IGF-II and IGFBP-6 regulate cellular contractility and proliferation in Dupuytren's disease

Abstract

Dupuytren's disease (DD) is a common and heritable fibrosis of the palmar fascia that typically manifests as permanent finger contractures. The molecular interactions that induce the development of hyper-contractile fibroblasts, or myofibroblasts, in DD are poorly understood. We have identified IGF2 and IGFBP6, encoding insulin-like growth factor (IGF)-II and IGF binding protein (IGFBP)-6 respectively, as reciprocally dysregulated genes and proteins in primary cells derived from contracture tissues (DD cells). Recombinant IGFBP-6 inhibited the proliferation of DD cells, patient-matched control (PF) cells and normal palmar fascia (CT) cells. Co-treatments with IGF-II, a high affinity IGFBP-6 ligand, were unable to rescue these effects. A non-IGF-II binding analog of IGFBP-6 also inhibited cellular proliferation, implicating IGF-II-independent roles for IGFBP-6 in this process. IGF-II enhanced the proliferation of CT cells, but not DD or PF cells, and significantly enhanced DD and PF cell contractility in stressed collagen lattices. While IGFBP-6 treatment did not affect cellular contractility, it abrogated the IGF-II-induced contractility of DD and PF cells in stressed collagen lattices. IGF-II also significantly increased the contraction of DD cells in relaxed lattices, however this effect was not evident in relaxed collagen lattices containing PF cells. The disparate effects of IGF-II on DD and PF cells in relaxed and stressed contraction models suggest that IGF-II can enhance lattice contractility through more than one mechanism. This is the first report to implicate IGFBP-6 as a suppressor of cellular proliferation and IGF-II as an inducer of cellular contractility in this connective tissue disease.

IGF2 expression and β-catenin levels are increased in Frozen Shoulder Syndrome

“…Increased β-catenin accumulation [17,19] and IGF2 expression [18] have been previously identi ed in DD tissue and primary broblasts compared with controls from adjacent, phenotypically non-brotic palmar fascia. As FSS and DD are clinically associated [3,20], we were interested to see if these characteristics were common to both connective tissue broses.…”

“…In contrast to its well-established roles in promoting cancer growth [30][31][32][33], relatively little is known about the roles of IGF-II in benign broproliferative diseases like FFS and DD. In addition to DD [18], IGF2 expression and IGF-II levels are reported to be increased in systemic sclerosisassociated pulmonary brosis [34]. IGF-II can act in combination with TGF-β1 signalling intermediates to promote myobroblast development in vitro [35] and both IGF-II and TGF-β1 can independently induce β-catenin translocation to the nucleus during epithelial mesenchymal transition (EMT) [36]; a process implicated in both cancer and brosis development [37][38][39].…”

“…Levels of β-catenin, an established signaling component of the Wnt/frizzled pathway [14][15][16], have been shown to be increased in DD [17]. More recently, expression of IGF2, encoding insulin-like growth factor-II (IGF-II), has been shown to be increased in DD [18]. In this report, β-catenin levels and IGF2 expression were assessed in tissues and cells derived from the rotator cu interval of patients with FSS and Rotator Cu Tear (RCT) to determine if disease-associated changes in these molecules are also evident in FSS and RCT.…”

“…Increased β-catenin levels have been causatively linked to increased broblast proliferation in aggressive bromatosis (desmoid tumor) [27,28] and hypertrophic scar formation [22]. As these conditions share many molecular similarities with FSS and DD [18,29], β-catenin is likely to play analogous broproliferative roles in these diseases. Western immunoblotting also revealed the presence of multiple molecular weight forms of β-catenin in FSS tissues, correlating with similar observations in DD tissues [17].…”

Recent insights into the actions of IGFBP-6

“…A recent study suggested that IGFBP-6 inhibited fibroblast proliferation by both IGF-dependent and -independent mechanisms (Raykha, et al 2013). Additionally, IGFBP-6-induced apoptosis appeared to be IGF-dependent (Hale, et al 2000) and IGF-independent (Iosef, et al 2008;Sueoka, et al 2000b) in different cell lines.…”