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

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

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  • 1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, NW 628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA.

Abstract

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.

PMID:
19628764
[PubMed - indexed for MEDLINE]
PMCID:
PMC2716960
Free PMC Article

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