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.