Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice

In cell culture systems insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) can both enhance and inhibit IGF-T action. To investigate the bio logical role of IGFBP-3 in vivo, transgenic (Tg) mice that constitutively o verexpress the human IGFBP-3 complementary DNA (cDNA) driven by the mouse p hosphoglycerate kinase I(PGK) and the cytomegalovirus (CMV) promoters were examined. Serum levels of human IGFBP-3 in CMVBP-3 and PGKBP-S Tg mice were 4.7 and 5.8 mug/ml, respectively and total IGFBP-3 was increased 4.9- and 7.7-fold compared with that in wild-type (Wt) mice. In PGKBP-8 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 ki dney and heart. The transgene- derived IGFBP-3 circulated as a 150-KDa tern ary complex, and serum IGF-I levels were elevated 1.9- to 2.8-fold in Tg mi ce compared with Wt mice, A significant reduction in birth weight of approx imately 10% and a modest-reduction in litter size were apparent in both Tg strains. Early postnatal growth, as assessed by both body weight and length , was significantly reduced in Tg mice compared with Wt mice. This was more marked in PGKBP-8 than in CMVBP-3 mice, who demonstrated a propensity to a diposity after weaning. The relative organ weights of brain and kidney were reduced in both Tg strains, whereas liver size and epididymal fat were sig nificantly increased in CMVBP-3, but not PGKBP-8, mice. Our data indicate t hat overexpression of IGFBP-3 is associated with modest intrauterine and po stnatal growth retardation despite elevated circulating IGF-I levels.