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Gene Review

Timp1  -  TIMP metallopeptidase inhibitor 1

Rattus norvegicus

Synonyms: Metalloproteinase inhibitor 1, TIMP-1, Timp, Timp-1, Tissue inhibitor of metalloproteinases 1
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Disease relevance of Timp1


High impact information on Timp1

  • The 28- and 38-kD proteins were shown to be identical to the tissue inhibitor of metalloproteinase-1 (TIMP-1) and the proenzyme form of cathepsin L, respectively [5].
  • 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 [6].
  • Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model [7].
  • TIMP-1 overexpression did not effect cell proliferation [8].
  • Overexpression of TIMP-1, -2, or -3, or a synthetic MMP inhibitor similarly inhibited SMC chemotaxis and invasion through reconstituted basement membrane [8].

Chemical compound and disease context of Timp1


Biological context of Timp1


Anatomical context of Timp1

  • Western blotting was used to identify a specific MMP, MMP2 (a gelatinase that digests basement membrane collagen and the dominant MMP observed on zymography) and a specific TIMP, TIMP2 [14].
  • RESULTS: MMP and TIMP coding transcripts were detectable in all liver cell types by reverse transcription-polymerase chain reaction; however, the cellular expression levels were markedly different as assessed by Northern blot analysis [17].
  • In the newly forming CL at 24 h after hCG administration, the luteal cells expressed TIMP-1, -2, and -3 mRNA, although the pattern of cellular expression was unique for each of the TIMPs [18].
  • Immunoreactive TIMP-1 was increased in experimental rats and primarily localized in alveolar macrophages [15].
  • The mRNAs for MMP-9, TIMP-1, and -3 were mainly expressed in epithelial cells on day 1-5 [19].

Associations of Timp1 with chemical compounds

  • TIMP-1 and TIMP-2 were constitutively expressed, and only TIMP-1 displayed a moderate increase with hyperoxia [20].
  • Terazosin evoked a significant increase in the activity of proMMP-2 and MMP-2 but did not affect TIMP [21].
  • All diabetes-associated changes in renal function and MMP/TIMP were attenuated after benazepril treatment with reduced IV-C accumulation [22].
  • All diabetes-associated changes in MMP and TIMP mRNA and activities were attenuated by perindopril treatment in association with reduced type IV collagen accumulation [23].
  • Pirfenidone partially inhibits the enhancement of the expression of TGF-beta 1 and TIMP-1 in lung tissue [24].

Physical interactions of Timp1


Regulatory relationships of Timp1

  • Our data suggest that FSH stimulation of TIMP-2 expression may be regulated independently to that of TIMP-1 [26].
  • CMT-3 posttreatment increased TIMP-1 level and thereby inhibited MMP-9, which in turn decreased TGF-beta1 and caspase-3 signaling pathways and improved survivability in septic rats [27].
  • TGF beta1 enhanced the expression of tissue inhibitors of metalloproteinases (TIMP) 1 and 3 and caused a modest decrease of TIMP 2 mRNA levels [28].
  • We conclude that emodin effectively inhibits PMA- and TGFbeta1-stimulated TIMP-1 expression in hepatic stellate cells by suppressing the AP-1 signaling pathway and extracellular signal-regulated kinase activation, respectively [29].
  • We recently demonstrated that IGFs inhibit bone collagen degradation, and we postulated that they may either inhibit the expression of interstitial collagenase or stimulate the synthesis of tissue inhibitors of metalloproteinase-1 (TIMP-1), -2, or -3 [30].

Other interactions of Timp1

  • Westerns were run on the MMPs known to cleave fibrillar collagen in the rat (MMP-8, -13, and -14) as well as TIMP-1, -2, and -4 [2].
  • In contrast, TIMP-1 and TIMP-3 expression in E19 scarring wounds increased six-fold and four-fold, respectively [31].
  • IL-10 exhibits an antifibrogenic effect by suppressing MMP-2 and TIMP-1 expression [32].
  • 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 [2].
  • Partial hepatectomy was followed by a dramatic increase of MMP-14 and to a lesser extent also of TIMP-1 expression; other MMPs and TIMPs were not significantly induced [33].

Analytical, diagnostic and therapeutic context of Timp1

  • RT-PCR demonstrated the presence of mRNA for metalloproteinase inhibitors TIMP1 and TIMP2 in PSCs while reverse zymography revealed the presence of functional TIMP2 in PSC secretions [14].
  • The present study was designed to assess whether expression of mRNA for extracellular matrix (ECM) components, metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) in glomeruli is affected by a low protein diet during the course of focal glomerulosclerosis (FGS) [34].
  • Total collagen IV, the different alpha(IV) chains, matrix degrading metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) were quantified by immunocytochemistry and/or Western blotting [35].
  • Correct polymerase chain reaction product amplification was confirmed by probing the blotted polymerase chain reaction product with a 32P-labeled oligonucleotide specific for a given MMP or TIMP [36].
  • There was a marked elevation of TIMP-1 mRNA expression after UUO, which was first noted at 12 h after ureteral ligation [37].


  1. 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]
  2. 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]
  3. Gelatinase B and TIMP-1 are regulated in a cell- and time-dependent manner in association with neuronal death and glial reactivity after global forebrain ischemia. Rivera, S., Ogier, C., Jourquin, J., Timsit, S., Szklarczyk, A.W., Miller, K., Gearing, A.J., Kaczmarek, L., Khrestchatisky, M. Eur. J. Neurosci. (2002) [Pubmed]
  4. Differential expression of extracellular matrix remodeling genes in rat model of hemorrhagic shock and resuscitation. Chen, H., Inocencio, R., Alam, H.B., Rhee, P., Koustova, E. J. Surg. Res. (2005) [Pubmed]
  5. Identification of a stimulator of steroid hormone synthesis isolated from testis. Boujrad, N., Ogwuegbu, S.O., Garnier, M., Lee, C.H., Martin, B.M., Papadopoulos, V. Science (1995) [Pubmed]
  6. 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]
  7. Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model. Allaire, E., Forough, R., Clowes, M., Starcher, B., Clowes, A.W. J. Clin. Invest. (1998) [Pubmed]
  8. Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. Baker, A.H., Zaltsman, A.B., George, S.J., Newby, A.C. J. Clin. Invest. (1998) [Pubmed]
  9. Hyperoxia decreases matrix metalloproteinase-9 and increases tissue inhibitor of matrix metalloproteinase-1 protein in the newborn rat lung: association with arrested alveolarization. Hosford, G.E., Fang, X., Olson, D.M. Pediatr. Res. (2004) [Pubmed]
  10. Rat liver fibrosis regresses better with pegylated interferon alpha2b and ursodeoxycholic acid treatments than spontaneous recovery. Tasci, I., Mas, M.R., Vural, S.A., Comert, B., Alcigir, G., Serdar, M., Mas, N., Isik, A.T., Ates, Y. Liver Int. (2006) [Pubmed]
  11. Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis. Arthur, M.J., Mann, D.A., Iredale, J.P. J. Gastroenterol. Hepatol. (1998) [Pubmed]
  12. Effect of glutathione depletion and hydrophilic bile acids on hepatic acute phase reaction in rats with extrahepatic cholestasis. Roeb, E., Purucker, E., Gartung, C., Geier, A., Jansen, B., Winograd, R., Matern, S. Scand. J. Gastroenterol. (2003) [Pubmed]
  13. The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen alpha1(I), TIMP-1 and MMP-2. Di Sario, A., Bendia, E., Macarri, G., Candelaresi, C., Taffetani, S., Marzioni, M., Omenetti, A., De Minicis, S., Trozzi, L., Benedetti, A. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. (2004) [Pubmed]
  14. 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]
  15. Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis. Ruiz, V., Ordóñez, R.M., Berumen, J., Ramírez, R., Uhal, B., Becerril, C., Pardo, A., Selman, M. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
  16. Leukemia inhibitory factor and oncostatin M stimulate collagenase-3 expression in osteoblasts. Varghese, S., Yu, K., Canalis, E. Am. J. Physiol. (1999) [Pubmed]
  17. Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1. Knittel, T., Mehde, M., Kobold, D., Saile, B., Dinter, C., Ramadori, G. J. Hepatol. (1999) [Pubmed]
  18. 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]
  19. 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]
  20. 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]
  21. Terazosin modifies the content of glycosaminoglycans and the activity of matrix metalloproteinase 2 in the rat ventral prostate. Mitropoulos, D., Papakonstantinou, E., Aletras, A.J., Kalinderis, N., Zervas, A., Hatzichristou, D., Karakiulakis, G. Eur. Urol. (2007) [Pubmed]
  22. 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]
  23. Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases. McLennan, S.V., Kelly, D.J., Cox, A.J., Cao, Z., Lyons, J.G., Yue, D.K., Gilbert, R.E. Diabetologia (2002) [Pubmed]
  24. Low dose pirfenidone suppresses transforming growth factor beta-1 and tissue inhibitor of metalloproteinase-1, and protects rats from lung fibrosis induced by bleomycina. Tian, X.L., Yao, W., Guo, Z.J., Gu, L., Zhu, Y.J. Chin. Med. Sci. J. (2006) [Pubmed]
  25. Induction of cell death in activated hepatic stellate cells by targeted gene expression of the thymidine kinase/ganciclovir system. Janoschek, N., van de Leur, E., Gressner, A.M., Weiskirchen, R. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  26. 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]
  27. Effect of chemically modified tetracycline on transforming growth factor-beta1 and caspase-3 activation in liver of septic rats. Maitra, S.R., Shapiro, M.J., Bhaduri, S., El-Maghrabi, M.R. Crit. Care Med. (2005) [Pubmed]
  28. Transforming growth factor beta1 inhibits collagenase 3 expression by transcriptional and post-transcriptional mechanisms in osteoblast cultures. Rydziel, S., Varghese, S., Canalis, E. J. Cell. Physiol. (1997) [Pubmed]
  29. Inhibitory Effect of Emodin on Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Expression in Rat Hepatic Stellate Cells. Gui, M., Zhang, Y.F., Xiao, Z.Y., Sun, P., Dai, J.F., Wang, S.F., Rui, Y.C., Zhang, J.P. Dig. Dis. Sci. (2007) [Pubmed]
  30. Insulin-like growth factors inhibit interstitial collagenase synthesis in bone cell cultures. Canalis, E., Rydziel, S., Delany, A.M., Varghese, S., Jeffrey, J.J. Endocrinology (1995) [Pubmed]
  31. Scarless fetal wounds are associated with an increased matrix metalloproteinase-to-tissue-derived inhibitor of metalloproteinase ratio. Dang, C.M., Beanes, S.R., Lee, H., Zhang, X., Soo, C., Ting, K. Plast. Reconstr. Surg. (2003) [Pubmed]
  32. Expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 in hepatic stellate cells during rat hepatic fibrosis and its intervention by IL-10. Zheng, W.D., Zhang, L.J., Shi, M.N., Chen, Z.X., Chen, Y.X., Huang, Y.H., Wang, X.Z. World J. Gastroenterol. (2005) [Pubmed]
  33. Expression of matrix metalloproteinases and their inhibitors during hepatic tissue repair in the rat. Knittel, T., Mehde, M., Grundmann, A., Saile, B., Scharf, J.G., Ramadori, G. Histochem. Cell Biol. (2000) [Pubmed]
  34. Low protein diet blunts the rise in glomerular gene expression in focal glomerulosclerosis. Nakamura, T., Fukui, M., Ebihara, I., Tomino, Y., Koide, H. Kidney Int. (1994) [Pubmed]
  35. Vitamin A deficiency alters the structure and collagen IV composition of rat renal basement membranes. Marín, M.P., Esteban-Pretel, G., Alonso, R., Sado, Y., Barber, T., Renau-Piqueras, J., Timoneda, J. J. Nutr. (2005) [Pubmed]
  36. Differential expression of matrix metalloproteinases and their tissue-derived inhibitors in cutaneous wound repair. Soo, C., Shaw, W.W., Zhang, X., Longaker, M.T., Howard, E.W., Ting, K. Plast. Reconstr. Surg. (2000) [Pubmed]
  37. Differential mRNA expression of renal cortical tissue inhibitor of metalloproteinase-1, -2, and -3 in experimental hydronephrosis. Engelmyer, E., van Goor, H., Edwards, D.R., Diamond, J.R. J. Am. Soc. Nephrol. (1995) [Pubmed]
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