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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

University Children’s Hospital (D.K., A.V.D.P., S.C., U.H., J.O., B.T.), 69120 Heidelberg, Germany; Center of Pharmacology (L.S.), Hannover Medical School, 30625 Hannover, Germany; Kolling Institute of Medical Research (B.S.), University of Sydney, Royal North Shore Hospital, 2006 Sydney, Australia; and Research Unit Genetics and Biometry (A.H.), Research Institute for the Biology of Farm Animals, 18196 Dummerstorf, Germany

Address all correspondence and requests for reprints to: Daniela Kiepe, M.D., University Children’s Hospital, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany. E-mail: daniela.kiepe{at}med.uni-heidelberg.de.

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-2^167–279, IGFBP-2^167–289, and IGFBP-2^104–289 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-2^104–289 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.

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