Defined carboxy-terminal fragments of insulin-like growth factor (IGF) binding protein-2 exert similar mitogenic activity on cultured rat growth plate chondrocytes as IGF-I

Daniela Kiepe, Anke Van Der Pas, Sonia Ciarmatori, Ludger Standker, Burkhardt Schütt, Andreas Hoeflich, Ulrike Hugel, Jun Oh, Burkhard Tonshoff

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    23 Citations (Scopus)

    Abstract

    The IGF/IGF binding protein (IGFBP) system is an important component in the hormonal regulation of longitudinal growth. Evidence from in vitro studies indicates that IGFBPs may have IGF-independent effects. We analyzed the biological activity of intact IGFBP-2 and defined carboxy-terminal IGFBP- 2 fragments isolated from human hemofiltrate in two cell culture systems of the growth plate: rat growth plate chondrocytes in primary culture and the mesenchymal chondrogenic cell line RCJ3.1C5.18. The IGFBP-2 fragments IGFBP- 2167–279, IGFBP-2167–289, and IGFBP-2104–289 exerted a strong (2- to 3-fold) mitogenic effect on growth plate chondrocytes, which was comparable with IGF-I in equimolar concentrations (7.8 nM) but was not mediated through the type 1 IGF receptor. In a dose-response experiment, the most effective concentration of IGFBP-2104–289 for the stimulation of cell proliferation was 10 nM. This biological activity of IGFBP-2 fragments was associated with cell membrane binding, demonstrated by Western blot analysis of fractionated cell lysates and immunohistochemistry. Whereas intact IGFBP-2 did not modulate chondrocyte proliferation, partially reduced (by dithiothreitol) full-length IGFBP-2 stimulated cell proliferation to a comparable extent (3.4-fold) as carboxy-terminal IGFBP-2 fragments. The mitogenic activity of these IGFBP-2 fragments and of partially reduced full-length IGFBP-2 was mediated through the use of the MAPK/ERK 1/2. These data imply a novel role of naturally occurring IGFBP-2 fragments for the endocrine and paracrine/autocrine regulation of longitudinal growth.
    Original languageEnglish
    Pages (from-to)4901-4911
    Number of pages11
    JournalEndocrinology
    Volume149
    Issue number10
    DOIs
    Publication statusPublished - 2008

    Keywords

    • Insulin, like growth factor, binding proteins
    • cell membranes
    • humans
    • rats

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