Pharmacological inhibition of the vitronectin receptor abrogates PDGF-BB-induced hepatic stellate cell migration and activation in vitro

Background/Aims: Activated hepatic stellate cells (HSC) play a central role in the development of liver fibrosis. Platelet-derived growth factor (PDGF)-BB and the integrin alpha nu beta 3 mediate mesenchymal cell migration and proliferation. However, their contribution and interaction during fibrogenic activation of HSC remains unclear. To this aim we investigated if PDFGF-BB and alpha nu beta 3 interact, and how far small molecular inhibitors of alpha nu beta 3 modulate PDGF-BB and serum-induced migration, proliferation and fibrogenic activation of HSC. Methods: Rat and human HSC were subjected to migration and proliferation assays in the presence or absence of a peptide or a nonpeptide alpha nu beta 3 inhibitor. Activation of mitogen-activated protein kinases (ERKI/2, p38), Akt, focal adhesion kinase (FAK), paxillin and beta 3 integrin was evaluated by phospho-specific Western blotting. Fibrosis related transcripts were determined by quantitative real-time PCR. Results: PDGF-BB-stimulated HSC migration which was blocked dose-dependently by the alpha nu beta 3 antagonists, with complete inhibition at 10(-6) M. alpha nu beta 3 blockage did not affect cell viability or proliferation, while it decreased phosphorylation of FAK, paxillin, 03 integrin and p38, but not of ERKI/2 or Akt. alpha nu beta 3 inhibition led to downregulation of certain profibrogenic transcripts, while it upregulated fibrolytic MMP-13 mRNA. Conclusions: Inhibition of integrin alpha nu beta 3 leads to abrogation of migration of HSC stimulated with PDGF-BB and to an antifibrogenic gene expression pattern. (C) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.