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Down-regulation of collagen and connective tissue growth factor expression with hepatocyte growth factor in lung

Galina S Bogatkevich1, Anna Ludwicka-Bradley, Kristin B Highland

  • 1Medical University of South Carolina, Charleston, SC 29425, USA. bogatkev@musc.edu

Arthritis and Rheumatism
|October 2, 2007
PubMed
Abstract

Insights

Hepatocyte growth factor (HGF) reduces collagen and connective tissue growth factor (CTGF) in scleroderma lung fibroblasts. This occurs through MAPK/MMP-1 and NF-kappaB pathways, offering potential therapeutic insights.

Area of Science:

  • Fibroblast biology
  • Cell signaling pathways
  • Connective tissue disorders

Background:

  • Scleroderma (systemic sclerosis [SSc]) is characterized by excessive collagen deposition in lung fibroblasts.
  • Connective tissue growth factor (CTGF) plays a significant role in fibrosis associated with SSc.
  • Hepatocyte growth factor (HGF) is investigated for its potential to modulate fibrotic processes.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which HGF down-regulates collagen and CTGF in SSc lung fibroblasts.
  • To identify the specific signaling pathways involved in HGF-mediated antifibrotic effects.

Main Methods:

  • Lung fibroblasts from SSc patients were utilized.
  • Expression levels of CTGF, collagen, and IkappaBalpha were assessed via immunoblotting.
  • MAPK phosphorylation, MMP-1 expression and activity, and NF-kappaB DNA binding activity were measured using various assays.

Main Results:

  • HGF activated MAPK (ERK-1/2) and MMP-1 while inhibiting NF-kappaB, leading to reduced CTGF and collagen.
  • Disruption of c-Met signaling (via Grb2 siRNA) reversed HGF's inhibitory effects on MMP-1, NF-kappaB, collagen, and CTGF.
  • MAPK inhibition (U0126) blocked MMP-1 activity and restored collagen/CTGF levels; MMP inhibition partially restored collagen/CTGF.
  • NF-kappaB inhibition synergized with HGF to fully abolish CTGF expression.

Conclusions:

  • HGF down-regulates CTGF accumulation in SSc lung fibroblasts through both MAPK/MMP-1 and NF-kappaB signaling pathways.
  • Collagen down-regulation by HGF is primarily mediated by the MAPK/MMP-1-dependent pathway.

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