajder, J.I., Selman, M. Am. J. Pathol. (1998) [Pubmed]
  19. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Phillips, P.A., McCarroll, J.A., Park, S., Wu, M.J., Pirola, R., Korsten, M., Wilson, J.S., Apte, M.V. Gut (2003) [Pubmed]
  20. Expression and activity of matrix metalloproteinase-2 and -9 in experimental granulation tissue. Inkinen, K., Turakainen, H., Wolff, H., Ravanti, L., Kähäri, V.M., Ahonen, J. APMIS (2000) [Pubmed]
  21. Follicle-stimulating hormone increases the expression of tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 and induces TIMP-1 AP-1 site binding complex(es) in prepubertal rat Sertoli cells. Ulisse, S., Farina, A.R., Piersanti, D., Tiberio, A., Cappabianca, L., D'Orazi, G., Jannini, E.A., Malykh, O., Stetler-Stevenson, W.G., D'Armiento, M. Endocrinology (1994) [Pubmed]
  22. Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid. Reif, S., Aeed, H., Shilo, Y., Reich, R., Kloog, Y., Kweon, Y.O., Bruck, R. J. Hepatol. (2004) [Pubmed]
  23. Enzymes active in the areas undergoing cartilage resorption during the development of the secondary ossification center in the tibiae of rats aged 0-21 days: II. Two proteinases, gelatinase B and collagenase-3, are implicated in the lysis of collagen fibrils. Davoli, M.A., Lamplugh, L., Beauchemin, A., Chan, K., Mordier, S., Mort, J.S., Murphy, G., Docherty, A.J., Leblond, C.P., Lee, E.R. Dev. Dyn. (2001) [Pubmed]
  24. Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis. Kossakowska, A.E., Edwards, D.R., Lee, S.S., Urbanski, L.S., Stabbler, A.L., Zhang, C.L., Phillips, B.W., Zhang, Y., Urbanski, S.J. Am. J. Pathol. (1998) [Pubmed]
  25. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Rosenberg, G.A., Estrada, E.Y., Dencoff, J.E. Stroke (1998) [Pubmed]
  26. Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat. Peterson, J.T., Li, H., Dillon, L., Bryant, J.W. Cardiovasc. Res. (2000) [Pubmed]
  27. Irradiation of rat mesangial cells alters the expression of gene products associated with the development of renal fibrosis. Zhao, W., O'Malley, Y., Robbins, M.E. Radiat. Res. (1999) [Pubmed]
  28. Effects of hypoxia, hyperoxia on the regulation of expression and activity of matrix metalloproteinase-2 in hepatic stellate cells. Chen, P.S., Zhai, W.R., Zhou, X.M., Zhang, J.S., Zhang, Y.E., Ling, Y.Q., Gu, Y.H. World J. Gastroenterol. (2001) [Pubmed]
  29. Epithelial cells up-regulate matrix metalloproteinases in cells within the same mammary carcinoma that have undergone an epithelial-mesenchymal transition. Martorana, A.M., Zheng, G., Crowe, T.C., O'Grady, R.L., Lyons, J.G. Cancer Res. (1998) [Pubmed]
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