tissue inhibitor of metalloproteinases


Summary: A family of secreted protease inhibitory proteins that regulates the activity of SECRETED MATRIX METALLOENDOPEPTIDASES. They play an important role in modulating the proteolysis of EXTRACELLULAR MATRIX, most notably during tissue remodeling and inflammatory processes.

Top Publications

  1. Lisboa R, Andrade M, Cunha Melo J. Toll-like receptor activation and mechanical force stimulation promote the secretion of matrix metalloproteinases 1, 3 and 10 of human periodontal fibroblasts via p38, JNK and NF-kB. Arch Oral Biol. 2013;58:731-9 pubmed publisher
    ..The expression of MMP-1, -2, -3, -8, -9, -10 and -13; TIMP (Tissue Inhibitor of Metalloproteinases) -1, -2 and -4; TNF-? (Tumour Necrosis Factor alpha); IL-1? (Interleukin 1 beta); ERK 1/2 (..
  2. Weir R, Clements S, Steedman T, Dargie H, McMurray J, Squire I, et al. Plasma TIMP-4 predicts left ventricular remodeling after acute myocardial infarction. J Card Fail. 2011;17:465-71 pubmed publisher
    ..Further study of the role of the TIMPs in the pathophysiology of postinfarction remodeling is warranted. ..
  3. Kucera K, Harrison L, Cappello M, Modis Y. Ancylostoma ceylanicum excretory-secretory protein 2 adopts a netrin-like fold and defines a novel family of nematode proteins. J Mol Biol. 2011;408:9-17 pubmed publisher
    ..Together, our results suggest that AceES-2 defines a novel family of nematode netrin-like proteins, which may function to modulate the host immune response to hookworm and other parasites. ..
  4. Tsarouhas K, Soufla G, Apostolakis S, Zaravinos A, Panagiotou M, Khoury M, et al. Transcriptional regulation of TIMPs in ascending aorta aneurysms. Thromb Res. 2010;126:399-405 pubmed publisher
    ..Surprisingly, the tissue inhibitor of metalloproteinases (TIMP)-3 was significantly more expressed in dilated aortic tissue compared to control tissue, ..
  5. Zitka O, Kukacka J, Krizkova S, Huska D, Adam V, Masarik M, et al. Matrix metalloproteinases. Curr Med Chem. 2010;17:3751-68 pubmed
  6. Amalinei C, Caruntu I, Giuşcă S, Bălan R. Matrix metalloproteinases involvement in pathologic conditions. Rom J Morphol Embryol. 2010;51:215-28 pubmed
  7. Liss M, Sreedhar N, Keshgegian A, Sauter G, Chernick M, Prendergast G, et al. Tissue inhibitor of metalloproteinase-4 is elevated in early-stage breast cancers with accelerated progression and poor clinical course. Am J Pathol. 2009;175:940-6 pubmed publisher
    ..Our findings prompt further evaluation of TIMP-4 as a simple prognostic marker that may help identify patients with early-stage breast cancer who could benefit from more aggressive treatment at diagnosis. ..
  8. Fu O, Hou M, Yang S, Huang S, Lee W. Cobalt chloride-induced hypoxia modulates the invasive potential and matrix metalloproteinases of primary and metastatic breast cancer cells. Anticancer Res. 2009;29:3131-8 pubmed
    ..e. primary cancer cells expressed a wider range of MMPs, in particular MMP-2, -7 and -9, than the metastatic ones. The data suggest that MMPs play no crucial roles in hypoxia-induced tumor progression in primary breast cancer cells. ..
  9. Mishra P, Tyagi N, Kundu S, Tyagi S. MicroRNAs are involved in homocysteine-induced cardiac remodeling. Cell Biochem Biophys. 2009;55:153-62 pubmed publisher
    ..These findings suggest that dicer and miRNAs especially miR-188 are involved in Hcy-induced cardiac remodeling. ..

More Information


  1. Pérez Sayáns García M, Suárez Peñaranda J, Gayoso Diz P, Barros Angueira F, Gandara Rey J, Garcia Garcia A. Tissue inhibitor of metalloproteinases in oral squamous cell carcinomas - a therapeutic target?. Cancer Lett. 2012;323:11-9 pubmed publisher
  2. Garofalo R, Cesari E, Vinci E, Castagna A. Role of metalloproteinases in rotator cuff tear. Sports Med Arthrosc Rev. 2011;19:207-12 pubmed publisher
    ..A better understanding of relationship and activity of these molecules could provide better strategies to optimize outcomes of rotator cuff therapy. ..
  3. Moore L, Fan D, Basu R, Kandalam V, Kassiri Z. Tissue inhibitor of metalloproteinases (TIMPs) in heart failure. Heart Fail Rev. 2012;17:693-706 pubmed publisher
    ..by a balance in the function of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs)...
  4. Zhang M, Zhu G, Gao H, Zhao S, Xue Y. Expression of tissue levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in gastric adenocarcinoma. J Surg Oncol. 2011;103:243-7 pubmed publisher
    ..The correlation between the increased expression of MMP-2, MMP-7, MMP-9, and MTI-MMP and clinicopathological parameters reflects a role in predicting the aggressive behavior of gastric cancer. ..
  5. Manon Jensen T, Itoh Y, Couchman J. Proteoglycans in health and disease: the multiple roles of syndecan shedding. FEBS J. 2010;277:3876-89 pubmed publisher
    ..Here, recent research into the shedding of syndecans and its physiological relevance are assessed. ..
  6. Zou J, Yuan B, Wang D, Li C, Wu J. [Changes of serum matrix metalloproteinases-9 and tissue inhibitors of metalloproteinases-9 in coal workers' pneumoconiosis]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2010;28:21-4 pubmed
    ..Dynamic observation of its concentration in group 0+ and health miners might contribute to the prevention, early diagnosis and differential diagnosis of CWP. ..
  7. Biolo A, Ramamurthy S, Connors L, O Hara C, Meier Ewert H, Soo Hoo P, et al. Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: relationship to structural, functional myocardial changes and to light chain amyloid deposition. Circ Heart Fail. 2008;1:249-57 pubmed publisher
  8. Vanhoutte D, Heymans S. TIMPs and cardiac remodeling: 'Embracing the MMP-independent-side of the family'. J Mol Cell Cardiol. 2010;48:445-53 pubmed publisher
    ..Finally, we identify where additional research is needed that will codetermine the possible future of TIMPs as therapeutic targets. ..
  9. Reel B, Sala Newby G, Huang W, Newby A. Diverse patterns of cyclooxygenase-independent metalloproteinase gene regulation in human monocytes. Br J Pharmacol. 2011;163:1679-90 pubmed publisher
  10. Kapral M, Wawszczyk J, Jurzak M, Dymitruk D, Węglarz L. Evaluation of the expression of metalloproteinases 2 and 9 and their tissue inhibitors in colon cancer cells treated with phytic acid. Acta Pol Pharm. 2010;67:625-9 pubmed
    ..The results of this study show that IP6 modulates MMP-2, TIMP-1 and TIMP-2 genes expression in colon cancer cells at the transcriptional level in a way dependent on its concentration and time of interaction. ..
  11. Löffek S, Schilling O, Franzke C. Series "matrix metalloproteinases in lung health and disease": Biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011;38:191-208 pubmed publisher
  12. Rivera S, Khrestchatisky M, Kaczmarek L, Rosenberg G, Jaworski D. Metzincin proteases and their inhibitors: foes or friends in nervous system physiology?. J Neurosci. 2010;30:15337-57 pubmed publisher
    ..The present review provides a state of the art overview of the involvement of the metzincin/TIMP system in these processes and the prospects of new therapeutic strategies based on the control of metalloproteinase activity. ..
  13. Mühl D, Nagy B, Woth G, Falusi B, Bogar L, Weber G, et al. Dynamic changes of matrix metalloproteinases and their tissue inhibitors in severe sepsis. J Crit Care. 2011;26:550-5 pubmed publisher
    ..Our results indicate that MMPs and TIMPs may play a crucial role in severe sepsis, especially TIMP-1, MMP-9, and possibly TIMP-2, after an extensive study. ..
  14. Koskivirta I, Kassiri Z, Rahkonen O, Kiviranta R, Oudit G, McKee T, et al. Mice with tissue inhibitor of metalloproteinases 4 (Timp4) deletion succumb to induced myocardial infarction but not to cardiac pressure overload. J Biol Chem. 2010;285:24487-93 pubmed publisher
    b>Tissue inhibitor of metalloproteinases 4 (TIMP4) is expressed highly in heart and found dysregulated in human cardiovascular diseases...
  15. Bourboulia D, Stetler Stevenson W. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin Cancer Biol. 2010;20:161-8 pubmed publisher
    ..In this review, we describe and discuss data that support the important role of MMPs and TIMPs in cancer cell adhesion and tumor progression. ..
  16. Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta. 2010;1803:55-71 pubmed publisher
    ..A series of studies using mice with specific TIMP gene deletions has illuminated the importance of these molecules in biology and pathology. ..
  17. Mishra P, Tyagi N, Sen U, Givvimani S, Tyagi S. H2S ameliorates oxidative and proteolytic stresses and protects the heart against adverse remodeling in chronic heart failure. Am J Physiol Heart Circ Physiol. 2010;298:H451-6 pubmed publisher
    ..The levels of ADAM-12, apoptosis, and fibrosis were robust and integrin were decreased in AVF hearts. The treatment with H(2)S donor attenuated the fibrosis, apoptosis, and decrease in integrin. ..
  18. Niebroj Dobosz I, Janik P, Sokołowska B, Kwiecinski H. Matrix metalloproteinases and their tissue inhibitors in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Eur J Neurol. 2010;17:226-31 pubmed publisher
    ..Although the role of changed MMPs/TIMPs level in the pathogenesis of ALS is not clear their analysis in serum may be used as prognostic factor and a potential marker for monitoring treatment effects. ..
  19. Moore C, Crocker S. An alternate perspective on the roles of TIMPs and MMPs in pathology. Am J Pathol. 2012;180:12-6 pubmed publisher
    ..This broader view reflects our emerging understanding that TIMP signaling and MMP inhibition represent two important functions of TIMPs that have the potential to affect tissue pathology. ..
  20. Del Buono A, Oliva F, Longo U, Rodeo S, Orchard J, Denaro V, et al. Metalloproteases and rotator cuff disease. J Shoulder Elbow Surg. 2012;21:200-8 pubmed publisher
    ..Further studies are needed to better define the mechanism of action, and whether these new strategies are safe and effective in larger models. ..
  21. Murphy G. Tissue inhibitors of metalloproteinases. Genome Biol. 2011;12:233 pubmed publisher
    ..There are clearly still questions to be answered with regard to their overall roles in biology. ..
  22. Tency I, Verstraelen H, Kroes I, Holtappels G, Verhasselt B, Vaneechoutte M, et al. Imbalances between matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in maternal serum during preterm labor. PLoS ONE. 2012;7:e49042 pubmed publisher
  23. Castro M, Rizzi E, Prado C, Rossi M, Tanus Santos J, Gerlach R. Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling. Matrix Biol. 2010;29:194-201 pubmed publisher
  24. Murphy G, Nagase H. Reappraising metalloproteinases in rheumatoid arthritis and osteoarthritis: destruction or repair?. Nat Clin Pract Rheumatol. 2008;4:128-35 pubmed publisher
    ..Work on the development of effective biomarkers is also essential before an effective evaluation of the new generations of specific inhibitors can be made. ..
  25. Bonnema D, Webb C, Pennington W, Stroud R, Leonardi A, Clark L, et al. Effects of age on plasma matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). J Card Fail. 2007;13:530-40 pubmed
    ..Matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) constitute one important proteolytic pathway affecting LV remodeling...
  26. Murphy G, Murthy A, Khokha R. Clipping, shedding and RIPping keep immunity on cue. Trends Immunol. 2008;29:75-82 pubmed publisher
  27. Page McCaw A. Remodeling the model organism: matrix metalloproteinase functions in invertebrates. Semin Cell Dev Biol. 2008;19:14-23 pubmed
    ..In worms and in flies, MMPs are regulated by the JNK pathway. ..
  28. Figueira R, Gomes L, Neto J, Silva F, Silva I, Sogayar M. Correlation between MMPs and their inhibitors in breast cancer tumor tissue specimens and in cell lines with different metastatic potential. BMC Cancer. 2009;9:20 pubmed publisher
    ..Therefore, the multi-factorial analysis of these molecules could provide new and independent prognostic information contributing to the determination of more adequate therapy strategies for each patient. ..
  29. Araujo B, Dolhnikoff M, Silva L, Elliot J, Lindeman J, Ferreira D, et al. Extracellular matrix components and regulators in the airway smooth muscle in asthma. Eur Respir J. 2008;32:61-9 pubmed publisher
  30. Gonzalez L, Pidal I, Junquera S, Corte M, Vazquez J, Rodriguez J, et al. Overexpression of matrix metalloproteinases and their inhibitors in mononuclear inflammatory cells in breast cancer correlates with metastasis-relapse. Br J Cancer. 2007;97:957-63 pubmed
    ..Therefore, this finding suggests that these host inflammatory cells could be a possible target for inhibition of metastasis. ..
  31. Donnini S, Monti M, Roncone R, Morbidelli L, Rocchigiani M, Oliviero S, et al. Peroxynitrite inactivates human-tissue inhibitor of metalloproteinase-4. FEBS Lett. 2008;582:1135-40 pubmed publisher
    ..HPLC/ESI-MS/MS analysis of peroxynitrite-treated TIMP-4 showed modifications at Y114, Y195, Y188 and Y190. In conclusion, TIMP-4 nitration might be a potential mechanism contributing to cardiovascular disease and cancer. ..
  32. Boden G, Song W, Kresge K, Mozzoli M, Cheung P. Effects of hyperinsulinemia on hepatic metalloproteinases and their tissue inhibitors. Am J Physiol Endocrinol Metab. 2008;295:E692-7 pubmed publisher
    ..We conclude that hyperinsulinemia, whether or not associated with insulin resistance, shifts the MMP/TIMP balance toward reduction of extracellular matrix degradation and thus may promote the development of hepatic fibrosis. ..
  33. Becher N, Hein M, Uldbjerg N, Danielsen C. Balance between matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in the cervical mucus plug estimated by determination of free non-complexed TIMP. Reprod Biol Endocrinol. 2008;6:45 pubmed publisher
    ..This indicates a potential to degrade extracellular matrix components depending on the balance between free non-complexed inhibitors and active enzymes...
  34. Bister V, Skoog T, Virolainen S, Kiviluoto T, Puolakkainen P, Saarialho Kere U. Increased expression of matrix metalloproteinases-21 and -26 and TIMP-4 in pancreatic adenocarcinoma. Mod Pathol. 2007;20:1128-40 pubmed
    ..The putative role of MMP-26 as a marker of metastases warrants further studies. Unlike other TIMPs, TIMP-4 was not upregulated in relation to aggressiveness of pancreatic cancer. ..
  35. Raffetto J, Khalil R. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol. 2008;75:346-59 pubmed
  36. Hilska M, Roberts P, Collan Y, Laine V, Kössi J, Hirsimäki P, et al. Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer. Int J Cancer. 2007;121:714-23 pubmed
    ..Different biologic behavior or different genetic development may explain the differences between colon and rectal cancers regarding the expression of MMP-2, TIMP-3 and TIMP-4. ..
  37. Yuan X, Mitchell B, Wilhelmus K. Expression of matrix metalloproteinases during experimental Candida albicans keratitis. Invest Ophthalmol Vis Sci. 2009;50:737-42 pubmed publisher
    ..This study was designed to investigate the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during the inception and progression of experimental keratomycosis...
  38. Clark I, Swingler T, Sampieri C, Edwards D. The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol. 2008;40:1362-78 pubmed publisher
    ..Control over MMP and/or tissue inhibitor of metalloproteinases (TIMP) activity in vivo occurs at different levels and involves factors such as regulation of gene ..
  39. Lee H, Lee G, Nah S, Lee K, Yang H, Kim Y, et al. Association of TIMP-4 gene polymorphism with the risk of osteoarthritis in the Korean population. Rheumatol Int. 2008;28:845-50 pubmed publisher
    ..We demonstrated that the C/T polymorphism which is located on the 3'-untranslational regions of the TIMP-4 gene might be associated with susceptibility to OA patients. ..
  40. Coussens A, Timms P, Boucher B, Venton T, Ashcroft A, Skolimowska K, et al. 1alpha,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection. Immunology. 2009;127:539-48 pubmed publisher
    ..1alpha,25(OH)(2)D(3) also induced secretion of IL-10 and PGE(2) from M. tuberculosis-infected PBMC. These findings represent a novel immunomodulatory role for 1alpha,25(OH)(2)D(3) in M. tuberculosis infection. ..
  41. Garcia Lopez G, Vadillo Ortega F, Merchant Larios H, Maida Claros R, Osorio M, Soriano Becerril D, et al. Evidence of in vitro differential secretion of 72 and 92 kDa type IV collagenases after selective exposure to lipopolysaccharide in human fetal membranes. Mol Hum Reprod. 2007;13:409-18 pubmed
  42. Hobeika M, Thompson R, Muhs B, Brooks P, Gagne P. Matrix metalloproteinases in peripheral vascular disease. J Vasc Surg. 2007;45:849-57 pubmed
    ..In addition, the importance of MMPs in the future diagnosis and treatment of peripheral vascular disease is discussed. ..
  43. Cockle J, Gopichandran N, Walker J, Levene M, Orsi N. Matrix metalloproteinases and their tissue inhibitors in preterm perinatal complications. Reprod Sci. 2007;14:629-45 pubmed
    ..MMPs are involved in the perinatal complications of prematurity and are potential targets for therapeutic intervention. Functional MMP genetic polymorphisms may assist in identifying patients at risk of complications. ..
  44. Jacobsen J, Visse R, Sørensen H, Enghild J, Brew K, Wewer U, et al. Catalytic properties of ADAM12 and its domain deletion mutants. Biochemistry. 2008;47:537-47 pubmed
    ..These results indicate unique enzymatic properties of ADAM12 among the members of the ADAM family of metalloproteinases. ..
  45. Vizoso F, Gonzalez L, Corte M, Rodriguez J, Vazquez J, Lamelas M, et al. Study of matrix metalloproteinases and their inhibitors in breast cancer. Br J Cancer. 2007;96:903-11 pubmed
  46. Lukaszewicz Zajac M, Mroczko B, Szmitkowski M. [The significance of metalloproteinases and their inhibitors in gastric cancer]. Postepy Hig Med Dosw (Online). 2009;63:258-65 pubmed
    ..Some clinical investigations have suggested the usefulness of MMP sand TIMPs as prognostic factors for the survival of gastric cancer patients. ..
  47. Aupperle H, Thielebein J, Kiefer B, Marz I, Dinges G, Schoon H, et al. Expression of genes encoding matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in normal and diseased canine mitral valves. J Comp Pathol. 2009;140:271-7 pubmed publisher
    ..MMPs and TIMPs are therefore likely to be involved in extracellular matrix metabolism in normal canine MVs and there are significant alterations in the expression of genes encoding these molecules during CVD. ..
  48. Melendez Zajgla J, del Pozo L, Ceballos G, Maldonado V. Tissue inhibitor of metalloproteinases-4. The road less traveled. Mol Cancer. 2008;7:85 pubmed publisher
    ..The present review summarizes the information available for this protein and also provides a putative structural model in order to propose potential relevant directions toward solving its function and role in diseases such as cancer. ..
  49. Sivakumar P, Gupta S, Sarkar S, Sen S. Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy. Mol Cell Biochem. 2008;307:159-67 pubmed
    ..Altogether, our data suggest an alteration of collagen, MMPs, various cytokines and particularly, LOX participates, in part, in the remodeling of the heart leading to cardiac dysfunction and HF. ..
  50. Partridge J, Madsen M, Ardi V, Papagiannakopoulos T, Kupriyanova T, Quigley J, et al. Functional analysis of matrix metalloproteinases and tissue inhibitors of metalloproteinases differentially expressed by variants of human HT-1080 fibrosarcoma exhibiting high and low levels of intravasation and metastasis. J Biol Chem. 2007;282:35964-77 pubmed
    ..Collectively, these findings demonstrate that tumor-derived MMPs may have protective functions in cancer cell intravasation, i.e. not promoting but rather catalytically interfering with the early stages of cancer dissemination. ..
  51. Ooi Y, Oh D, Rhee D. Effect of bimatoprost, latanoprost, and unoprostone on matrix metalloproteinases and their inhibitors in human ciliary body smooth muscle cells. Invest Ophthalmol Vis Sci. 2009;50:5259-65 pubmed publisher
  52. Vairaktaris E, Serefoglou Z, Avgoustidis D, Yapijakis C, Critselis E, Vylliotis A, et al. Gene polymorphisms related to angiogenesis, inflammation and thrombosis that influence risk for oral cancer. Oral Oncol. 2009;45:247-53 pubmed publisher
    ..Based on these findings and previous reports, possible interactions of the implicated factors leading to OSCC development, as well as an algorithm of risk estimation are discussed. ..