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GPO10, a collagen analog, effectively promotes activation of collagen‐bound pro‐Matrix‐Metalloproteinase‐2 in fibrotic liver tissue stimulating cell proliferation and migration
Author(s) -
Ruehl Martin,
Freise Christian,
Seja Marion,
Erben Ulrike,
Farndale Richard,
Schuppan Detlef,
Zeitz Martin,
Somasundaram Rajan
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1007-b
Subject(s) - hepatic stellate cell , matrix metalloproteinase , chemistry , cell growth , cell migration , microbiology and biotechnology , extracellular matrix , type i collagen , cell , zymography , matrix (chemical analysis) , biophysics , biochemistry , endocrinology , biology , chromatography
Matrix‐metalloproteinase 2 (MMP‐2) degrades denatured collagens and plays a key role in liver fibrogenesis/lysis. We previously showed that proMMP‐2 binds to non‐substrate ECM‐collagens and is released and activated by the collagen‐analog GPO 10 . The aim of this study was to elucidate cell‐specific events initiated by GPO 10 ‐induced proMMP‐2 activation. Methods: GPO 10 ‐induced proMMP‐2 activation was shown by gel‐zymography and substrate turnover. The hepatic stellate cell line CFSC was treated with nanomolar concentrations of pro‐ and activated MMP‐2 with and without specific MMP‐inhibition (ilomastat) and GPO 10 . DNA‐synthesis was measured by [³H]‐thymidine‐incorporation. Additionally, a MMP‐2‐dependent migration assay was performed. Results: A 10‐fold molar excess of GPO 10 led to complete activation of proMMP‐2 whereas GAP 10 (control‐peptide) had no effect. Active MMP‐2 and GPO 10 stimulated CFSC‐proliferation up to 35% and 20% compared to max. stimulated cells, resp. GPO 10 –induced proliferation was completely blocked by ilomastat. MMP‐2 and GPO 10 ‐activated proMMP‐2 specifically induced strong cell migration. Conclusion: GPO 10 activates collagen‐bound proMMP‐2 thus enhancing proliferation and migration of mesenchymal and hepatic stellate cells Local modulation of MMP‐activity by GPO 10 may open a new therapeutic approach in liver fibrosis.