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Cytokine functions of TIMP-1

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Abstract

The tissue inhibitors of metalloproteinases (TIMPs) are well recognized for their role in extracellular matrix remodeling by controlling the activity of matrix metalloproteinases (MMPs). Independent of MMP inhibition, TIMPs act as signaling molecules with cytokine-like activities thereby influencing various biological processes including cell growth, apoptosis, differentiation, angiogenesis, and oncogenesis. Recent studies on TIMP-1’s cytokine functions have identified complex regulatory networks involving a specific surface receptor and subsequent signaling pathways including miRNA-mediated posttranscriptional regulation of gene expression that ultimately control the fate and behavior of the cells. The present review summarizes the current knowledge on TIMP-1 as a cytokine modulator of cell functions, outlines recent progress in defining molecular pathways that transmit TIMP-1 signals from the cell periphery into the nucleus, and discusses TIMP-1’s role as a cytokine in the pathophysiology of cancer and other human diseases.

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References

  1. Woolley DE, Roberts DR, Evanson JM (1975) Inhibition of human collagenase activity by a small molecular weight serum protein. Biochem Biophys Res Commun 66(2):747–754

    CAS  PubMed  Google Scholar 

  2. Bauer EA, Stricklin GP, Jeffrey JJ, Eisen AZ (1975) Collagenase production by human skin fibroblasts. Biochem Biophys Res Commun 64(1):232–240

    CAS  PubMed  Google Scholar 

  3. Westbrook CA, Gasson JC, Gerber SE, Selsted ME, Golde DW (1984) Purification and characterization of human T-lymphocyte-derived erythroid-potentiating activity. J Biol Chem 259(16):9992–9996

    CAS  PubMed  Google Scholar 

  4. Docherty AJ, Lyons A, Smith BJ, Wright EM, Stephens PE, Harris TJ, Murphy G, Reynolds JJ (1985) Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 318:66–69

    CAS  PubMed  Google Scholar 

  5. Gasson JC, Golde DW, Kaufman SE, Westbrook CA, Hewick RM, Kaufman RJ, Wong GG, Temple PA, Leary AC, Brown EL et al (1985) Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature 315:768–771

    CAS  PubMed  Google Scholar 

  6. Stetler Stevenson WG, Krutzsch HC, Liotta LA (1989) Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. J Biol Chem 264:17374–17378

    CAS  PubMed  Google Scholar 

  7. Pavloff N, Staskus PW, Kishnani NS, Hawkes SP (1992) A new inhibitor of metalloproteinases from chicken: ChIMP-3. A third member of the TIMP family. J Biol Chem 267(24):17321–17326

    CAS  PubMed  Google Scholar 

  8. Greene J, Wang M, Liu YE, Raymond LA, Rosen C, Shi YE (1996) Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 271(48):30375–30380

    CAS  PubMed  Google Scholar 

  9. Murphy G, Nagase H (2008) Progress in matrix metalloproteinase research. Mol Aspects Med 29(5):290–308

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174

    CAS  PubMed  Google Scholar 

  11. Kramer F, Milting H (2011) Novel biomarkers in human terminal heart failure and under mechanical circulatory support. Biomarkers 16(Suppl 1):S31–S41

    CAS  PubMed  Google Scholar 

  12. Marchesi C, Dentali F, Nicolini E, Maresca AM, Tayebjee MH, Franz M, Guasti L, Venco A, Schiffrin EL, Lip GY, Grandi AM (2012) Plasma levels of matrix metalloproteinases and their inhibitors in hypertension: a systematic review and meta-analysis. J Hypertens 30(1):3–16

    CAS  PubMed  Google Scholar 

  13. Wurtz SO, Schrohl AS, Mouridsen H, Brunner N (2008) TIMP-1 as a tumor marker in breast cancer—an update. Acta Oncol 47(4):580–590

    PubMed  Google Scholar 

  14. Lee JH, Choi JW, Kim YS (2011) Plasma or serum TIMP-1 is a predictor of survival outcomes in colorectal cancer: a meta-analysis. J Gastrointestin Liver Dis 20(3):287–291

    PubMed  Google Scholar 

  15. Lambert E, Dasse E, Haye B, Petitfrere E (2004) TIMPs as multifacial proteins. Crit Rev Oncol Hematol 49(3):187–198

    PubMed  Google Scholar 

  16. Stetler-Stevenson WG (2008) Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal 1(27):re6

    PubMed Central  PubMed  Google Scholar 

  17. Murphy G (2011) Tissue inhibitors of metalloproteinases. Genome Biol 12(11):233

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Brew K, Nagase H (2010) The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 1803(1):55–71

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Murphy G, Houbrechts A, Cockett MI, Williamson RA, O’Shea M, Docherty AJ (1991) The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity. Biochemistry 30:8097–8102 [published erratum appears in Biochemistry 1991 Oct 22;30(42):10362]

    CAS  PubMed  Google Scholar 

  20. Zhang J, Bai S, Tanase C, Nagase H, Sarras MP Jr (2003) The expression of tissue inhibitor of metalloproteinase 2 (TIMP-2) is required for normal development of zebrafish embryos. Dev Genes Evol 213(8):382–389

    CAS  PubMed  Google Scholar 

  21. Jaworski DM, Soloway P, Caterina J, Falls WA (2006) Tissue inhibitor of metalloproteinase-2(TIMP-2)-deficient mice display motor deficits. J Neurobiol 66(1):82–94

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124(4):619–626

    CAS  PubMed  Google Scholar 

  23. Boudreau N, Werb Z, Bissell MJ (1996) Suppression of apoptosis by basement membrane requires three-dimensional tissue organization and withdrawal from the cell cycle. Proc Natl Acad Sci USA 93(8):3509–3513

    CAS  PubMed  Google Scholar 

  24. Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8(3):221–233

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Aspects Med 29(5):258–289

    CAS  PubMed  Google Scholar 

  27. Wingfield PT, Sax JK, Stahl SJ, Kaufman J, Palmer I, Chung V, Corcoran ML, Kleiner DE, Stetler-Stevenson WG (1999) Biophysical and functional characterization of full-length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli. Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions. J Biol Chem 274(30):21362–21368

    CAS  PubMed  Google Scholar 

  28. Stetler-Stevenson WG (2008) The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2. Cancer Metastasis Rev 27(1):57–66

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Gasson JC, Bersch N, Golde DW (1985) Characterization of purified human erythroid-potentiating activity. Prog Clin Biol Res 184:95–104

    CAS  PubMed  Google Scholar 

  30. Bertaux B, Hornebeck W, Eisen AZ, Dubertret L (1991) Growth stimulation of human keratinocytes by tissue inhibitor of metalloproteinases. J Invest Dermatol 97(4):679–685

    CAS  PubMed  Google Scholar 

  31. Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K (1992) Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett 298:29–32

    CAS  PubMed  Google Scholar 

  32. Saika S, Kawashima Y, Okada Y, Tanaka SI, Yamanaka O, Ohnishi Y, Ooshima A (1998) Recombinant TIMP-1 and -2 enhance the proliferation of rabbit corneal epithelial cells in vitro and the spreading of rabbit corneal epithelium in situ. Curr Eye Res 17(1):47–52

    CAS  PubMed  Google Scholar 

  33. Stetler Stevenson WG, Bersch N, Golde DW (1992) Tissue inhibitor of metalloproteinase-2 (TIMP-2) has erythroid- potentiating activity. FEBS Lett 296:231–234

    CAS  PubMed  Google Scholar 

  34. Hayakawa T, Yamashita K, Ohuchi E, Shinagawa A (1994) Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). J Cell Sci 107(Pt 9):2373–2379

    CAS  PubMed  Google Scholar 

  35. Chesler L, Golde DW, Bersch N, Johnson MD (1995) Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases-1. Blood 86(12):4506–4515

    CAS  PubMed  Google Scholar 

  36. Wang T, Yamashita K, Iwata K, Hayakawa T (2002) Both tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 activate Ras but through different pathways. Biochem Biophys Res Commun 296(1):201–205

    CAS  PubMed  Google Scholar 

  37. Akahane T, Akahane M, Shah A, Thorgeirsson UP (2004) TIMP-1 stimulates proliferation of human aortic smooth muscle cells and Ras effector pathways. Biochem Biophys Res Commun 324(1):440–445

    CAS  PubMed  Google Scholar 

  38. Lu Y, Liu S, Zhang S, Cai G, Jiang H, Su H, Li X, Hong Q, Zhang X, Chen X (2011) Tissue inhibitor of metalloproteinase-1 promotes NIH3T3 fibroblast proliferation by activating p-Akt and cell cycle progression. Mol Cells 31(3):225–230

    PubMed  Google Scholar 

  39. Fowell AJ, Collins JE, Duncombe DR, Pickering JA, Rosenberg WM, Benyon RC (2011) Silencing tissue inhibitors of metalloproteinases (TIMPs) with short interfering RNA reveals a role for TIMP-1 in hepatic stellate cell proliferation. Biochem Biophys Res Commun 407(2):277–282

    CAS  PubMed  Google Scholar 

  40. Rossi L, Ergen AV, Goodell MA (2011) TIMP-1 deficiency subverts cell-cycle dynamics in murine long-term HSCs. Blood 117(24):6479–6488

    CAS  PubMed  Google Scholar 

  41. Ould-yahoui A, Tremblay E, Sbai O, Ferhat L, Bernard A, Charrat E, Gueye Y, Lim NH, Brew K, Risso JJ, Dive V, Khrestchatisky M, Rivera S (2009) A new role for TIMP-1 in modulating neurite outgrowth and morphology of cortical neurons. PLoS One 4(12):e8289

    PubMed Central  PubMed  Google Scholar 

  42. Hernandez-Guillamon M, Delgado P, Ortega L, Pares M, Rosell A, Garcia-Bonilla L, Fernandez-Cadenas I, Borrell-Pages M, Boada M, Montaner J (2009) Neuronal TIMP-1 release accompanies astrocytic MMP-9 secretion and enhances astrocyte proliferation induced by beta-amyloid 25–35 fragment. J Neurosci Res 87(9):2115–2125

    CAS  PubMed  Google Scholar 

  43. Fata JE, Leco KJ, Moorehead RA, Martin DC, Khokha R (1999) Timp-1 is important for epithelial proliferation and branching morphogenesis during mouse mammary development. Dev Biol 211(2):238–254

    CAS  PubMed  Google Scholar 

  44. Taube ME, Liu XW, Fridman R, Kim HR (2006) TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27(KIP1) protein. Oncogene 25(21):3041–3048

    CAS  PubMed  Google Scholar 

  45. Guedez L, Stetler-Stevenson WG, Wolff L, Wang J, Fukushima P, Mansoor A, Stetler-Stevenson M (1998) In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1. J Clin Invest 102(11):2002–2010

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Han X, Sun Y, Scott S, Bleich D (2001) Tissue inhibitor of metalloproteinase-1 prevents cytokine-mediated dysfunction and cytotoxicity in pancreatic islets and beta-cells. Diabetes 50(5):1047–1055

    CAS  PubMed  Google Scholar 

  47. Guedez L, Mansoor A, Birkedal-Hansen B, Lim MS, Fukushima P, Venzon D, Stetler-Stevenson WG, Stetler-Stevenson M (2001) Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis. Blood 97(6):1796–1802

    CAS  PubMed  Google Scholar 

  48. Vorotnikova E, Tries M, Braunhut S (2004) Retinoids and TIMP1 prevent radiation-induced apoptosis of capillary endothelial cells. Radiat Res 161(2):174–184

    CAS  PubMed  Google Scholar 

  49. Chromek M, Tullus K, Lundahl J, Brauner A (2004) Tissue inhibitor of metalloproteinase 1 activates normal human granulocytes, protects them from apoptosis, and blocks their transmigration during inflammation. Infect Immun 72(1):82–88

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Jung KK, Liu XW, Chirco R, Fridman R, Kim HR (2006) Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J 25(17):3934–3942

    CAS  PubMed  Google Scholar 

  51. Liu XW, Bernardo MM, Fridman R, Kim HR (2003) Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathway. J Biol Chem 278(41):40364–40372

    CAS  PubMed  Google Scholar 

  52. Liu XW, Taube ME, Jung KK, Dong Z, Lee YJ, Roshy S, Sloane BF, Fridman R, Kim HR (2005) Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells from extrinsic cell death: a potential oncogenic activity of tissue inhibitor of metalloproteinase-1. Cancer Res 65(3):898–906

    CAS  PubMed  Google Scholar 

  53. Wilk CM, Schildberg FA, Lauterbach MA, Cadeddu RP, Frobel J, Westphal V, Tolba RH, Hell SW, Czibere A, Bruns I, Haas R (2013) The tissue inhibitor of metalloproteinases-1 improves migration and adhesion of hematopoietic stem and progenitor cells. Exp Hematol. doi:10.1016/j.exphem.2013.04.010

  54. Pols MS, Klumperman J (2009) Trafficking and function of the tetraspanin CD63. Exp Cell Res 315(9):1584–1592

    CAS  PubMed  Google Scholar 

  55. Lambert E, Boudot C, Kadri Z, Soula-Rothhut M, Sowa ML, Mayeux P, Hornebeck W, Haye B, Petitfrere E (2003) Tissue inhibitor of metalloproteinases-1 signalling pathway leading to erythroid cell survival. Biochem J 372(Pt 3):767–774

    CAS  PubMed  Google Scholar 

  56. Lambert E, Bridoux L, Devy J, Dasse E, Sowa ML, Duca L, Hornebeck W, Martiny L, Petitfrere-Charpentier E (2009) TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival. Int J Biochem Cell Biol 41(5):1102–1115

    CAS  PubMed  Google Scholar 

  57. Yu Q, Stamenkovic I (1999) Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 13:35–48

    CAS  PubMed  Google Scholar 

  58. Bridoux L, Etique N, Lambert E, Thevenard J, Sowa ML, Belloy N, Dauchez M, Martiny L, Charpentier E (2013) A crucial role for Lyn in TIMP-1 erythroid cell survival signalling pathway. FEBS Lett 587(10):1524–1528

    CAS  PubMed  Google Scholar 

  59. Li G, Fridman R, Kim HR (1999) Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells. Cancer Res 59(24):6267–6275

    CAS  PubMed  Google Scholar 

  60. Ashutosh, Chao C, Borgmann K, Brew K, Ghorpade A (2012) Tissue inhibitor of metalloproteinases-1 protects human neurons from staurosporine and HIV-1-induced apoptosis: mechanisms and relevance to HIV-1-associated dementia. Cell Death Dis 3:e332

  61. Guo LJ, Luo XH, Xie H, Zhou HD, Yuan LQ, Wang M, Liao EY (2006) Tissue inhibitor of matrix metalloproteinase-1 suppresses apoptosis of mouse bone marrow stromal cell line MBA-1. Calcif Tissue Int 78(5):285–292

    CAS  PubMed  Google Scholar 

  62. Scheid MP, Schubert KM, Duronio V (1999) Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase. J Biol Chem 274(43):31108–31113

    CAS  PubMed  Google Scholar 

  63. Yu C, Minemoto Y, Zhang J, Liu J, Tang F, Bui TN, Xiang J, Lin A (2004) JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Mol Cell 13(3):329–340

    CAS  PubMed  Google Scholar 

  64. Ahonen M, Poukkula M, Baker AH, Kashiwagi M, Nagase H, Eriksson JE, Kahari VM (2003) Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. Oncogene 22(14):2121–2134

    CAS  PubMed  Google Scholar 

  65. Baker AH, Zaltsman AB, George SJ, Newby AC (1998) 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. J Clin Invest 101(6):1478–1487

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Lim MS, Guedez L, Stetler-Stevenson WG, Stetler-Stevenson M (1999) Tissue inhibitor of metalloproteinase-2 induces apoptosis in human T lymphocytes. Ann N Y Acad Sci 878:522–523

    CAS  PubMed  Google Scholar 

  67. Valente P, Fassina G, Melchiori A, Masiello L, Cilli M, Vacca A, Onisto M, Santi L, Stetler-Stevenson WG, Albini A (1998) TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis. Int J Cancer 75(2):246–253

    CAS  PubMed  Google Scholar 

  68. Boudreau N, Sympson CJ, Werb Z, Bissell MJ (1995) Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267(5199):891–893

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Alexander CM, Howard EW, Bissell MJ, Werb Z (1996) Rescue of mammary epithelial cell apoptosis and entactin degradation by a tissue inhibitor of metalloproteinases-1 transgene. J Cell Biol 135(6 Pt 1):1669–1677

    CAS  PubMed  Google Scholar 

  70. Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJ, Benyon C, Iredale JP (2002) Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem 277(13):11069–11076

    CAS  PubMed  Google Scholar 

  71. Hahn-Dantona E, Ruiz JF, Bornstein P, Strickland DK (2001) The low density lipoprotein receptor-related protein modulates levels of matrix metalloproteinase 9 (MMP-9) by mediating its cellular catabolism. J Biol Chem 276(18):15498–15503

    CAS  PubMed  Google Scholar 

  72. Murate T, Yamashita K, Ohashi H, Kagami Y, Tsushita K, Kinoshita T, Hotta T, Saito H, Yoshida S, Mori KJ et al (1993) Erythroid potentiating activity of tissue inhibitor of metalloproteinases on the differentiation of erythropoietin-responsive mouse erythroleukemia cell line, ELM-I-1-3, is closely related to its cell growth potentiating activity. Exp Hematol 21(1):169–176

    CAS  PubMed  Google Scholar 

  73. Petitfrere E, Kadri Z, Boudot C, Sowa ML, Mayeux P, Haye B, Billat C (2000) Involvement of the p38 mitogen-activated protein kinase pathway in tissue inhibitor of metalloproteinases-1-induced erythroid differentiation. FEBS Lett 485(2–3):117–121

    CAS  PubMed  Google Scholar 

  74. Dasse E, Bridoux L, Baranek T, Lambert E, Salesse S, Sowa ML, Martiny L, Trentesaux C, Petitfrere E (2007) Tissue inhibitor of metalloproteinase-1 promotes hematopoietic differentiation via caspase-3 upstream the MEKK1/MEK6/p38alpha pathway. Leukemia 21(4):595–603

    CAS  PubMed  Google Scholar 

  75. Stetler-Stevenson M, Mansoor A, Lim M, Fukushima P, Kehrl J, Marti G, Ptaszynski K, Wang J, Stetler-Stevenson WG (1997) Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in reactive and neoplastic lymphoid cells. Blood 89(5):1708–1715

    CAS  PubMed  Google Scholar 

  76. Guedez L, Courtemanch L, Stetler-Stevenson M (1998) Tissue inhibitor of metalloproteinase (TIMP)-1 induces differentiation and an antiapoptotic phenotype in germinal center B cells. Blood 92(4):1342–1349

    CAS  PubMed  Google Scholar 

  77. Guedez L, Martinez A, Zhao S, Vivero A, Pittaluga S, Stetler-Stevenson M, Raffeld M, Stetler-Stevenson WG (2005) Tissue inhibitor of metalloproteinase 1 (TIMP-1) promotes plasmablastic differentiation of a Burkitt lymphoma cell line: implications in the pathogenesis of plasmacytic/plasmablastic tumors. Blood 105(4):1660–1668

    CAS  PubMed  Google Scholar 

  78. Kim YS, Seo DW, Kong SK, Lee JH, Lee ES, Stetler-Stevenson M, Stetler-Stevenson WG (2008) TIMP1 induces CD44 expression and the activation and nuclear translocation of SHP1 during the late centrocyte/post-germinal center B cell differentiation. Cancer Lett 269(1):37–45

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147

    CAS  PubMed  Google Scholar 

  80. Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P (2007) MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood 109(9):4055–4063

    CAS  PubMed  Google Scholar 

  81. Egea V, Zahler S, Rieth N, Neth P, Popp T, Kehe K, Jochum M, Ries C (2012) Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/beta-catenin signaling. Proc Natl Acad Sci USA 109(6):E309–E316

    CAS  PubMed  Google Scholar 

  82. Schiltz C, Marty C, de Vernejoul MC, Geoffroy V (2008) Inhibition of osteoblastic metalloproteinases in mice prevents bone loss induced by oestrogen deficiency. J Cell Biochem 104(5):1803–1817

    CAS  PubMed  Google Scholar 

  83. Schiltz C, Prouillet C, Marty C, Merciris D, Collet C, de Vernejoul MC, Geoffroy V (2010) Bone loss induced by Runx2 over-expression in mice is blunted by osteoblastic over-expression of TIMP-1. J Cell Physiol 222(1):219–229

    CAS  PubMed  Google Scholar 

  84. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480

    CAS  PubMed  Google Scholar 

  85. Neth P, Ciccarella M, Egea V, Hoelters J, Jochum M, Ries C (2006) Wnt signaling regulates the invasion capacity of human mesenchymal stem cells. Stem Cells 24(8):1892–1903

    CAS  PubMed  Google Scholar 

  86. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Perez-Martinez L, Jaworski DM (2005) Tissue inhibitor of metalloproteinase-2 promotes neuronal differentiation by acting as an anti-mitogenic signal. J Neurosci 25(20):4917–4929

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Jaworski DM, Perez-Martinez L (2006) Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression is regulated by multiple neural differentiation signals. J Neurochem 98(1):234–247

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Shen Y, Winkler IG, Barbier V, Sims NA, Hendy J, Levesque JP (2010) Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. PLoS One 5(9):e13086

    PubMed Central  PubMed  Google Scholar 

  90. Bernot D, Barruet E, Poggi M, Bonardo B, Alessi MC, Peiretti F (2010) Down-regulation of tissue inhibitor of metalloproteinase-3 (TIMP-3) expression is necessary for adipocyte differentiation. J Biol Chem 285(9):6508–6514

    CAS  PubMed  Google Scholar 

  91. Risau W (1997) Mechanisms of angiogenesis. Nature 386(6626):671–674

    CAS  PubMed  Google Scholar 

  92. Handsley MM, Edwards DR (2005) Metalloproteinases and their inhibitors in tumor angiogenesis. Int J Cancer 115(6):849–860

    CAS  PubMed  Google Scholar 

  93. Takigawa M, Nishida Y, Suzuki F, Kishi J, Yamashita K, Hayakawa T (1990) Induction of angiogenesis in chick yolk-sac membrane by polyamines and its inhibition by tissue inhibitors of metalloproteinases (TIMP and TIMP-2). Biochem Biophys Res Commun 171(3):1264–1271

    CAS  PubMed  Google Scholar 

  94. Lee S, Zheng M, Kim B, Rouse BT (2002) Role of matrix metalloproteinase-9 in angiogenesis caused by ocular infection with herpes simplex virus. J Clin Invest 110(8):1105–1111

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Taraboletti G, Garofalo A, Belotti D, Drudis T, Borsotti P, Scanziani E, Brown PD, Giavazzi R (1995) Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases. J Natl Cancer Inst 87(4):293–298

    CAS  PubMed  Google Scholar 

  96. Scroyen I, Jacobs F, Cosemans L, De Geest B, Lijnen HR (2010) Blood vessel density in de novo formed adipose tissue is decreased upon overexpression of TIMP-1. Obesity (Silver Spring) 18(3):638–640

    Google Scholar 

  97. Bloomston M, Shafii A, Zervos EE, Rosemurgy AS (2002) TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis. J Surg Res 102(1):39–44

    CAS  PubMed  Google Scholar 

  98. Akahane T, Akahane M, Shah A, Connor CM, Thorgeirsson UP (2004) TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Exp Cell Res 301(2):158–167

    CAS  PubMed  Google Scholar 

  99. Stetler-Stevenson WG, Seo DW (2005) TIMP-2: an endogenous inhibitor of angiogenesis. Trends Mol Med 11(3):97–103

    CAS  PubMed  Google Scholar 

  100. Neri A, Megha T, Bettarini F, Tacchini D, Mastrogiulio MG, Marrelli D, Pinto E, Tosi P (2012) Is tissue inhibitor of metalloproteinase-1 a new prognosticator for breast cancer? An analysis of 266 cases. Hum Pathol 43(8):1184–1191

    CAS  PubMed  Google Scholar 

  101. Oh WK, Vargas R, Jacobus S, Leitzel K, Regan MM, Hamer P, Pierce K, Brown-Shimer S, Carney W, Ali SM, Kantoff PW, Lipton A (2011) Elevated plasma tissue inhibitor of metalloproteinase-1 levels predict decreased survival in castration-resistant prostate cancer patients. Cancer 117(3):517–525

    CAS  PubMed  Google Scholar 

  102. Gouyer V, Conti M, Devos P, Zerimech F, Copin MC, Creme E, Wurtz A, Porte H, Huet G (2005) Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent. Cancer 103(8):1676–1684

    CAS  PubMed  Google Scholar 

  103. Wang CS, Wu TL, Tsao KC, Sun CF (2006) Serum TIMP-1 in gastric cancer patients: a potential prognostic biomarker. Ann Clin Lab Sci 36(1):23–30

    PubMed  Google Scholar 

  104. Aaberg-Jessen C, Christensen K, Offenberg H, Bartels A, Dreehsen T, Hansen S, Schroder HD, Brunner N, Kristensen BW (2009) Low expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in glioblastoma predicts longer patient survival. J Neurooncol 95(1):117–128

    CAS  PubMed  Google Scholar 

  105. Kluger HM, Hoyt K, Bacchiocchi A, Mayer T, Kirsch J, Kluger Y, Sznol M, Ariyan S, Molinaro A, Halaban R (2011) Plasma markers for identifying patients with metastatic melanoma. Clin Cancer Res 17(8):2417–2425

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Guedez L, Stetler-Stevenson WG (2010) The prognostic value of TIMP-1 in multiple myeloma. Leuk Res 34(5):576–577

    CAS  PubMed  Google Scholar 

  107. Terpos E, Dimopoulos MA, Shrivastava V, Leitzel K, Christoulas D, Migkou M, Gavriatopoulou M, Anargyrou K, Hamer P, Kastritis E, Carney W, Lipton A (2010) High levels of serum TIMP-1 correlate with advanced disease and predict for poor survival in patients with multiple myeloma treated with novel agents. Leuk Res 34(3):399–402

    CAS  PubMed  Google Scholar 

  108. Zhao J, Guan JL (2009) Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev 28(1–2):35–49

    PubMed  Google Scholar 

  109. Ridnour LA, Barasch KM, Windhausen AN, Dorsey TH, Lizardo MM, Yfantis HG, Lee DH, Switzer CH, Cheng RY, Heinecke JL, Brueggemann E, Hines HB, Khanna C, Glynn SA, Ambs S, Wink DA (2012) Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. PLoS One 7(9):e44081

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Jung YS, Liu XW, Chirco R, Warner RB, Fridman R, Kim HR (2012) TIMP-1 induces an EMT-like phenotypic conversion in MDCK cells independent of its MMP-inhibitory domain. PLoS One 7(6):e38773

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Bigelow RL, Williams BJ, Carroll JL, Daves LK, Cardelli JA (2009) TIMP-1 overexpression promotes tumorigenesis of MDA-MB-231 breast cancer cells and alters expression of a subset of cancer promoting genes in vivo distinct from those observed in vitro. Breast Cancer Res Treat 117(1):31–44

    CAS  PubMed  Google Scholar 

  112. Kopitz C, Gerg M, Bandapalli OR, Ister D, Pennington CJ, Hauser S, Flechsig C, Krell HW, Antolovic D, Brew K, Nagase H, Stangl M, von Weyhern CW, Brucher BL, Brand K, Coussens LM, Edwards DR, Kruger A (2007) Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling. Cancer Res 67(18):8615–8623

    CAS  PubMed  Google Scholar 

  113. Schelter F, Grandl M, Seubert B, Schaten S, Hauser S, Gerg M, Boccaccio C, Comoglio P, Kruger A (2011) Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10. Clin Exp Metastasis 28(8):793–802

    CAS  PubMed  Google Scholar 

  114. Schelter F, Halbgewachs B, Baumler P, Neu C, Gorlach A, Schrotzlmair F, Kruger A (2011) Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1alpha. Clin Exp Metastasis 28(2):91–99

    CAS  PubMed  Google Scholar 

  115. Wang T, Lv JH, Zhang XF, Li CJ, Han X, Sun YJ (2010) Tissue inhibitor of metalloproteinase-1 protects MCF-7 breast cancer cells from paclitaxel-induced apoptosis by decreasing the stability of cyclin B1. Int J Cancer 126(2):362–370

    CAS  PubMed  Google Scholar 

  116. Djafarzadeh R, Mojaat A, Vicente AB, von Luttichau I, Nelson PJ (2004) Exogenously added GPI-anchored tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) displays enhanced and novel biological activities. Biol Chem 385(7):655–663

    CAS  PubMed  Google Scholar 

  117. Djafarzadeh R, Milani V, Rieth N, von Luettichau I, Skrablin PS, Hofstetter M, Noessner E, Nelson PJ (2009) TIMP-1-GPI in combination with hyperthermic treatment of melanoma increases sensitivity to FAS-mediated apoptosis. Cancer Immunol Immunother 58(3):361–371

    CAS  PubMed  Google Scholar 

  118. Raggi MC, Djafarzadeh R, Muenchmeier N, Hofstetter M, Jahn B, Rieth N, Nelson PJ (2009) Peritumoral administration of GPI-anchored TIMP-1 inhibits colon carcinoma growth in Rag-2 gamma chain-deficient mice. Biol Chem 390(9):893–897

    CAS  PubMed  Google Scholar 

  119. Djafarzadeh R, Noessner E, Engelmann H, Schendel DJ, Notohamiprodjo M, von Luettichau I, Nelson PJ (2006) GPI-anchored TIMP-1 treatment renders renal cell carcinoma sensitive to FAS-meditated killing. Oncogene 25(10):1496–1508

    CAS  PubMed  Google Scholar 

  120. Notohamiprodjo S, Djafarzadeh R, Rieth N, Hofstetter M, Jaeckel C, Nelson PJ (2012) Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF- beta 1 activation and reduces regulatory ID gene expression. Biol Chem 393(12):1463–1470

    CAS  PubMed  Google Scholar 

  121. Flisiak I, Zaniewski P, Chodynicka B (2008) Plasma TGF-beta1, TIMP-1, MMP-1 and IL-18 as a combined biomarker of psoriasis activity. Biomarkers 13(5):549–556

    CAS  PubMed  Google Scholar 

  122. Mannello F, Jung K (2008) Blood sampling affects circulating TIMP-1 concentration, a useful biomarker in estimating liver fibrosis stages. Hepatology 48(2):688–689 (author reply 689–690)

    PubMed  Google Scholar 

  123. Kelly D, Squire IB, Khan SQ, Dhillon O, Narayan H, Ng KH, Quinn P, Davies JE, Ng LL (2010) Usefulness of plasma tissue inhibitors of metalloproteinases as markers of prognosis after acute myocardial infarction. Am J Cardiol 106(4):477–482

    CAS  PubMed  Google Scholar 

  124. Vanhoutte D, Heymans S (2010) TIMPs and cardiac remodeling: ‘embracing the MMP-independent-side of the family’. J Mol Cell Cardiol 48(3):445–453

    CAS  PubMed  Google Scholar 

  125. Singla DK, McDonald DE (2007) Factors released from embryonic stem cells inhibit apoptosis of H9c2 cells. Am J Physiol Heart Circ Physiol 293(3):H1590–H1595

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Glass C, Singla DK (2012) Overexpression of TIMP-1 in embryonic stem cells attenuates adverse cardiac remodeling following myocardial infarction. Cell Transpl 21(9):1931–1944

    Google Scholar 

  127. Seo DW, Li H, Guedez L, Wingfield PT, Diaz T, Salloum R, Wei BY, Stetler-Stevenson WG (2003) TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114(2):171–180

    CAS  PubMed  Google Scholar 

  128. Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M, Baker A, Anand-Apte B (2003) A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 9(4):407–415

    CAS  PubMed  Google Scholar 

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Acknowledgments

Work in C.R.’s laboratory is funded by grants from the Institute of Cardiovascular Prevention, Ludwig-Maximilians-University of Munich and by contract from the German Federal Ministry of Defense research project M/SABX/8A002.

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  1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University of Munich, Pettenkoferstrasse 9b, 80336, Munich, Germany

    Christian Ries

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Ries, C. Cytokine functions of TIMP-1. Cell. Mol. Life Sci. 71, 659–672 (2014). https://doi.org/10.1007/s00018-013-1457-3

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  • DOI: https://doi.org/10.1007/s00018-013-1457-3

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