Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1994 Mar;144(3):528–537.

Differential Expression of Matrix-Metalloproteinase-1 and -2 Genes in Normal and Fibrotic Human Liver

Stefano Milani, Hermann Herbst, Detlef Schuppan, Cecilia Grappone, Giulia Pellegrini, Massimo Pinzani, Alessandro Casini, Antonio Calabró, Giuseppe Ciancio, Francesco Stefanini, Andrew K Ciancio, Calogero Surrenti
PMCID: PMC1887080  PMID: 8129038

Abstract

Altered degradation of extracellular matrix has been implicated in the pathogenesis of hepatic fibrosis. We investigated levels and cellular sites of gene expression of two major collagebn-degrading enzymes, matrix-metalloproteinase (MMP)-l (fibroblast type-interstitial collagenase)and MMP-2 (72-kd gelatinase, type IV collagenase) in five normal and 18 fibrotic human livers as well as in cultured human hepatic fat-storing cells by Northern blot analysis and in situ hybridization. Fatstoring cells expressed both MMP-1 and MMP-2 RNA in vitro. In vivo, MMP-1 was undetectable in mesenchymal and parenchymal cells of all liver specimens, whereas MMP-2 transcripts were expressed in all livers by vimentin-positive, CD68 negative mesenchymal cells. Mesenchymal cells of all fibrotic livers displayed high transcript levels of transforming growth factor-β1, which is known to modulate MMP expression. Along with de novo fibrogenesis and possibly influenced by transforming growth factor-β1, expression of MMP-2 in the absence of MMP-1 expression may be responsible for the quantitative and qualitative changes of extracellular matrix observed in chronic liver disease.

Full text

PDF
528

Images in this article

531Figure 1
on p.531
532Figure 2
on p.532
532Figure 3
on p.532
533Figure 4
on p.533
534Figure 5
on p.534
535Figure 7
on p.535

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arthur M. J., 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 Oct;84(4):1076–1085. doi: 10.1172/JCI114270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arthur M. J. Matrix degradation in the liver. Semin Liver Dis. 1990 Feb;10(1):47–55. doi: 10.1055/s-2008-1040456. [DOI] [PubMed] [Google Scholar]
  3. Arthur M. J., Stanley A., Iredale J. P., Rafferty J. A., Hembry R. M., Friedman S. L. Secretion of 72 kDa type IV collagenase/gelatinase by cultured human lipocytes. Analysis of gene expression, protein synthesis and proteinase activity. Biochem J. 1992 Nov 1;287(Pt 3):701–707. doi: 10.1042/bj2870701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Braun L., Mead J. E., Panzica M., Mikumo R., Bell G. I., Fausto N. Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1539–1543. doi: 10.1073/pnas.85.5.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Campbell E. J., Cury J. D., Lazarus C. J., Welgus H. G. Monocyte procollagenase and tissue inhibitor of metalloproteinases. Identification, characterization, and regulation of secretion. J Biol Chem. 1987 Nov 25;262(33):15862–15868. [PubMed] [Google Scholar]
  6. Carter E. A., McCarron M. J., Alpert E., Isselbacher K. J. Lysyl oxidase and collagenase in experimental acute and chronic liver injury. Gastroenterology. 1982 Mar;82(3):526–534. [PubMed] [Google Scholar]
  7. Castilla A., Prieto J., Fausto N. Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med. 1991 Apr 4;324(14):933–940. doi: 10.1056/NEJM199104043241401. [DOI] [PubMed] [Google Scholar]
  8. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  9. Clark S. D., Kobayashi D. K., Welgus H. G. Regulation of the expression of tissue inhibitor of metalloproteinases and collagenase by retinoids and glucocorticoids in human fibroblasts. J Clin Invest. 1987 Nov;80(5):1280–1288. doi: 10.1172/JCI113203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Edwards D. R., Murphy G., Reynolds J. J., Whitham S. E., Docherty A. J., Angel P., Heath J. K. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J. 1987 Jul;6(7):1899–1904. doi: 10.1002/j.1460-2075.1987.tb02449.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Emonard H., Grimaud J. A. Active and latent collagenase activity during reversal of hepatic fibrosis in murine schistosomiasis. Hepatology. 1989 Jul;10(1):77–83. doi: 10.1002/hep.1840100116. [DOI] [PubMed] [Google Scholar]
  12. Friedman S. L. Cellular sources of collagen and regulation of collagen production in liver. Semin Liver Dis. 1990 Feb;10(1):20–29. doi: 10.1055/s-2008-1040454. [DOI] [PubMed] [Google Scholar]
  13. Friedman S. L., Roll F. J., Boyles J., Arenson D. M., Bissell D. M. Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem. 1989 Jun 25;264(18):10756–10762. [PubMed] [Google Scholar]
  14. Goldberg G. I., Wilhelm S. M., Kronberger A., Bauer E. A., Grant G. A., Eisen A. Z. Human fibroblast collagenase. Complete primary structure and homology to an oncogene transformation-induced rat protein. J Biol Chem. 1986 May 15;261(14):6600–6605. [PubMed] [Google Scholar]
  15. Hasty K. A., Pourmotabbed T. F., Goldberg G. I., Thompson J. P., Spinella D. G., Stevens R. M., Mainardi C. L. Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases. J Biol Chem. 1990 Jul 15;265(20):11421–11424. [PubMed] [Google Scholar]
  16. Huhtala P., Chow L. T., Tryggvason K. Structure of the human type IV collagenase gene. J Biol Chem. 1990 Jul 5;265(19):11077–11082. [PubMed] [Google Scholar]
  17. MacSween R. N., Burt A. D. Histologic spectrum of alcoholic liver disease. Semin Liver Dis. 1986 Aug;6(3):221–232. doi: 10.1055/s-2008-1040605. [DOI] [PubMed] [Google Scholar]
  18. Maruyama K., Feinman L., Fainsilber Z., Nakano M., Okazaki I., Lieber C. S. Mammalian collagenase increases in early alcoholic liver disease and decreases with cirrhosis. Life Sci. 1982 Apr 19;30(16):1379–1384. doi: 10.1016/0024-3205(82)90023-6. [DOI] [PubMed] [Google Scholar]
  19. Maruyama K., Feinman L., Okazaki I., Lieber C. S. Direct measurement of neutral collagenase activity in homogenates from baboon and human liver. Biochim Biophys Acta. 1981 Mar 13;658(1):124–131. doi: 10.1016/0005-2744(81)90255-2. [DOI] [PubMed] [Google Scholar]
  20. Milani S., Herbst H., Schuppan D., Hahn E. G., Stein H. In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: evidence for predominant expression in nonparenchymal liver cells. Hepatology. 1989 Jul;10(1):84–92. doi: 10.1002/hep.1840100117. [DOI] [PubMed] [Google Scholar]
  21. Milani S., Herbst H., Schuppan D., Stein H., Surrenti C. Transforming growth factors beta 1 and beta 2 are differentially expressed in fibrotic liver disease. Am J Pathol. 1991 Dec;139(6):1221–1229. [PMC free article] [PubMed] [Google Scholar]
  22. Milani S., Herbst H., Schuppan D., Surrenti C., Riecken E. O., Stein H. Cellular localization of type I III and IV procollagen gene transcripts in normal and fibrotic human liver. Am J Pathol. 1990 Jul;137(1):59–70. [PMC free article] [PubMed] [Google Scholar]
  23. Montfort I., Pérez-Tamayo R. Collagenase in experimental carbon tetrachloride cirrhosis of the liver. Am J Pathol. 1978 Aug;92(2):411–420. [PMC free article] [PubMed] [Google Scholar]
  24. Murphy G., McAlpine C. G., Poll C. T., Reynolds J. J. Purification and characterization of a bone metalloproteinase that degrades gelatin and types IV and V collagen. Biochim Biophys Acta. 1985 Sep 20;831(1):49–58. doi: 10.1016/0167-4838(85)90148-7. [DOI] [PubMed] [Google Scholar]
  25. Okazaki I., Maruyama K. Collagenase activity in experimental hepatic fibrosis. Nature. 1974 Nov 1;252(5478):49–50. doi: 10.1038/252049a0. [DOI] [PubMed] [Google Scholar]
  26. Overall C. M., Wrana J. L., Sodek J. Transcriptional and post-transcriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-beta 1 in human fibroblasts. Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. J Biol Chem. 1991 Jul 25;266(21):14064–14071. [PubMed] [Google Scholar]
  27. Perez-Tamayo R., Montfort I., Gonzalez E. Collagenolytic activity in experimental cirrhosis of the liver. Exp Mol Pathol. 1987 Dec;47(3):300–308. doi: 10.1016/0014-4800(87)90015-3. [DOI] [PubMed] [Google Scholar]
  28. Pinzani M., Failli P., Ruocco C., Casini A., Milani S., Baldi E., Giotti A., Gentilini P. Fat-storing cells as liver-specific pericytes. Spatial dynamics of agonist-stimulated intracellular calcium transients. J Clin Invest. 1992 Aug;90(2):642–646. doi: 10.1172/JCI115905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pérez Tamayo R. Is cirrhosis of the liver experimentally produced by CCl4 and adequate model of human cirrhosis? Hepatology. 1983 Jan-Feb;3(1):112–120. doi: 10.1002/hep.1840030118. [DOI] [PubMed] [Google Scholar]
  30. Salo T., Lyons J. G., Rahemtulla F., Birkedal-Hansen H., Larjava H. Transforming growth factor-beta 1 up-regulates type IV collagenase expression in cultured human keratinocytes. J Biol Chem. 1991 Jun 25;266(18):11436–11441. [PubMed] [Google Scholar]
  31. Salo T., Turpeenniemi-Hujanen T., Tryggvason K. Tumor-promoting phorbol esters and cell proliferation stimulate secretion of basement membrane (type IV) collagen-degrading metalloproteinase by human fibroblasts. J Biol Chem. 1985 Jul 15;260(14):8526–8531. [PubMed] [Google Scholar]
  32. Schuetz E. G., Li D., Omiecinski C. J., Muller-Eberhard U., Kleinman H. K., Elswick B., Guzelian P. S. Regulation of gene expression in adult rat hepatocytes cultured on a basement membrane matrix. J Cell Physiol. 1988 Mar;134(3):309–323. doi: 10.1002/jcp.1041340302. [DOI] [PubMed] [Google Scholar]
  33. Takahashi S., Dunn M. A., Seifter S. Liver collagenase in murine schistosomiasis. Gastroenterology. 1980 Jun;78(6):1425–1431. [PubMed] [Google Scholar]
  34. Takahashi S., Koda K. Radioimmunoassay of soluble and insoluble collagenases in fibrotic liver. Biochem J. 1984 May 15;220(1):157–164. doi: 10.1042/bj2200157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Welgus H. G., Jeffrey J. J., Stricklin G. P., Eisen A. Z. The gelatinolytic activity of human skin fibroblast collagenase. J Biol Chem. 1982 Oct 10;257(19):11534–11539. [PubMed] [Google Scholar]
  36. Whitham S. E., Murphy G., Angel P., Rahmsdorf H. J., Smith B. J., Lyons A., Harris T. J., Reynolds J. J., Herrlich P., Docherty A. J. Comparison of human stromelysin and collagenase by cloning and sequence analysis. Biochem J. 1986 Dec 15;240(3):913–916. doi: 10.1042/bj2400913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Woessner J. F., Jr Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991 May;5(8):2145–2154. [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES