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

Hidekata Yasuoka, Eileen Hsu, Ximena D. Ruiz, Richard A. Steinman, Augustine M.K. Choi, Carol A. Feghali-Bostwick

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)605-615
Number of pages11
JournalAmerican Journal of Pathology
Volume175
Issue number2
DOIs
Publication statusPublished - 2009 Aug

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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