title: 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.
authors.affiliation: Cell & Molecular Biology Laboratory, Hand & Upper Limb Centre, Canada. craykha@hotmail.com
authors.forename: Christina
authors.initials: C
authors.lastname: Raykha
authors.forename: Justin
authors.initials: J
authors.lastname: Crawford
authors.forename: Bing Siang
authors.initials: BS
authors.lastname: Gan
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.forename: Leon A
authors.initials: LA
authors.lastname: Bach
authors.forename: David B
authors.initials: DB
authors.lastname: O'Gorman
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D004387:Dupuytren Contracture / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000502:physiology*; D008024:Ligands; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018976:Insulin-Like Growth Factor Binding Protein 6; D008024:Ligands; D007335:Insulin-Like Growth Factor II
keywords: Dupuytren's disease; Fibrosis; Insulin-like growth factor binding protein-6; Insulin-like growth factor-II; Myofibroblast