Skip to main content
SpringerLink
Log in

Soluble Arg-Gly-Asp Peptides Reduce Collagen Accumulation in Cultured Rat Hepatic Stellate Cells

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Hepatic stellate cells play a central role inthe pathogenesis of liver fibrosis, both via productionof extracellular matrix proteins and through secretionof matrix metalloproteinases. In this study, effects of soluble cell adhesion peptides oncollagen type I accumulation and on expression of matrixmetalloproteinases were analyzed. First, we revealed theexpression of α5-integrin on hepaticstellate cells by immunostaining. Treatment with 100μg/ml of soluble Arg-Gly-Asp (RGD) peptides was foundto reduce accumulation of type I collagen without anyeffects on its transcriptional level in rat hepatic stellate cells, whereas a control peptideGly-Arg-Gly-Glu-Ser (GRGES) had no such effect. SolubleRGD peptides also increased the secretion of collagenaseby stellate cells. These data suggested that reduced accumulation of type I collagen caused by theRGD peptide ligation to integrins on hepatic stellatecells was partly due to stimulated expression ofcollagenase by stellate cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Blomhoff R, Wake K: Perisinusoidal stellate cells of the liver: Important roles in retinol metabolism and fibrosis. FASEB J 5:271–277, 1991

    Google Scholar 

  2. Gressner AM, Bachem MG: Cellular sources of noncollagenous matrix proteins: Role of fat-storing cells in fibrogenesis. Semin Liver Dis 10:30–46, 1990

    Google Scholar 

  3. Friedman SL: The cellular basis of hepaticfibrosis: Mechanisms and treatment strategies. N Engl J Med 328:1828–1835, 1993

    Google Scholar 

  4. Friedman SL: Cellular sources of collagen and regulation of collagen production in liver. Semin Liver Dis 10:20–29, 1990

    Google Scholar 

  5. Martinez-Hernandez A: The hepatic extracellular matrix. II.Electron immunohistochemical studies in rats with CCl4-induced cirrhosis. Lab Invest 53:166–186, 1985

    Google Scholar 

  6. Clement B, Grimaud JA, Campion JP, Deugnier Y, Guillouzo A: Cell types involved in collagen and fibronectin production in normal and fibrotic human liver. Hepatology 6:225–234, 1986

    Google Scholar 

  7. De Leeuw AM, McCarthy SP, Geerts A, Knook DL: Purified rat liver fat-storing cells in culture divide and contain collagen. Hepatology 4:392–403, 1984

    Google Scholar 

  8. Friedman SL, Roll FJ, Boyles J, Bissell DM: Hepatic lipocytes: The principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci USA 82:8681–8685, 1985

    Google Scholar 

  9. Kawase T, Shiratori Y, Sugimoto T: Collagen production by rat liver fat storing cells in 1 degree culture. Exp Cell Biol 54:183–192, 1986

    Google Scholar 

  10. Arenson DM, Friedman SL, Bissell DM: Formation of extracellular matrix in normal rat liver: Lipocytes as a major source of proteoglycan. Gastroenterology 95:441–447, 1988

    Google Scholar 

  11. Maher JJ, Friedman SL, Roll FJ, Bissell DM: Immunolocalization of laminin in normal rat liver and biosynthesis of laminin by hepatic lipocytes in primary culture. Gastroenterology 94:1053–1062, 1988

    Google Scholar 

  12. Gressner AM, Haarmann R: Regulation of hyaluronate synthesis in rat liver fat-storing cell cultures by Kupffer cells. J Hepatol 7:310–318, 1988

    Google Scholar 

  13. Pinzani M, Gesualdo L, Sabbah GM, Abboud HE: Effects of platelet derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat storing cells. J Clin Invest 84:1786–1793, 1989

    Google Scholar 

  14. Friedman SL, Arthur MJP: Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet derived growth factor receptors. J Clin Invest 84:1780–1785, 1989

    Google Scholar 

  15. Casini A, Pinzani M, Milani S, Grappone C, Galli G, Jezequel AM, Schuppan D, Rotella CM, Surrenti C: Regulation of extracellular matrix synthesis by transforming growth factor b 1 in human fat-storing cells. Gastroenterology 105:245–253, 1993

    Google Scholar 

  16. Davis BH, Pratt BM, Madri JA: Retinol and extracellular collagen matrices modulate hepatic Ito cell collagen phenotype and cellular retinol binding protein levels. J Biol Chem 262:10280–10286, 1987

    Google Scholar 

  17. Davis BH: Transforming growth factor beta responsiveness is modulated by the extracellular collagen matrix during hepatic Ito cell culture. J Cell Physiol 136:547–553, 1988

    Google Scholar 

  18. Friedman SL, Wei SH, Blaner WS: Retinol release by activated rat hepatic lipocytes: Regulation by Kupffer cell-conditioned medium and PDGF. Am J Physiol 264:G947–G952, 1993

    Google Scholar 

  19. Brown LF, Dubin D, Lavigne L, Logan B, Dvork HF, Vandewater L: Macrophages and fibroblasts express embryonic fibronectins during cutaneous wound healing. Am J Pathol 142:793–801, 1993

    Google Scholar 

  20. Barnes JL, Hastings RR, De La Garza MA: Sequential expression of cellular fibronectin by platelets, macrophages, and mesangial cells in proliferative glomerulonephritis. Am J Pathol 145:585–597, 1994

    Google Scholar 

  21. Martinez-Hernandez A, Amenta PS: The extracellular matrix in hepatic regeneration. FASEB J 9:1401–1410, 1995

    Google Scholar 

  22. Friedman SL, Roll FJ, Boyles J, Arenson DM, Bissel DM: Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem 264:10756–10762, 1989

    Google Scholar 

  23. Ruoslahti E, Pierschbacher MD: New perspective s in cell adhesion: RGD and Integrins. Science 238:491–497, 1987

    Google Scholar 

  24. Boucaut JC, Darribere T, Poole TJ, Aoyama H, Yamada KM, Thiery JP: Biologically active synthetic peptides as probes of embryonic development: A competitive peptide inhibitor of fibronectin function inhibits gastrulation in Amphibian embryos and neural crest cell migration in avian embryos. J Cell Biol 99:1822–1830, 1984

    Google Scholar 

  25. Yamada KM: Fibronectins: Structure, functions and receptors. Curr Opin Cell Biol 1:956–963, 1989

    Google Scholar 

  26. Werb Z, Tremble PM, Behrendsten O, Crowley E, Damsky CH: Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J Cell Biol 109:877–889, 1989

    Google Scholar 

  27. Goldberg GI, Wilhelm SM, Kronenberger A, Bauer EA, Grant GA, Eisen AZ: Human fibroblast collagenase. Complete primary structure and homology to an oncogene transformation induced rat protein. J Biol Chem 261:6600–6605, 1986

    Google Scholar 

  28. Salo T, Turpeenniemi-Hujansen T, Tryggvason K: Tumorpromoting phorbol esters and cell proliferation stimulate secretion of basement membrane (Type IV) collagen-degrading metalloproteinase by human fibroblasts. J Biol Chem 260:8526–8531, 1985

    Google Scholar 

  29. Yokoi Y, Namihisa T, Kuroda H, Komatsu I, Miyazaki A, Watanabe S, Usui K: Immunocytochemical detection of desmin in fat-storing cells (Ito cells). Hepatology 4:709–714, 1984

    Google Scholar 

  30. Moshage H, Casini A, Lieber CS: Acetaldehyde selective ly increases collagen synthesis in cultured rat fat-storing cells but not in hepatocytes. Hepatology 12:511–518, 1990

    Google Scholar 

  31. Brunk KC, Jones KC, James TW: Assay for nanogram quantities of DNA in cellular homogenates. Anal Biochem 2:497–500, 1979

    Google Scholar 

  32. Herron GS, Banda MJ, Clark EJ, Gabrilovic J, Werb Z: Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. J Biol Chem 26:2814–2818, 1986

    Google Scholar 

  33. Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685, 1970

    Google Scholar 

  34. Towbin H, Staehelin T, Gordon J: Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354, 1979

    Google Scholar 

  35. Genovese C, Rocue D, Kream B: Construction of DNA sequence s complementary to rat α1, and β2 collagen mRNA and their use in studying the regulation of type I collagen synthesis by 1,25-dihydroxyvitamin D. Biochemistry 23:6210–6216, 1984

    Google Scholar 

  36. Nudel U, Zakut R, Shari M, Neuman S, Levy Z, Yaffe D: The nucleotide sequence of the rat cytoplasmic beta-actin gene. Nucleic Acids Res 11:1759–1771, 1983

    Google Scholar 

  37. Carloni V, Romanelli RG, Pinzani M, Laffi G, Gentilini P: Expression and function of integrin receptors for collagen and laminin in cultured human hepatic stellate cells. Gastroenterology 110:1127–1136, 1996

    Google Scholar 

  38. Jarnagin WR, Rockey DC, Koteliansky VE, Wang SS, Bissel DM: Expression of variant fibronectins in wound healing: Cellular source and biological activities of the E III A segment in rat hepatic fibrogenesis. J Cell Biol 127:2037–2048, 1994

    Google Scholar 

  39. Bruck R, Hershkoviz R, Lider O, Aeed H, Zaidel L, Matas Z, Barg J, Halpern Z: Inhibition of experimentally-induced liver cirrhosis in rats by a nonpeptidic mimetic of the extracellular matrix-associated Arg-Gly-Asp epitope. J Hepatol 24:731–738, 1996

    Google Scholar 

Download references

Authors
  1. Hiroaki Iwamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hironori Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazuhiro Kotoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Makoto Nakamuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hajime Nawata
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iwamoto, H., Sakai, H., Kotoh, K. et al. Soluble Arg-Gly-Asp Peptides Reduce Collagen Accumulation in Cultured Rat Hepatic Stellate Cells. Dig Dis Sci 44, 1038–1045 (1999). https://doi.org/10.1023/A:1026633302985

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026633302985

Search

Navigation