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The 16-kDa Proteolytic Fragment of Insulin-Like Growth Factor (IGF) Binding Protein-3 Inhibits the Mitogenic Action of Fibroblast Growth Factor on Mouse Fibroblasts with a Targeted Disruption of the Type 1 IGF Receptor Gene

Unité de Recherches sur la Régulation de la Croissance, U.142, Institut National de la Santé et de la Recherche Médicale, Hôpital Saint Antoine, 75571 Paris Cedex 12, France

Address all correspondence and requests for reprints to: Michel Binoux, M.D., INSERM U142, Hôpital Sainte Antoine, 184 rue du Faubourg Saint Antoine, Paris, Cedex 12 75571, France.

We previously reported that a 16-kDa proteolytic fragment of IGF Binding Protein-3 (IGFBP-3), which is devoid of affinity for IGFs, inhibits the mitogenic effects of IGF-I on chick embryo fibroblasts. Here, we set out to determine if the fragment had biological effects on fibroblasts from mouse embryos homozygous for a targeted disruption of the Type 1 IGF receptor gene. In the cell clone used, bFGF (but not IGF, EGF or PDGF) was mitogenic in serum-free medium, increasing ¹⁴C-thymidine uptake by a factor of 10–15 within 24 hours and doubling cell proliferation. The 16-kDa fragment, isolated by HPLC following limited proteolysis of recombinant human (rh) IGFBP-3 by plasmin, in both assays dose-dependently (20 to 100 ng/ml) inhibited (up to 100%) maximal stimulation induced by 25 ng/ml bFGF, whereas intact IGFBP-3 had virtually no effect. Similar results were obtained with control wild-type cells. In the latter, the mitogenic activity of 1% fetal calf serum (equal to that of 25 ng/ml bFGF) was inhibited by only 25–30% by 100 ng/ml 16-kDa fragment or 200 ng/ml rhIGFBP-3. This agrees with an antagonistic action, affecting the mitogenic activity of serum that is attributable to IGFs.

The 16-kDa IGFBP-3 fragment therefore appears to be a potent inhibitor of mitogenic signals resulting from activation of both the type 1 IGF and FGF receptors.

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