Study of the in vivo functions of the insulin-like growth factor binding proteins (IGFBPs) is complicated by their variety (six molecular species) and the differences in their expression related to tissue of origin and stage of development. To investigate the physiological role of IGFBP-1 in the bloodstream, we induced hepatic overexpression of IGFBP-1 in transgenic mice, placing human IGFBP-1 (hIGFBP-1) cDNA under the control of the ␣1-antitrypsin promoter so as to obtain liver-specific

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... ion. Five transgenic founder mice were raised, only two of which (lines 124 and 149) produced transgenic offspring. Northern blotting revealed transgene expression exclusively in the liver during fetal life and unchanged through to adulthood, whereas expression of the endogenous gene was undetectable beyond 10 -15 days postnatally. hIGFBP-1 was detected by western immunoblotting in the plasma of transgenic mice and IRMAs yielded mean concentrations of 2.41 Ϯ 0.33 ng/ml and 13.69 Ϯ 1.42 ng/ml in homozygous animals of lines 124 and 149, respectively. In the latter, IGFBP-1 levels were distinctly higher than in heterozygotes (2.99 Ϯ 0.39 ng/ml), P Ͻ 0.0001. These levels remained stable in each given animal and did not change with age. Plasma concentrations of IGF-I measured in line 149 exhibited the well-known profile of an increase from birth up to puberty. Values for heterozygotes were similar to those for wild-type mice, with adult levels (544 Ϯ 98 ng/ml) slightly below those of controls (630 Ϯ 56 ng/ml), P Ͻ 0.05. In homozygotes they were distinctly lower, with adult levels of 370 Ϯ 75 ng/ml, P ϭ 0.001. In heterozygous and homozygous adults, there was a negative correlation between IGF-I and IGFBP-1 concentrations (r ϭ 0.8, P Ͻ 0.0001), suggesting a link between transgene expression and IGF-I levels.