Paired related homeobox protein 1 regulates PDGF-induced chemotaxis of hepatic stellate cells in liver fibrosis

Lab Invest. 2017 Sep;97(9):1020-1032. doi: 10.1038/labinvest.2017.65. Epub 2017 Jul 24.

Abstract

Activation of the platelet-derived growth factor (PDGF)/PDGF beta receptor (PDGFβR) axis has a critical role in liver fibrosis. However, the mechanisms that regulate the PDGF signaling are yet to be elucidated. The present study demonstrates that paired related homeobox protein 1 (Prrx1) is involved in PDGF-dependent hepatic stellate cell (HSCs) migration via modulation of the expression of metalloproteinases MMP2 and MMP9. PDGF elevated the level of Prrx1 through the activation of ERK/Sp1 and PI3K/Akt/Ets1 pathways. In vivo, an adenoviral-mediated Prrx1 shRNA administration attenuated liver fibrosis in thioacetamide-induced fibrotic models. These studies reveal a role of Prrx1 as a modulator of PDGF-dependent signaling in HSCs, and inhibiting its expression may offer a therapeutic approach for hepatic fibrosis.

MeSH terms

  • Animals
  • Cell Line
  • Chemotaxis / physiology*
  • Hepatic Stellate Cells / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Liver / pathology
  • Liver Cirrhosis / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Platelet-Derived Growth Factor / metabolism*
  • Rats
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Signal Transduction

Substances

  • Homeodomain Proteins
  • PRRX1 protein, rat
  • Platelet-Derived Growth Factor
  • Receptor, Platelet-Derived Growth Factor beta