IGFBP-5 induces epithelial and fibroblast responses consistent with the fibrotic response

Abstract

Fibrosis involves activation of fibroblasts, increased production of collagen and fibronectin and transdifferentiation into contractile myofibroblasts. The process resembles aspects of wound-healing but remains unresolved and can be life-threatening when manifest in the kidneys, lungs and liver, in particular. The causes are largely unknown, but recent suggestions that repetitive micro-injury results in the eventual failure of epithelial cell repair due to replicative senescence are gaining favour. This is consistent with the onset of fibrotic diseases in middle age. Because epithelial injury often involves blood loss, inflammatory responses associated with the fibrotic response have been considered as therapeutic targets. However, this has proved largely unsuccessful and focus is now switching to earlier events in the process. These include EMT (epithelial-mesenchymal transition) and fibroblast activation in the absence of inflammation. TGFbeta1 (transforming growth factor-beta1) induces both EMT and fibroblast activation and is considered to be a major pro-fibrotic factor. Recently, IGFBP-5 [IGF (insulin-like growth factor)-binding protein-5] has also been shown to induce similar effects on TGFbeta1, and is strongly implicated in the process of senescence. It also stimulates migration of peripheral blood mononuclear cells, implicating it in the inflammatory response. In this paper, we examine the evidence for a role of IGFBP-5 in fibrosis and highlight its structural relationship with other matrix proteins and growth factors also implicated in tissue remodelling.

Relative Roles of TGF-βand IGFBP-5 in Idiopathic Pulmonary Fibrosis

“…Using biosensor technology, we showed a novel, direct, high affinity interaction of IGFBP-5 with α 2 and β 1 integrins leading to the activation of ILK and Akt and improved epithelial cell adhesion and survival (our unpublished observations). Apoptosis of epithelial cells induces IGFBP-5 which activates tissue plasminogen activator (tPA), generating plasmin, and also interacts with several matricellular proteins [50]. Thus, IGFBP-5 may act as a central mediator in the initial response of epithelial cell injury.…”

Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls

“…Similar prognostic significance of IGFBPs was also recently recorded for early stage, surgically resected NSCLC [Shersher et al 2011]. The intricacies of the IGF-independent action of IGFBPs are beyond the scope of this review but have been described in several cancer models [Chang et al 2002;Dunlap et al 2007;Firth and Baxter, 2002;Hoeflich et al 2001;Li et al 2010;Migita et al 2010;Sureshbabu et al 2009;Walker et al 2007;Wolpin et al 2007].…”

An ocular view of the IGF–IGFBP system

“…IGFBP-2 has been shown to inhibit IGF-induced responses, therefore the loss of IGFBP-2 in the early reactive phenotype may lead to increased growth factor activity and IGF mediated tractional force generation [99,103]. IGFBP-5 has also been shown to induce migration of human lung fibroblasts and induction of skin fibrosis, where migration of lung fibroblasts was via IGF independent mechanisms [104,105]. Similarly, inflammation has been linked to the pathogenesis of PVR, and IGFBP-5 has been shown to induce migration of mononuclear cells [104,106].…”

“…IGFBP-5 has also been shown to induce migration of human lung fibroblasts and induction of skin fibrosis, where migration of lung fibroblasts was via IGF independent mechanisms [104,105]. Similarly, inflammation has been linked to the pathogenesis of PVR, and IGFBP-5 has been shown to induce migration of mononuclear cells [104,106]. The presence of IGFBP-5 in a fibrotic state in different cell types may suggest a function of IGFBP-5 in mediating ocular fibrosis.…”