The fibrotic phenotype induced by IGFBP-5 is regulated by MAPK activation and egr-1-dependent and -independent mechanisms

Am J Pathol. 2009 Aug;175(2):605-15. doi: 10.2353/ajpath.2009.080991. Epub 2009 Jul 23.


We have previously shown that insulin-like growth factor (IGF) binding protein- 5 (IGFBP-5) is overexpressed in lung fibrosis and induces the production of extracellular matrix components, such as collagen and fibronectin, both in vitro and in vivo. The exact mechanism by which IGFBP-5 exerts these novel fibrotic effects is unknown. We thus examined the signaling cascades that mediate IGFBP-5-induced fibrosis. We demonstrate for the first time that IGFBP-5 induction of extracellular matrix occurs independently of IGF-I, and results from IGFBP-5 activation of MAPK signaling, which facilitates the translocation of IGFBP-5 to the nucleus. We examined the effects of IGFBP-5 on early growth response (Egr)-1, a transcription factor that is central to growth factor-mediated fibrosis. Egr-1 was up-regulated by IGFBP-5 in a MAPK-dependent manner and bound to nuclear IGFBP-5. In fibroblasts from Egr-1 knockout mice, induction of fibronectin by IGFBP-5 was abolished. Expression of Egr-1 in these cells rescued the extracellular matrix-promoting effects of IGFBP-5. Moreover, IGFBP-5 induced cell migration in an Egr-1-dependent manner. Notably, Egr-1 levels, similar to IGFBP-5, were increased in vivo in lung tissues and in vitro in primary fibroblasts of patients with pulmonary idiopathic fibrosis. Taken together, our findings suggest that IGFBP-5 induces a fibrotic phenotype via the activation of MAPK signaling and the induction of nuclear Egr-1 that interacts with IGFBP-5 and promotes fibrotic gene transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • Cell Movement
  • Cell Nucleus / metabolism
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism*
  • Enzyme Activation
  • Fibronectins / biosynthesis
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5 / genetics
  • Insulin-Like Growth Factor Binding Protein 5 / metabolism*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Transcription, Genetic


  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Fibronectins
  • Insulin-Like Growth Factor Binding Protein 5
  • Mitogen-Activated Protein Kinase Kinases