Journal of Hepatology
Volume 46, Issue 5 , Pages 955-975 , May 2007

Expression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies

  • Stefanie Hemmann

      Affiliations

    • Department of Medicine II, Gastroenterology, University Hospital Giessen & Marburg GmbH, Paul-Meimberg-Str. 5, 35392 Giessen, Germany
    • ,
  • Jürgen Graf

      Affiliations

    • Department of Anaesthesiology and Intensive Care, University Hospital Giessen & Marburg GmbH, Baldingerstrasse 1, 35033 Marburg, Germany
    • ,
  • Martin Roderfeld

      Affiliations

    • Department of Medicine II, Gastroenterology, University Hospital Giessen & Marburg GmbH, Paul-Meimberg-Str. 5, 35392 Giessen, Germany
    • ,
  • Elke Roeb

      Affiliations

    • Department of Medicine II, Gastroenterology, University Hospital Giessen & Marburg GmbH, Paul-Meimberg-Str. 5, 35392 Giessen, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49 641 9942338; fax: +49 641 9942339.

References 

  1. Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis. 2001;21:351–372
  2. Somerville RP, Oblander SA, Apte SS. Matrix metalloproteinases: old dogs with new tricks. Genome Biol. 2003;4:216
  3. Iredale JP. Tissue inhibitors of metalloproteinases in liver fibrosis. Int J Biochem Cell Biol. 1997;29:43–54
  4. Iredale JP, Benyon RC, Arthur MJ, Ferris WF, Alcolado R, Winwood PJ, et al. Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatology. 1996;24:176–184
  5. Knittel T, Mehde M, Kobold D, Saile B, Dinter C, Ramadori G. Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1. J Hepatol. 1999;30:48–60
  6. Watanabe T, Niioka M, Hozawa S, Kameyama K, Hayashi T, Arai M, et al. Gene expression of interstitial collagenase in both progressive and recovery phase of rat liver fibrosis induced by carbon tetrachloride. J Hepatol. 2000;33:224–235
  7. Han YP, Zhou L, Wang J, Xiong S, Garner WL, French SW, et al. Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen. J Biol Chem. 2004;279:4820–4828
  8. Lee HS, Miau LH, Chen CH, Chiou LL, Huang GT, Yang PM, et al. Differential role of p38 in IL-1alpha induction of MMP-9 and MMP-13 in an established liver myofibroblast cell line. J Biomed Sci. 2003;10:757–765
  9. Sakaki H, Matsumiya T, Kusumi A, Imaizumi T, Satoh H, Yoshida H, et al. Interleukin-1beta induces matrix metalloproteinase-1 expression in cultured human gingival fibroblasts: role of cyclooxygenase-2 and prostaglandin E2. Oral Dis. 2004;10:87–93
  10. Yasui H, Andoh A, Bamba S, Inatomi O, Ishida H, Fujiyama Y. Role of fibroblast growth factor-2 in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human intestinal myofibroblasts. Digestion. 2004;69:34–44
  11. Suzuki K, Enghild JJ, Morodomi T, Salvesen G, Nagase H. Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin). Biochemistry. 1990;29:10261–10270
  12. Knauper V, Bailey L, Worley JR, Soloway P, Patterson ML, Murphy G. Cellular activation of proMMP-13 by MT1-MMP depends on the C-terminal domain of MMP-13. FEBS Lett. 2002;532:127–130
  13. Overall CM, Wrana JL, Sodek J. Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. J Biol Chem. 1989;264:1860–1869
  14. Schaefer B, Rivas-Estilla AM, Meraz-Cruz N, Reyes-Romero MA, Hernandez-Nazara ZH, Dominguez-Rosales JA, et al. Reciprocal modulation of matrix metalloproteinase-13 and type I collagen genes in rat hepatic stellate cells. Am J Pathol. 2003;162:1771–1780
  15. Lechuga CG, Hernandez-Nazara ZH, Dominguez Rosales JA, Morris ER, Rincon AR, Rivas-Estilla AM, et al. TGF-beta1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k. Am J Physiol Gastrointest Liver Physiol. 2004;287:G974–G987
  16. Arendt E, Ueberham U, Bittner R, Gebhardt R, Ueberham E. Enhanced matrix degradation after withdrawal of TGF-beta1 triggers hepatocytes from apoptosis to proliferation and regeneration. Cell Prolif. 2005;38:287–299
  17. Lichtinghagen R, Bahr MJ, Wehmeier M, Michels D, Haberkorn CI, Arndt B, et al. Expression and coordinated regulation of matrix metalloproteinases in chronic hepatitis C and hepatitis C virus-induced liver cirrhosis. Clin Sci (Lond). 2003;105:373–382
  18. Okamoto K, Mimura K, Murawaki Y, Yuasa I. Association of functional gene polymorphisms of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 with the progression of chronic liver disease. J Gastroenterol Hepatol. 2005;20:1102–1108
  19. Yata Y, Takahara T, Furui K, Zhang LP, Watanabe A. Expression of matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 in acute liver injury. J Hepatol. 1999;30:419–424
  20. Yan S, Chen GM, Yu CH, Zhu GF, Li YM, Zheng SS. Expression pattern of matrix metalloproteinases-13 in a rat model of alcoholic liver fibrosis. Hepatobiliary Pancreat Dis Int. 2005;4:569–572
  21. Wang DR, Sato M, Li LN, Miura M, Kojima N, Senoo H. Stimulation of pro-MMP-2 production and activation by native form of extracellular type I collagen in cultured hepatic stellate cells. Cell Struct Funct. 2003;28:505–513
  22. Yang C, Zeisberg M, Mosterman B, Sudhakar A, Yerramalla U, Holthaus K, et al. Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors. Gastroenterology. 2003;124:147–159
  23. Ikeda K, Wakahara T, Wang YQ, Kadoya H, Kawada N, Kaneda K. In vitro migratory potential of rat quiescent hepatic stellate cells and its augmentation by cell activation. Hepatology. 1999;29:1760–1767
  24. Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem. 1995;270:5331–5338
  25. Takahara T, Furui K, Yata Y, Jin B, Zhang LP, Nambu S, et al. Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers. Hepatology. 1997;26:1521–1529
  26. Preaux AM, Mallat A, Nhieu JT, D’ortho MP, Hembry RM, Mavier P. Matrix metalloproteinase-2 activation in human hepatic fibrosis regulation by cell-matrix interactions. Hepatology. 1999;30:944–950
  27. Theret N, Lehti K, Musso O, Clement B. MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells. Hepatology. 1999;30:462–468
  28. Olaso E, Ikeda K, Eng FJ, Xu L, Wang LH, Lin HC, et al. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest. 2001;108:1369–1378
  29. Zhou X, Hovell CJ, Pawley S, Hutchings MI, Arthur MJ, Iredale JP, et al. Expression of matrix metalloproteinase-2 and -14 persists during early resolution of experimental liver fibrosis and might contribute to fibrolysis. Liver Int. 2004;24:492–501
  30. Lichtinghagen R, Michels D, Haberkorn CI, Arndt B, Bahr M, Flemming P, et al. Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C. J Hepatol. 2001;34:239–247
  31. El-Gindy I, El Rahman AT, El-Alim MA, Zaki SS. Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non-invasive markers of hepatic fibrosis in patients with HCV related chronic liver disease. Egypt J Immunol. 2003;10:27–35
  32. Takahara T, Furui K, Funaki J, Nakayama Y, Itoh H, Miyabayashi C, et al. Increased expression of matrix metalloproteinase-II in experimental liver fibrosis in rats. Hepatology. 1995;21:787–795
  33. Parsons CJ, Bradford BU, Pan CQ, Cheung E, Schauer M, Knorr A, et al. Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats. Hepatology. 2004;40:1106–1115
  34. Watanabe T, Niioka M, Ishikawa A, Hozawa S, Arai M, Maruyama K, et al. Dynamic change of cells expressing MMP-2 mRNA and MT1-MMP mRNA in the recovery from liver fibrosis in the rat. J Hepatol. 2001;35:465–473
  35. Will H, Atkinson SJ, Butler GS, Smith B, Murphy G. The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation Regulation by TIMP-2 and TIMP-3.. J Biol Chem. 1996;271:17119–17123
  36. Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest. 1998;102:538–549
  37. Harty MW, Huddleston HM, Papa EF, Puthawala T, Tracy AP, Ramm GA, et al. Repair after cholestatic liver injury correlates with neutrophil infiltration and matrix metalloproteinase 8 activity. Surgery. 2005;138:313–320
  38. Kossakowska AE, Edwards DR, Lee SS, Urbanski LS, Stabbler AL, Zhang CL, et al. Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis. Am J Pathol. 1998;153:1895–1902
  39. Benyon RC, Hovell CJ, Da GM, Jones EH, Iredale JP, Arthur MJ. Progelatinase A is produced and activated by rat hepatic stellate cells and promotes their proliferation. Hepatology. 1999;30:977–986
  40. Parola M, Robino G. Oxidative stress-related molecules and liver fibrosis. J Hepatol. 2001;35:297–306
  41. Galli A, Svegliati-Baroni G, Ceni E, Milani S, Ridolfi F, Salzano R, et al. Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism. Hepatology. 2005;41:1074–1084
  42. Nagase H, Enghild JJ, Suzuki K, Salvesen G. Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4-aminophenyl)mercuric acetate. Biochemistry. 1990;29:5783–5789
  43. Imai K, Yokohama Y, Nakanishi I, Ohuchi E, Fujii Y, Nakai N, et al. Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties. J Biol Chem. 1995;270:6691–6697
  44. Knauper V, Wilhelm SM, Seperack PK, DeClerck YA, Langley KE, Osthues A, et al. Direct activation of human neutrophil procollagenase by recombinant stromelysin. Biochem J. 1993;295:581–586
  45. Ogata Y, Enghild JJ, Nagase H. Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. J Biol Chem. 1992;267:3581–3584
  46. Knauper V, Lopez-Otin C, Smith B, Knight G, Murphy G. Biochemical characterization of human collagenase-3. J Biol Chem. 1996;271:1544–1550
  47. Herbst H, Heinrichs O, Schuppan D, Milani S, Stein H. Temporal and spatial patterns of transin/stromelysin RNA expression following toxic injury in rat liver. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60:295–300
  48. Knittel T, Mehde M, Grundmann A, Saile B, Scharf JG, Ramadori G. Expression of matrix metalloproteinases and their inhibitors during hepatic tissue repair in the rat. Histochem Cell Biol. 2000;113:443–453
  49. Shek FW, Benyon RC, Walker FM, McCrudden PR, Pender SL, Williams EJ, et al. Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am J Pathol. 2002;160:1787–1798
  50. Murawaki Y, Ikuta Y, Okamoto K, Koda M, Kawasaki H. Serum matrix metalloproteinase-3 (stromelysin-1) concentration in patients with chronic liver disease. J Hepatol. 1999;31:474–481
  51. Jiang Y, Liu J, Waalkes M, Kang YJ. Changes in the gene expression associated with carbon tetrachloride-induced liver fibrosis persist after cessation of dosing in mice. Toxicol Sci. 2004;79:404–410
  52. Giannelli G, Bergamini C, Marinosci F, Fransvea E, Napoli N, Maurel P, et al. Antifibrogenic effect of IFN-alpha2b on hepatic stellate cell activation by human hepatocytes. J Interferon Cytokine Res. 2006;26:301–308
  53. Roderfeld M, Geier A, Dietrich CG, Sievert E, Jansen B, Gartung C, et al. Cytokine blockade inhibits hepatic tissue inhibitor of metalloproteinase-1 expression and up-regulates matrix metalloproteinase-9 in toxic liver injury. Liver Int. 2006;26:579–586
  54. Ramos-DeSimone N, Hahn-Dantona E, Sipley J, Nagase H, French DL, Quigley JP. Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem. 1999;274:13066–13076
  55. Reif S, Somech R, Brazovski E, Reich R, Belson A, Konikoff FM, et al. Matrix metalloproteinases 2 and 9 are markers of inflammation but not of the degree of fibrosis in chronic hepatitis C. Digestion. 2005;71:124–130
  56. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14:163–176
  57. Cao Q, Mak KM, Lieber CS. Dilinoleoylphosphatidylcholine prevents transforming growth factor-beta1-mediated collagen accumulation in cultured rat hepatic stellate cells. J Lab Clin Med. 2002;139:202–210
  58. Roeb E, Graeve L, Hoffmann R, Decker K, Edwards DR, Heinrich PC. Regulation of tissue inhibitor of metalloproteinases-1 gene expression by cytokines and dexamethasone in rat hepatocyte primary cultures. Hepatology. 1993;18:1437–1442
  59. Roeb E, Graeve L, Mullberg J, Matern S, Rose-John S. TIMP-1 protein expression is stimulated by IL-1 beta and IL-6 in primary rat hepatocytes. FEBS Lett. 1994;349:45–49
  60. Roeb E, Rose-John S, Erren A, Edwards DR, Matern S, Graeve L, et al. Tissue inhibitor of metalloproteinases-2 (TIMP-2) in rat liver cells is increased by lipopolysaccharide and prostaglandin E2. FEBS Lett. 1995;357:33–36
  61. Roeb E, Purucker E, Breuer B, Nguyen H, Heinrich PC, Rose-John S, et al. TIMP expression in toxic and cholestatic liver injury in rat. J Hepatol. 1997;27:535–544
  62. Iredale JP. Tissue inhibitors of metalloproteinases in liver fibrosis. Int J Biochem Cell Biol. 1997;29:43–54
  63. Herbst H, Wege T, Milani S, Pellegrini G, Orzechowski HD, Bechstein WO, et al. Tissue inhibitor of metalloproteinase-1 and -2 RNA expression in rat and human liver fibrosis. Am J Pathol. 1997;150:1647–1659
  64. Benyon RC, Iredale JP, Goddard S, Winwood PJ, Arthur MJ. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology. 1996;110:821–831
  65. Iredale JP, Goddard S, Murphy G, Benyon RC, Arthur MJ. Tissue inhibitor of metalloproteinase-I and interstitial collagenase expression in autoimmune chronic active hepatitis and activated human hepatic lipocytes. Clin Sci (Lond). 1995;89:75–81
  66. Yata Y, Takahara T, Furui K, Zhang LP, Jin B, Watanabe A. Spatial distribution of tissue inhibitor of metalloproteinase-1 mRNA in chronic liver disease. J Hepatol. 1999;30:425–432
  67. Bergheim I, Guo L, Davis MA, Duveau I, Arteel GE. Critical role of plasminogen activator inhibitor-1 in cholestatic liver injury and fibrosis. J Pharmacol Exp Ther. 2006;316:592–600
  68. Yoshiji H, Kuriyama S, Miyamoto Y, Thorgeirsson UP, Gomez DE, Kawata M, et al. Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model. Hepatology. 2000;32:1248–1254
  69. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, et al. Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse. Hepatology. 2002;36:850–860
  70. Majid MA, Smith VA, Easty DL, Baker AH, Newby AC. Adenovirus mediated gene delivery of tissue inhibitor of metalloproteinases-3 induces death in retinal pigment epithelial cells. Br J Ophthalmol. 2002;86:97–101
  71. Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJ, et al. 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. 2002;277:11069–11076
  72. Murphy F, Waung J, Collins J, Arthur MJ, Nagase H, Mann D, et al. N-Cadherin cleavage during activated hepatic stellate cell apoptosis is inhibited by tissue inhibitor of metalloproteinase-1. Comp Hepatol. 2004;3:S8
  73. Ruiz V, Ordonez RM, Berumen J, Ramirez R, Uhal B, Becerril C, et al. Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis. Am J Physiol Lung Cell Mol Physiol. 2003;285:L1026–L1036
  74. Selman M, Ruiz V, Cabrera S, Segura L, Ramirez R, Barrios R, et al. TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment?. Am J Physiol Lung Cell Mol Physiol. 2000;279:L562–L574
  75. Johnson TS, Haylor JL, Thomas GL, Fisher M, El Nahas AM. Matrix metalloproteinases and their inhibitions in experimental renal scarring. Exp Nephrol. 2002;10:182–195
  76. Horstrup JH, Gehrmann M, Schneider B, Ploger A, Froese P, Schirop T, et al. Elevation of serum and urine levels of TIMP-1 and tenascin in patients with renal disease. Nephrol Dial Transplant. 2002;17:1005–1013
  77. Phillips PA, McCarroll JA, Park S, Wu MJ, Pirola R, Korsten M, et al. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut. 2003;52:275–282
  78. Ishihara T, Hayasaka A, Yamaguchi T, Kondo F, Saisho H. Immunohistochemical study of transforming growth factor-beta 1, matrix metalloproteinase-2,9, tissue inhibitors of metalloproteinase-1,2, and basement membrane components at pancreatic ducts in chronic pancreatitis. Pancreas. 1998;17:412–418
  79. Boker KH, Pehle B, Steinmetz C, Breitenstein K, Bahr M, Lichtinghagen R. Tissue inhibitors of metalloproteinases in liver and serum/plasma in chronic active hepatitis C and HCV-induced cirrhosis. Hepatogastroenterology. 2000;47:812–819
  80. Wang Z, Juttermann R, Soloway PD. TIMP-2 is required for efficient activation of proMMP-2 in vivo. J Biol Chem. 2000;275:26411–26415
  81. Jaworski DM, Soloway P, Caterina J, Falls WA. Tissue inhibitor of metalloproteinase-2(TIMP-2)-deficient mice display motor deficits. J Neurobiol. 2006;66:82–94
  82. Benyon RC, Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis. 2001;21:373–384
  83. Issa R, Zhou X, Trim N, Millward-Sadler H, Krane S, Benyon C, et al. Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. FASEB J. 2003;17:47–49
  84. Ueberham E, Low R, Ueberham U, Schonig K, Bujard H, Gebhardt R. Conditional tetracycline-regulated expression of TGF-beta1 in liver of transgenic mice leads to reversible intermediary fibrosis. Hepatology. 2003;37:1067–1078
  85. Iimuro Y, Nishio T, Morimoto T, Nitta T, Stefanovic B, Choi SK, et al. Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat. Gastroenterology. 2003;124:445–458
  86. D’Armiento J, DiColandrea T, Dalal SS, Okada Y, Huang MT, Conney AH, et al. Collagenase expression in transgenic mouse skin causes hyperkeratosis and acanthosis and increases susceptibility to tumorigenesis. Mol Cell Biol. 1995;15:5732–5739
  87. Okazaki I, Watanabe T, Hozawa S, Arai M, Maruyama K. Molecular mechanism of the reversibility of hepatic fibrosis: with special reference to the role of matrix metalloproteinases. J Gastroenterol Hepatol. 2000;15:D26–D32
  88. Preaux AM, D’ortho MP, Bralet MP, Laperche Y, Mavier P. Apoptosis of human hepatic myofibroblasts promotes activation of matrix metalloproteinase-2. Hepatology. 2002;36:615–622
  89. Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov SA, et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell. 1999;99:81–92
  90. Aimes RT, Quigley JP. Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4- and 1/4-length fragments. J Biol Chem. 1995;270:5872–5876
  91. Kerkvliet EH, Docherty AJ, Beertsen W, Everts V. Collagen breakdown in soft connective tissue explants is associated with the level of active gelatinase A (MMP-2) but not with collagenase. Matrix Biol. 1999;18:373–380
  92. Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem. 1997;272:2446–2451
  93. Apte SS, Fukai N, Beier DR, Olsen BR. The matrix metalloproteinase-14 (MMP-14) gene is structurally distinct from other MMP genes and is co-expressed with the TIMP-2 gene during mouse embryogenesis. J Biol Chem. 1997;272:25511–25517
  94. Siller-Lopez F, Sandoval A, Salgado S, Salazar A, Bueno M, Garcia J, et al. Treatment with human metalloproteinase-8 gene delivery ameliorates experimental rat liver cirrhosis. Gastroenterology. 2004;126:1122–1133
  95. Zhou X, Murphy FR, Gehdu N, Zhang J, Iredale JP, Benyon RC. Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem. 2004;279:23996–24006
  96. Roderfeld M, Weiskirchen R, Wagner S, Berres ML, Henkel C, Grotzinger J, et al. Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice. FASEB J. 2006;20:444–454
  97. Nie QH, Cheng YQ, Xie YM, Zhou YX, Cao YZ. Inhibiting effect of antisense oligonucleotides phosphorthioate on gene expression of TIMP-1 in rat liver fibrosis. World J Gastroenterol. 2001;7:363–369
  98. Nothnick WB. Disruption of the tissue inhibitor of metalloproteinase-1 gene results in altered reproductive cyclicity and uterine morphology in reproductive-age female mice. Biol Reprod. 2000;63:905–912
  99. Riley SC, Leask R, Chard T, Wathen NC, Calder AA, Howe DC. Secretion of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases into the intrauterine compartments during early pregnancy. Mol Hum Reprod. 1999;5:376–381
  100. Waterhouse P, Denhardt DT, Khokha R. Temporal expression of tissue inhibitors of metalloproteinases in mouse reproductive tissues during gestation. Mol Reprod Dev. 1993;35:219–226
  101. Mohammed FF, Pennington CJ, Kassiri Z, Rubin JS, Soloway PD, Ruther U, et al. Metalloproteinase inhibitor TIMP-1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration. Hepatology. 2005;41:857–867
  102. Olle EW, Ren X, McClintock SD, Warner RL, Deogracias MP, Johnson KJ, et al. Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice. Hepatology. 2006;44:540–549
  103. Salgado S, Garcia J, Vera J, Siller F, Bueno M, Miranda A, et al. Liver cirrhosis is reverted by urokinase-type plasminogen activator gene therapy. Mol Ther. 2000;2:545–551
  104. Miranda-Diaz A, Rincon AR, Salgado S, Vera-Cruz J, Galvez J, Islas MC, et al. Improved effects of viral gene delivery of human uPA plus biliodigestive anastomosis induce recovery from experimental biliary cirrhosis. Mol Ther. 2004;9:30–37
  105. Arthur MJ. Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2000;279:G245–G249
  106. McCrudden R, Iredale JP. Liver fibrosis, the hepatic stellate cell and tissue inhibitors of metalloproteinases. Histol Histopathol. 2000;15:1159–1168
  107. Ioannidis JP, Lau J. Can quality of clinical trials and meta-analyses be quantified?. Lancet. 1998;352:590–591
  108. Graf J, Doig GS, Cook DJ, Vincent JL, Sibbald WJ. Randomized, controlled clinical trials in sepsis: has methodological quality improved over time?. Crit Care Med. 2002;30:461–472
  109. Statistically significant. Nat Med 2005;11:1.
  110. Mignini LE, Khan KS. Methodological quality of systematic reviews of animal studies: a survey of reviews of basic research. BMC Med Res Methodol. 2006;6:10
  111. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?. Lancet. 1998;352:609–613
  112. Lang TA, Secic M. How to report statistics in medicine Philadelphia: ACP; 1997.
  113. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials. 1996;17:1–12
  114. Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA. 1996;276:637–639
  115. Dans AL, Dans LF, Guyatt GH, Richardson S. Users’ guides to the medical literature: XIV. How to decide on the applicability of clinical trial results to your patient. Evidence-Based Medicine Working Group. JAMA. 1998;279:545–549
  116. Guyatt GH, Sackett DL, Sinclair JC, Hayward R, Cook DJ, Cook RJ. Users’ guides to the medical literature. IX. A method for grading health care recommendations. Evidence-Based Medicine Working Group. JAMA. 1995;274:1800–1804
  117. Oxman AD, Cook DJ, Guyatt GH. Users’ guides to the medical literature. VI. How to use an overview. Evidence-Based Medicine Working Group. JAMA. 1994;272:1367–1371
  118. Wang CH, Lee TH, Lu CN, Chou WY, Hung KS, Concejero AM, et al. Electroporative alpha-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation. Gene Ther. 2006;13:1000–1009
  119. Tasci I, Mas MR, Vural SA, Comert B, Alcigir G, Serdar M, et al. Rat liver fibrosis regresses better with pegylated interferon alpha2b and ursodeoxycholic acid treatments than spontaneous recovery. Liver Int. 2006;26:261–268
  120. Popov Y, Patsenker E, Bauer M, Niedobitek E, Schulze-Krebs A, Schuppan D. Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NF{kappa}B. J Biol Chem. 2006;281:15090–15098
  121. Neef M, Ledermann M, Saegesser H, Schneider V, Widmer N, Decosterd LA, et al. Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term. J Hepatol. 2006;44:167–175
  122. Migita K, Maeda Y, Abiru S, Nakamura M, Komori A, Yokoyama T, et al. Immunosuppressant FK506 inhibits matrix metalloproteinase-9 induction in TNF-alpha-stimulated human hepatic stellate cells. Life Sci. 2006;78:2510–2515
  123. Li G, Xie Q, Shi Y, Li D, Zhang M, Jiang S, et al. Inhibition of connective tissue growth factor by siRNA prevents liver fibrosis in rats. J Gene Med. 2006;
  124. Lee TH, Jawan B, Chou WY, Lu CN, Wu CL, Kuo HM, et al. Alpha-melanocyte-stimulating hormone gene therapy reverses carbon tetrachloride induced liver fibrosis in mice. J Gene Med. 2006;8:764–772
  125. Huang YH, Shi MN, Zheng WD, Zhang LJ, Chen ZX, Wang XZ. Therapeutic effect of interleukin-10 on CCl4-induced hepatic fibrosis in rats. World J Gastroenterol. 2006;12:1386–1391
  126. Hu QW, Liu GT. Effects of bicyclol on dimethylnitrosamine-induced liver fibrosis in mice and its mechanism of action. Life Sci. 2006;79:606–612
  127. Guido M, De FL, Olivari N, Leandro G, Felder M, Corrocher R, et al. Effects of interferon plus ribavirin treatment on NF-kappaB, TGF-beta1, and metalloproteinase activity in chronic hepatitis C. Mod Pathol. 2006;19:1047–1054
  128. Ebrahimkhani MR, Kiani S, Oakley F, Kendall T, Shariftabrizi A, Tavangar SM, et al. Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats. Gut. 2006;55:1606–1616
  129. Chou WY, Lu CN, Lee TH, Wu CL, Hung KS, Concejero AM, et al. Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation. Acta Pharmacol Sin. 2006;27:469–476
  130. Cao Q, Mak KM, Lieber CS. DLPC and SAMe combined prevent leptin-stimulated TIMP-1 production in LX-2 human hepatic stellate cells by inhibiting HO-mediated signal transduction. Liver Int. 2006;26:221–231
  131. Zheng WD, Zhang LJ, Shi MN, Chen ZX, Chen YX, Huang YH, et al. 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. World J Gastroenterol. 2005;11:1753–1758
  132. Yoshiji H, Noguchi R, Kuriyama S, Ikenaka Y, Yoshii J, Yanase K, et al. Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol. 2005;288:G907–G913
  133. Xidakis C, Ljumovic D, Manousou P, Notas G, Valatas V, Kolios G, et al. Production of pro- and anti-fibrotic agents by rat Kupffer cells; the effect of octreotide. Dig Dis Sci. 2005;50:935–941
  134. Oakley F, Meso M, Iredale JP, Green K, Marek CJ, Zhou X, et al. Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology. 2005;128:108–120
  135. Nakamuta M, Higashi N, Kohjima M, Fukushima M, Ohta S, Kotoh K, et al. Epigallocatechin-3-gallate, a polyphenol component of green tea, suppresses both collagen production and collagenase activity in hepatic stellate cells. Int J Mol Med. 2005;16:677–681
  136. Nakamuta M, Kohjima M, Fukushima M, Morizono S, Kotoh K, Kobayashi N, et al. Cyclosporine suppresses cell growth and collagen production in hepatic stellate cells. Transplant Proc. 2005;37:4598–4602
  137. Marinosci F, Bergamini C, Fransvea E, Napoli N, Maurel P, Dentico P, et al. Clinical role of serum and tissue matrix metalloprotease-9 expression in chronic HCV patients treated with pegylated IFN-alpha2b and ribavirin. J Interferon Cytokine Res. 2005;25:453–458
  138. Lin Y, Xie WF, Chen YX, Zhang X, Zeng X, Qiang H, et al. Treatment of experimental hepatic fibrosis by combinational delivery of urokinase-type plasminogen activator and hepatocyte growth factor genes. Liver Int. 2005;25:796–807
  139. Li X, Meng Y, Yang XS, Mi LF, Cai SX. ACEI attenuates the progression of CCl4-induced rat hepatic fibrogenesis by inhibiting TGF-beta1, PDGF-BB, NF-kappaB and MMP-2,9. World J Gastroenterol. 2005;11:4807–4811
  140. Lebensztejn DM, Sobaniec-Lotowska ME, Bauer M, Kaczmarski M, Voelker M, Schuppan D. Serum fibrosis markers as predictors of an antifibrotic effect of interferon alfa in children with chronic hepatitis B. Eur J Gastroenterol Hepatol. 2005;17:843–848
  141. Jiang W, Wang JY, Yang CQ, Liu WB, Wang YQ, He BM. Effects of a plasmid expressing antisense tissue inhibitor of metalloproteinase-1 on liver fibrosis in rats. Chin Med J (Engl). 2005;118:192–197
  142. Hung KS, Lee TH, Chou WY, Wu CL, Cho CL, Lu CN, et al. Interleukin-10 gene therapy reverses thioacetamide-induced liver fibrosis in mice. Biochem Biophys Res Commun. 2005;336:324–331
  143. Hsu YC, Lin YL, Chiu YT, Shiao MS, Lee CY, Huang YT. Antifibrotic effects of Salvia miltiorrhiza on dimethylnitrosamine-intoxicated rats. J Biomed Sci. 2005;12:185–195
  144. Fiorucci S, Rizzo G, Antonelli E, Renga B, Mencarelli A, Riccardi L, et al. A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther. 2005;314:584–595
  145. Di SA, Bendia E, Taffetani S, Omenetti A, Candelaresi C, Marzioni M, et al. Hepatoprotective and antifibrotic effect of a new silybin–phosphatidylcholine–vitamin E complex in rats. Dig Liver Dis. 2005;37:869–876
  146. de Gouville AC, Boullay V, Krysa G, Pilot J, Brusq JM, Loriolle F, et al. Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis. Br J Pharmacol. 2005;145:166–177
  147. Chen M, Wang GJ, Diao Y, Xu RA, Xie HT, Li XY, et al. Adeno-associated virus mediated interferon-gamma inhibits the progression of hepatic fibrosis in vitro and in vivo. World J Gastroenterol. 2005;11:4045–4051
  148. Zhang LJ, Chen YX, Chen ZX, Huang YH, Yu JP, Wang XZ. Effect of interleukin-10 and platelet-derived growth factor on expressions of matrix metalloproteinases-2 and tissue inhibitor of metalloproteinases-1 in rat fibrotic liver and cultured hepatic stellate cells. World J Gastroenterol. 2004;10:2574–2579
  149. Yeh TS, Ho YP, Huang SF, Yeh JN, Jan YY, Chen MF. Thalidomide salvages lethal hepatic necroinflammation and accelerates recovery from cirrhosis in rats. J Hepatol. 2004;41:606–612
  150. Uchio K, Graham M, Dean NM, Rosenbaum J, Desmouliere A. Down-regulation of connective tissue growth factor and type I collagen mRNA expression by connective tissue growth factor antisense oligonucleotide during experimental liver fibrosis. Wound Repair Regen. 2004;12:60–66
  151. Thirunavukkarasu C, Yang Y, Subbotin VM, Harvey SA, Fung J, Gandhi CR. Endothelin receptor antagonist TAK-044 arrests and reverses the development of carbon tetrachloride induced cirrhosis in rats. Gut. 2004;53:1010–1019
  152. Takahara T, Sugiyama K, Zhang LP, Ando O, Fujii M, Yata Y, et al. Cotreatment with interferon-alpha and -gamma reduces liver fibrosis in a rat model. Hepatol Res. 2004;28:146–154
  153. Reif S, Aeed H, Shilo Y, Reich R, Kloog Y, Kweon YO, et al. Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid. J Hepatol. 2004;41:235–241
  154. Refik Mas M, Comert B, Oncu K, Vural SA, Akay C, Tasci I, et al. The effect of taurine treatment on oxidative stress in experimental liver fibrosis. Hepatol Res. 2004;28:207–215
  155. Matsui H, Ikeda K, Nakajima Y, Horikawa S, Imanishi Y, Kawada N. Sulfur-containing amino acids attenuate the development of liver fibrosis in rats through down-regulation of stellate cell activation. J Hepatol. 2004;40:917–925
  156. Kotoh K, Nakamuta M, Kohjima M, Fukushima M, Morizono S, Kobayashi N, et al. Arg-Gly-Asp (RGD) peptide ameliorates carbon tetrachloride-induced liver fibrosis via inhibition of collagen production and acceleration of collagenase activity. Int J Mol Med. 2004;14:1049–1053
  157. Flisiak R, Al-Kadasi H, Jaroszewicz J, Prokopowicz D, Flisiak I. Effect of lamivudine treatment on plasma levels of transforming growth factor beta1, tissue inhibitor of metalloproteinases-1 and metalloproteinase-1 in patients with chronic hepatitis B. World J Gastroenterol. 2004;10:2661–2665
  158. Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology. 2004;127:1497–1512
  159. Duplantier JG, Dubuisson L, Senant N, Freyburger G, Laurendeau I, Herbert JM, et al. A role for thrombin in liver fibrosis. Gut. 2004;53:1682–1687
  160. Di Sario A, Bendia E, Macarri G, Candelaresi C, Taffetani S, Marzioni M, et al. The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen alpha1(I), TIMP-1 and MMP-2. Dig Liver Dis. 2004;36:744–751
  161. Campo GM, Avenoso A, Campo S, D’Ascola A, Ferlazzo AM, Calatroni A. The antioxidant and antifibrogenic effects of the glycosaminoglycans hyaluronic acid and chondroitin-4-sulphate in a subchronic rat model of carbon tetrachloride-induced liver fibrogenesis. Chem Biol Interact. 2004;148:125–138
  162. Bruck R, Schey R, Aeed H, Hochman A, Genina O, Pines M. A protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis. Liver Int. 2004;24:169–176
  163. Woo SW, Lee SH, Kang HC, Park EJ, Zhao YZ, Kim YC, et al. Butein suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture. J Pharm Pharmacol. 2003;55:347–352
  164. Sakaida I, Hironaka K, Terai S, Okita K. Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells. Life Sci. 2003;72:943–959
  165. Lee SH, Nan JX, Zhao YZ, Woo SW, Park EJ, Kang TH, et al. The chalcone butein from Rhus verniciflua shows antifibrogenic activity. Planta Med. 2003;69:990–994
  166. Han HL, Lang ZW. Changes in serum and histology of patients with chronic hepatitis B after interferon alpha-2b treatment. World J Gastroenterol. 2003;9:117–121
  167. Bennett RG, Kharbanda KK, Tuma DJ. Inhibition of markers of hepatic stellate cell activation by the hormone relaxin. Biochem Pharmacol. 2003;66:867–874
  168. Spira G, Mawasi N, Paizi M, Anbinder N, Genina O, Alexiev R, et al. Halofuginone, a collagen type I inhibitor improves liver regeneration in cirrhotic rats. J Hepatol. 2002;37:331–339
  169. Raetsch C, Jia JD, Boigk G, Bauer M, Hahn EG, Riecken EO, et al. Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis. Gut. 2002;50:241–247
  170. Perez MJ, Suarez A, Gomez-Capilla JA, Sanchez-Medina F, Gil A. Dietary nucleotide supplementation reduces thioacetamide-induced liver fibrosis in rats. J Nutr. 2002;132:652–657
  171. Garcia L, Hernandez I, Sandoval A, Salazar A, Garcia J, Vera J, et al. Pirfenidone effectively reverses experimental liver fibrosis. J Hepatol. 2002;37:797–805
  172. Dubuisson L, Desmouliere A, Decourt B, Evade L, Bedin C, Boussarie L, et al. Inhibition of rat liver fibrogenesis through noradrenergic antagonism. Hepatology. 2002;35:325–331
  173. Williams EJ, Benyon RC, Trim N, Hadwin R, Grove BH, Arthur MJ, et al. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut. 2001;49:577–583
  174. Wasser S, Lim GY, Ong CN, Tan CE. Anti-oxidant ebselen causes the resolution of experimentally induced hepatic fibrosis in rats. J Gastroenterol Hepatol. 2001;16:1244–1253
  175. Ninomiya T, Yoon S, Nagano H, Kumon Y, Seo Y, Kasuga M, et al. Significance of serum matrix metalloproteinases and their inhibitors on the antifibrogenetic effect of interferon-alfa in chronic hepatitis C patients. Intervirology. 2001;44:227–231
  176. Lee SH, Nan JX, Sohn DH. Tetrandrine prevents tissue inhibitor of metalloproteinase-1 messenger RNA expression in rat liver fibrosis. Pharmacol Toxicol. 2001;89:214–216
  177. Jonsson JR, Clouston AD, Ando Y, Kelemen LI, Horn MJ, Adamson MD, et al. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology. 2001;121:148–155
  178. Jia JD, Bauer M, Cho JJ, Ruehl M, Milani S, Boigk G, et al. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1. J Hepatol. 2001;35:392–398
  179. Bruck R, Genina O, Aeed H, Alexiev R, Nagler A, Avni Y, et al. Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats. Hepatology. 2001;33:379–386
  180. Bruck R, Shirin H, Aeed H, Matas Z, Hochman A, Pines M, et al. Prevention of hepatic cirrhosis in rats by hydroxyl radical scavengers. J Hepatol. 2001;35:457–464
  181. Miyahara T, Schrum L, Rippe R, Xiong S, Yee HF, Motomura K, et al. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem. 2000;275:35715–35722
  182. Mitsuda A, Suou T, Ikuta Y, Kawasaki H. Changes in serum tissue inhibitor of matrix metalloproteinase-1 after interferon alpha treatment in chronic hepatitis C. J Hepatol. 2000;32:666–672
  183. Hironaka K, Sakaida I, Matsumura Y, Kaino S, Miyamoto K, Okita K. Enhanced interstitial collagenase (matrix metalloproteinase-13) production of Kupffer cell by gadolinium chloride prevents pig serum-induced rat liver fibrosis. Biochem Biophys Res Commun. 2000;267:290–295
  184. Godichaud S, Krisa S, Couronne B, Dubuisson L, Merillon JM, Desmouliere A, et al. Deactivation of cultured human liver myofibroblasts by trans-resveratrol, a grapevine-derived polyphenol. Hepatology. 2000;31:922–931
  185. Cho JJ, Hocher B, Herbst H, Jia JD, Ruehl M, Hahn EG, et al. An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology. 2000;118:1169–1178
  186. Bueno MR, Daneri A, rmendariz-Borunda J. Cholestasis-induced fibrosis is reduced by interferon alpha-2a and is associated with elevated liver metalloprotease activity. J Hepatol. 2000;33:915–925
  187. DeLano WL. The PyMOL User’s Manual. San Carlos, CA, USA: 2002.

PII: S0168-8278(07)00112-2

doi: 10.1016/j.jhep.2007.02.003

Journal of Hepatology
Volume 46, Issue 5 , Pages 955-975 , May 2007

Article Tools

* Image Usage & Resolution