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Institute of Molecular Animal Breeding (A.H., M.W., H.L., E.W.) and Laboratory of Molecular Biology (T.F., G.J.A.), Gene Center, and Institute of Veterinary Pathology (R.W.), Ludwig-Maximilian University, 81377 Munich, Germany; Musculoskeletal Diseases Center (S.M.), Loma Linda, California 92357; Endocrinology Laboratory (J.F.), University Child Hospital, 72070 Tübingen, Germany; and Institute of Clinical Chemistry (H.J.K.), Clinic Harlaching, 81545 Munich, Germany
Address all correspondence and requests for reprints to: Dr. Andreas Hoeflich, Institute of Molecular Animal Breeding/Gene Center, Ludwig-Maximilian University, Feodor-Lynen-Strasse 25, 81377 Munich, Germany. E-mail: hoeflich{at}lmb.uni-muenchen.de
Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) has been shown to inhibit IGF-dependent cell proliferation in a number of in vitro studies. However, no in vivo model of IGFBP-2 overexpression has been established so far. Therefore, we have generated transgenic mice, in which expression of a mouse IGFBP-2 complementary DNA is controlled by the cytomegalovirus (CMV) promoter. In two independent transgenic strains, transgene expression was highest in pancreas and stomach, followed by skeletal muscle, heart, colon, spleen, adipose tissue, brain, and kidney. Within the pancreas, IGFBP-2 expression was found in the islets but not in the exocrine part. Serum IGFBP-2 levels of CMV-IGFBP-2 transgenic mice were about 3-fold (P < 0.05) increased, compared with controls, whereas serum levels of IGF-I and IGF-II were unaffected by IGFBP-2 overexpression. Fasted serum glucose and fasted insulin levels were slightly reduced in transgenic mice, compared with controls. Postprandial serum glucose insulin levels were not affected by the genotype. At days later than 23, body weights of transgenic mice were significantly (P < 0.05) reduced in both sexes, compared with nontransgenic littermates. This reduction in body weight was mainly attributable to significantly (P < 0.05) lower carcass weights of CMV-IGFBP-2 transgenic vs. control mice. In contrast, absolute organ weights were not (or only as a tendency) reduced, except for the weight of the spleen, which was significantly (P < 0.05) lower in male transgenic than in control mice. Our data suggest that IGFBP-2 represents a negative regulator of postnatal growth in mice, potentially by reducing the bioavailability of IGF-I.
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