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Biochim Biophys Acta. 2013 Oct;1832(10):1511-9. doi: 10.1016/j.bbadis.2013.04.018. Epub 2013 Apr 24.

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

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1
Cell & Molecular Biology Laboratory, Hand & Upper Limb Centre, Canada. craykha@hotmail.com

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.

KEYWORDS:

Dupuytren's disease; Fibrosis; Insulin-like growth factor binding protein-6; Insulin-like growth factor-II; Myofibroblast

PMID:
23623986
DOI:
10.1016/j.bbadis.2013.04.018
[Indexed for MEDLINE]
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