Subscribe to RSS
DOI: 10.1055/s-2001-17552
Extracellular Matrix Degradation and the Role of Hepatic Stellate Cells
Publication History
Publication Date:
01 October 2001 (online)
![](https://www.thieme-connect.de/media/sld/200103/lookinside/thumbnails/10.1055-s-2001-17552-1.jpg)
ABSTRACT
Following liver injury, hepatic stellate cells (HSCs) become activated and express a combination of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs). In the early phases of liver injury (and primary cell culture), HSCs transiently express MMP-3, MMP-13, and uroplasminogen activator (uPA) and exhibit a matrix-degrading phenotype. In the later stages of liver injury and HSC activation, the pattern changes and the cells express a combination of MMPs that have the ability to degrade normal liver matrix, while inhibiting degradation of the fibrillar collagens that accumulate in liver fibrosis. This pattern is characterized by the combination of pro-MMP-2 and membrane type 1 (MT1)-MMP expression, which drive pericellular generation of active MMP-2 and local degradation of normal liver matrix. In addition there is a marked increase in expression of TIMP-1 leading to a more global inhibition of degradation of fibrillar liver collagens by interstitial collagenases (MMP-1/MMP-13). These pathways play a significant role in the progression of liver fibrosis. Following cessation of liver injury, the pattern reverses and TIMP-1 in particular is rapidly downregulated. This phase is characterized by increasing activity of collagenases, degradation of liver matrix, and regression of liver fibrosis.
KEYWORD
Cirrhosis - liver fibrosis - matrix degradation - matrix metalloproteinases - tissue inhibitor of metalloproteinases
REFERENCES
- 1 Nagase H, Woessner Jr F J. Matrix metalloproteinases. J Biol Chem . 1999; 30 21491-21494
- 2 Quantin B, Murphy G, Breathnach R. Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members. Biochemistry . 1989; 28 5327-5334
- 3 Banyai L, Patthy L. Evidence for the involvement of type II domains in collagen binding by 72kDa type IV procollagenase. FEBS Lett . 1991; 282 23-25
- 4 Aimes R T, Quigley J P. 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
- 5 Holmbeck K, Bianco P, Caterina J. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell . 1999; 99 81-92
- 6 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
- 7 Quinn C O, Scott D K, Brinckerhoff C E, Matrisian L M, Jeffrey J J, Partridge N C. Rat collagenase. Cloning, amino acid sequence comparison, and parathyroid hormone regulation in osteoblastic cells. J Biol Chem . 1990; 265 22342-22347
- 8 Henriet P, Rousseau G G, Eeckhout Y. Cloning and sequencing of mouse collagenase cDNA-divergence of mouse and rat collagenases from the other mammalian collagenases. FEBS Lett . 1992; 310 175-178
- 9 Mitchell P G, Magna H A, Reeves L M. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest . 1996; 97 761-768
- 10 Knauper V, Lopezotin C, Smith B, Knight G, Murphy G. Biochemical characterization of human collagenase-3. J Biol Chem . 1996; 271 1544-1550
- 11 Krane S M, Byrne M H, Lemaitre V. Different collagenase gene products have different roles in degradation of type I collagen. J Biol Chem . 1996; 271 28509-28515
- 12 Vater C A, Harris Jr D E, Siegel R C. Native cross-links in collagen fibrils induce resistance to human synovial collagenase. Biochem J . 1979; 181 639-645
- 13 Seiki M. Membrane-type matrix metalloproteinases. APMIS . 1999; 107 137-143
- 14 Gruber B L, Marchee M J, Suzuki K, Schwartz L B, Okada Y, Nagase H, Ramamurthy N S. Synovial procollagenase activation by human mast cell tryptase dependence upon matrix metalloproteinase 3 activation. J Clin Invest . 1989; 84 1657-1662
- 15 Okada Y, Nakanishi I. Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 (gelatinase) by human neutrophil elastase and cathepsin G. FEBS Lett . 1989; 249 353-356
- 16 Irigoyen J P, Munoz-Canoves P, Montero L, Koziczak M, Nagamine Y. The plasminogen activator system: biology and regulation. Cell Mol Life Sci . 1999; 56 104-132
- 17 Suzuki K, Enghild J J, Morodomi T, Salvesen G, Nagase H. Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin). Biochemistry . 1990; 29 10261-10270
- 18 Murphy G, Stanton H, Cowell S. Mechanisms for pro matrix metalloproteinase activation. APMIS . 1999; 109 38-44
- 19 Sato H, Kinoshita T, Takino T, Nakayama K, Seiki M. Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS Lett . 1996; 393 101-104
- 20 Sato H, Takino T, Okada Y. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature . 1994; 370 61-65
- 21 Strongin A Y, Collier I, Bannikov G, Marmer B L, Grant G A, Goldberg G I. 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
- 22 Butler G S, Butler M J, Atkinson S J. The TIMP2 membrane type 1 metalloproteinase ``receptor'' regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem . 1998; 273 871-880
- 23 Ward R V, Atkinson S J, Slocombe P M, Docherty A JP, Reynolds J J, Murphy G. Tissue inhibitor of metalloproteinases-2 inhibits the activation of 72kDa progelatinase by fibroblast membranes. Biochim Biophys Acta . 1991; 1079 242-246
- 24 Deryugina E I, Ratnikov B, Monosov E. MT1-MMP initiates activation of pro-MMP-2 and integrin alpha beta 3 promotes maturation of MMP-2 in breast carcinoma cells. Exp Cell Res . 2001; 263 209-223
- 25 Cowell S, Knauper V, Stewart M L. Induction of matrix metalloproteinase activation cascades based on membrane type I matrix metalloproteinase. Biochem J . 1998; 331 453-458
- 26 Knauper V, Will H, Lopez-Otin C. Cellular mechanisms for human procollagenase-3 (MMP-13) activation-evidence that MT1-MMP (MMP-14) and gelatinase A (MMP-2) are able to generate activate enzyme. J Biol Chem . 1996; 271 17124-17131
- 27 Balbin M, Pendas A M, Uria J A, Jimenez M G, Freije J P, Lopez-Otin C. Expression and regulation of collagenase-3 (MMP-13) in human malignant tumors. APMIS . 1999; 107 45-53
- 28 Uria J A, Jimenez M G, Balbin M, Freije J MP, Lopez-Otin C. Differential effects of transforming growth factor-beta on the expression of collagenase-1 and collagenase-3 in human fibroblasts. J Biol Chem . 1998; 273 9769-9777
- 29 Pan L, Eckhoff C, Brinckerhoff C E. Suppression of collagenase gene expression by all-trans and 9-cis retinoic acid is ligand dependent and requires both RARs and RXRs. J Cell Biochem . 1995; 57 575-589
- 30 Bigg H F, Cawston T E. All-trans-retinoic acid interacts synergistically with basic fibroblast growth factor and epidermal growth factor to stimulate the production of tissue inhibitor of metalloproteinases from fibroblasts. Arch Biochem Biophys . 1995; 319 74-83
- 31 Okuno M, Sato T, Kitamoto T. Increased 9, 13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a potential link between retinoid loss and TGF-beta mediated fibrogenesis in vivo. J Hepatol . 1999; 30 1073-1080
- 32 Overall C M, Wrana J L, Sudek J. Independent regulation of collagenase, 72kD progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. J Biol Chem . 1989; 264 1860-1869
- 33 Marti H P, Lee L, Kashgarian M, Lovett D H. Transforming growth factor-beta 1 stimulates glomerular mesangial cell synthesis of the 72-kD type IV collagenase. Am J Pathol . 1994; 144 82-94
- 34 Miralles F, Battelino T, Czernichow P, Scharfmann R. TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2. J Cell Biol . 1998; 143 827-836
- 35 Riikonen T, Westermarck J, Koivisto L, Broberg A, Kahari V M, Heino J. Integrin alpha 2 beta 1 is a positive regulator of collagenase (MMP-1) and collagen alpha 1(I) gene expression. J Biol Chem . 1995; 270 13548-13552
- 36 Seltzer J L, Lee A Y, Akers K T, Sudbeck B, Southon E A, Wayner E A, Eisen A Z. Activation of 72-kDa type IV collagenase/gelatinase by normal fibroblasts in collagen lattices is mediated by integrin receptors but is not related to lattice contraction. Exp Cell Res . 1994; 213 365-374
- 37 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
- 38 Takahara T, Furui K, Funaki J. Increased expression of matrix metalloproteinase-II in experimental liver fibrosis in rats. Hepatology . 1995; 21 787-795
- 39 Gomez D E, Alonso D F, Yoshiji H, Thorgeirsson U P. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol . 1997; 74 111-122
- 40 Will H, Atkinson S J, Butler G S, 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
- 41 Murphy G, Willenbrock F. Tissue inhibitors of matrix metalloproteinases. Meth Enzymol . 1995; 248 496-510
- 42 Caterina N C, Windsor L J, Yermovsky A E. Replacement of conserved cysteines in human tissue inhibitor of metalloproteinases-1. J Biol Chem . 1997; 272 32141-32149
- 43 Goldberg G I, Strongin A, Collier I E, Genrich L T, Marmer B L. Interaction of 92-kDa type-IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin. J Biol Chem . 1992; 267 4583-4591
- 44 Howard E W, Banda M J. Binding of tissue inhibitor of metalloproteinases 2 to two distinct sites on human 72-kDa gelatinase. J Biol Chem . 1991; 266 17972-17977
- 45 Leco K J, Khokha R, Pavloff N. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem . 1994; 269 9352-9360
- 46 Edwards D R, Murphy G, Reynolds J J. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J . 1987; 6 1899-1904
- 47 Mackay A R, Ballin M, Pelina M D. Effect of phorbol ester and cytokines on matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in tumor and normal cell lines. Invasion Metastasis . 1992; 12 168-184
- 48 Zafarullah M, Su S, Martel-Pelletier J. Tissue inhibitor of metalloproteinase-2 (TIMP-2) mRNA is constitutively expressed in bovine, human normal, and osteoarthritic articular chondrocytes. J Cell Biochem . 1996; 60 211-217
- 49 Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K. 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 . 1992; 298 29-32
- 50 Stetlerstevenson W G, Bersch N, Golde D W. Tissue inhibitor of metalloproteinase-2 (TIMP-2) has erythroid- potentiating activity. FEBS Lett . 1992; 296 231-234
- 51 Nemeth J A, Rafe A, Steiner M, Goolsby C L. TIMP-2 growth-stimulatory activity: a concentration- and cell type-specific response in the presence of insulin. Exp Cell Res . 1996; 224 110-115
- 52 Hayakawa T, Yamashita K, Ohuchi E, Shinagawa A. Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). J Cell Sci . 1994; 107 2373-2379
- 53 Corcoran M L, Stetlerstevenson W G. Tissue inhibitor of metalloproteinase-2 stimulates fibroblast proliferation via a cAMP-dependent mechanism. J Biol Chem . 1995; 270 13453-13459
- 54 Chesler L, Golde D W, Bersch N, Johnson M D. Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases. Blood . 1995; 86 4506-4515
- 55 Zhao W-Q, Li H, Yamashita K. Cell cycle-associated accumulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) in the nuclei of human gingival fibroblasts. J Cell Sci . 1998; 111 1147-1153
- 56 Baker A H, George S J, Zaltsman A B, Murphy G, Newby A C. Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br J Cancer . 1998; 79 1347-1355
- 57 Baker A H, Zaltsman A B, George S J, Newby A C. Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. J Clin Invest . 1998; 101 1478-1487
- 58 Leco K J, Apte S S, Taniguchi G T, Hawkes S P, Khokha R, Schultz G A, Edwards D R. Murine tissue inhibitor of metalloproteinases-4 (TIMP-4): cDNA isolation and expression in adult mouse tissues. FEBS Lett . 1997; 401 213-217
- 59 Vyas S K, Leyland H, Gentry J, Arthur M JP. Rat hepatic lipocytes synthesize and secrete transin (stromelysin) is expressed in early primary culture. Gastroenterology . 1995; 109 889-898
- 60 Iredale J P, Goddard S, Murphy G, Benyon R C, Arthur M JP. Tissue inhibitor of metalloproteinase-1 and interstitial collagenase expression in autoimmune chronic active hepatitis and activated human hepatic lipocytes. Clin Sci . 1995; 89 75-81
- 61 Iredale J P, Benyon R C, Arthur M JP. 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
- 62 Leyland H, Gentry J, Arthur M JP, Benyon R C. The plasminogen-activating system in hepatic stellate cells. Hepatology . 1996; 24 1172-1178
- 63 Benyon R C, Iredale J P, Goddard S, Winwood P J, Arthur M JP. Expression of tissue inhibitor of metalloproteinases-1 and -2 is increased in fibrotic human liver. Gastroenterology . 1996; 110 821-831
- 64 Arthur M JP, Friedman S L, Roll F J, Bissell D M. Lipocytes from normal rat liver release a neutral metalloproteinase that degrades basement membrane (type IV) collagen. J Clin Invest . 1989; 84 1076-1085
- 65 Benyon R C, Hovell C J, Gaca M DA, Jones E H, Iredale J P, Arthur M JP. Progelatinase A is produced and activated by rat hepatic stellate cells and promotes their proliferation. Hepatology . 1999; 30 977-986
- 66 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
- 67 Olaso E, Eng F, Lin C, Yancopoulos G, Friedman S L. The discoidin domain receptor 2 (DDR2) is induced during stellate cell activation, mediates cell growth and matrix metalloproteinase 2 expression, and is regulated by extracellular matrix. Hepatology . 1999; 30 1009
- 68 Godichaud S, Krisa S, Couronne B. Deactivation of cultured human liver myofibroblasts by trans-resveratrol, a grapevine-derived polyphenol. Hepatology . 2000; 31 922-931
- 69 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] . 1991; 60 295-300
- 70 Knittel T, Mehde M, Grundmann A, Saile B, Scharf J G, Ramadori G. Expression of matrix metalloproteinases and their inhibitors during hepatic tissue repair in the rat. Histochem Cell Biol . 2000; 113 443-453
- 71 Nieto N, Dominguez-Rosales J A, Fontana L. Rat hepatic stellate cells contribute to the acute-phase response with increased expression of alpha1(I) and alpha1(IV) collagens, tissue inhibitor of metalloproteinase-1, and matrix-metalloproteinase-2 messenger RNAs. Hepatology . 2001; 33 597-607
- 72 Kim T-H, Mars W M, Stolz D B, Petersen B E, Michalopoulos G K. Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology . 1997; 26 896-904
- 73 Kim T H, Mars W M, Stolz D B, Michalopoulos G K. Expression and activation of pro-MMP-2 and pro-MMP-9 during rat liver regeneration. Hepatology . 2000; 31 75-82
- 74 Shimizu M, Hara A, Okuno M. Mechanism of retarded liver regeneration in plasminogen activator-deficient mice: impaired activation of hepatocyte growth factor after Fas-mediated massive hepatic apoptosis. Hepatology . 2001; 33 569-576
- 75 Schiff E R, Heathcote J, Dienstag J L. Improvements in liver histology and cirrhosis with extended lamivudine therapy. Hepatology . 2000; 32 546
- 76 Hammel P, Couvelard A, O'Toole D. Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med . 2001; 344 418-423
- 77 Takahara T, Furui K, Yata Y. Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers. Hepatology . 1997; 26 1521-1529
- 78 Herbst H, Wege T, Milani S. Tissue inhibitor of metalloproteinase-1 and -2 RNA expression in rat and human liver fibrosis. Am J Pathol . 1997; 150 1647-1659
- 79 Yata Y, Takahara T, Furui K, Zhang L P, Jin B, Watanabe A. Spatial distribution of tissue inhibitor of metalloproteinase-1 mRNA in chronic liver disease. J Hepatol . 1999; 30 425-432
- 80 Yoshiji H, Kuriyama S, Miyamoto Y. Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model. Hepatology . 2000; 32 1248-1254
- 81 Iredale J P, Benyon R C, Pickering J. 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
- 82 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
- 83 Watanabe T, Niioka M, Hozawa S. 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
- 84 Atkinson S J, Patterson M L, Butler M J, Murphy G. Membrane type 1 matrix metalloproteinase and gelatinase A synergistically degrade type 1 collagen in a cell model. FEBS Lett . 2001; 491 222-226