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Gene Review

TIMP3  -  TIMP metallopeptidase inhibitor 3

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Disease relevance of TIMP3

  • Transfection of cytomegalovirus (CMV) promoter-Sp1 plasmid increased TIMP-3 promoter (-940 to +376)-driven luciferase activity [1].
  • Unlike many of the recently described genes that cause human retinal disease, TIMP-3 is preferentially expressed in the RPE of the normal eye, as opposed to the photoreceptors [2].
  • Expression of TIMP-3 in the RPE is consistent with the recent demonstration of TIMP-3 mutations in patients with Sorsby's fundus dystrophy, a condition marked by the early onset of choroidal neovascularization in the macula [2].

High impact information on TIMP3


Biological context of TIMP3

  • TGF-beta did not alter stability of the TIMP-3 transcripts in RNA decay time-courses, suggesting a transcriptional control [5].
  • DNA sequencing of bovine TIMP-3 cDNA revealed an open reading frame of a 211-amino-acid protein containing signal peptide and 12 conserved cysteines [5].
  • These results suggest that the expression of MMPs-2, 3 and 9 and TIMP-3 is likely to be discoordinately regulated due to interaction with collagen and/or TGF-beta1 in bovine endometrium, and thereby different sets of MMPs may be associated with ECM remodeling during implantation and placentation in vivo [6].

Anatomical context of TIMP3

  • Freshly released chondrocytes constitutively expressed three transcripts of TIMP-3 that are induced by serum factors [5].
  • To clarify the mechanism of extracellular matrix (ECM) remodeling in bovine endometrium, we investigated the regulation of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-3 (TIMP-3) in bovine endometrial stromal cells (BESCs) on type-I collagen gel [6].
  • Localization of TIMP-3 mRNA expression to the retinal pigment epithelium [2].
  • TIMP-3 mRNA expression was detected strongly in the retinal pigment epithelium (RPE) and to a minor extent in the ciliary epithelium, but not at any other site within the eye [2].
  • In bovine synovial fibroblasts, TNF-alpha did not affect a recently identified inhibitor, TIMP-3, but induced stromelysin mRNA expression in a dose- and time-dependent fashion (3- to 5-fold) which required de novo protein synthesis [7].

Associations of TIMP3 with chemical compounds


Other interactions of TIMP3

  • We examined the implication of protein kinases in the TGF-beta-mediated induction of TIMP-3 expression by utilizing activators and inhibitors of these enzymes [8].
  • TIMP-3 protein was localized to granulosal and thecal layers of preovulatory follicles and adjacent ovarian stroma, whereas TIMP-4 immunoreactivity was localized to granulosal and thecal cells and ovarian blood vessels [9].

Analytical, diagnostic and therapeutic context of TIMP3

  • In situ hybridization was performed on frozen sections of albino mouse eyes using riboprobes generated to the 3' untranslated region of TIMP-3 [2].
  • Ovaries containing preovulatory follicles were collected at 0, 12 and 20 h after GnRH injection for real-time PCR quantification of TIMP-3 and TIMP-4 mRNAs and immunohistochemical localization studies [9].


  1. TGF-beta-induced expression of tissue inhibitor of metalloproteinases-3 gene in chondrocytes is mediated by extracellular signal-regulated kinase pathway and Sp1 transcription factor. Qureshi, H.Y., Sylvester, J., Mabrouk, M.E., Zafarullah, M. J. Cell. Physiol. (2005) [Pubmed]
  2. Localization of TIMP-3 mRNA expression to the retinal pigment epithelium. Della, N.G., Campochiaro, P.A., Zack, D.J. Invest. Ophthalmol. Vis. Sci. (1996) [Pubmed]
  3. Oncostatin M up-regulates tissue inhibitor of metalloproteinases-3 gene expression in articular chondrocytes via de novo transcription, protein synthesis, and tyrosine kinase- and mitogen-activated protein kinase-dependent mechanisms. Li, W.Q., Zafarullah, M. J. Immunol. (1998) [Pubmed]
  4. Transforming growth factor Beta1 induction of tissue inhibitor of metalloproteinases 3 in articular chondrocytes is mediated by reactive oxygen species. Li, W.Q., Qureshi, H.Y., Liacini, A., Dehnade, F., Zafarullah, M. Free Radic. Biol. Med. (2004) [Pubmed]
  5. Regulation of tissue inhibitor of metalloproteinases-3 gene expression by transforming growth factor-beta and dexamethasone in bovine and human articular chondrocytes. Su, S., Dehnade, F., Zafarullah, M. DNA Cell Biol. (1996) [Pubmed]
  6. Discoordinate regulation of expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases-3 in bovine endometrial stromal cells on type-I collagen gel. Hirata, M., Sato, T., Tsumagari, M., Hashizume, K., Ito, A. Biol. Pharm. Bull. (2003) [Pubmed]
  7. Induction of stromelysin gene expression by tumor necrosis factor alpha is inhibited by dexamethasone, salicylate, and N-acetylcysteine in synovial fibroblasts. Morin, I., Li, W.Q., Su, S., Ahmad, M., Zafarullah, M. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  8. Up-regulation of tissue inhibitor of metalloproteinases-3 gene expression by TGF-beta in articular chondrocytes is mediated by serine/threonine and tyrosine kinases. Su, S., DiBattista, J.A., Sun, Y., Li, W.Q., Zafarullah, M. J. Cell. Biochem. (1998) [Pubmed]
  9. Localization and temporal regulation of tissue inhibitors of metalloproteinases 3 and 4 in bovine preovulatory follicles. Li, Q., Bakke, L.J., Pursley, J.R., Smith, G.W. Reproduction (2004) [Pubmed]
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