Phenotypic Manifestations of Insulin-Like Growth Factor-Binding Protein-3 Overexpression in Transgenic Mice1

In cell culture systems insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) can both enhance and inhibit IGF-I action. To investigate the biological role of IGFBP-3 in vivo, transgenic (Tg) mice that constitutively overexpress the human IGFBP-3 complementary DNA (cDNA) driven by the mouse phosphoglycerate kinase I (PGK) and the cytomegalovirus (CMV) promoters were examined. Serum levels of human IGFBP-3 in CMVBP-3 and PGKBP-3 Tg mice were 4.7 and 5.8μ g/ml, respectively and total IGFBP-3 was increased 4.9- and 7.7-fold compared with that in wild-type (Wt) mice. In PGKBP-3 Tg mice the levels of transgene expression were similar in all tissues. Although CMVBP-3 mice demonstrated similar levels of expression of the transgene as PGKBP-3 mice in most tissues, markedly elevated expression was apparent in the kidney and heart. The transgene-derived IGFBP-3 circulated as a 150-kDa ternary complex, and serum IGF-I levels were elevated 1.9- to 2.8-fold in Tg mice compared with Wt mice. A significant reduct...