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

Abstract

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 5.8 microgram/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 reduction in birth weight of approximately 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-3 than in CMVBP-3 mice, who demonstrated a propensity to adiposity after weaning. The relative organ weights of brain and kidney were reduced in both Tg strains, whereas liver size and epididymal fat were significantly increased in CMVBP-3, but not PGKBP-3, mice. Our data indicate that overexpression of IGFBP-3 is associated with modest intrauterine and postnatal growth retardation despite elevated circulating IGF-I levels.

Insulin-like growth factor-binding protein 5 ( Igfbp5 ) compromises survival, growth, muscle development, and fertility in mice

“…A striking phenotype observed for Igfbp5-overexpressing mice was the increased brain fractional weight. In marked contrast, overexpression of Igfbp1 or Igfbp3 induced decreased fractional brain weight (24,32) with Igfbp2 overexpression having little effect (33). IGFBP-5 has been proposed to potentiate IGF-I activity in neural tissue (7), and Igfbp5 and Igf1 are coexpressed in brain (34); thus, it is possible that the relative increase in brain weight was due to the targeting of IGF activity to type 1 receptors by IGFBP-5.…”

Identification of STAT-1 as a Molecular Target of IGFBP-3 in the Process of Chondrogenesis

“…In these conditions IGF-I has been also reported increased (up to 3.5-fold), leading to the hypothesis that the net result in rheumatoid arthritis and osteoarthritis would be an increase of unbound IGFBP-3 that might determine decreased cell growth and apoptosis through its IGF-independent action (41,42). The other observation regarding the role of IGFBP-3 in the growth process derives from the growth pattern of transgenic mice overexpressing IGFBP-3 (43). Transgenic mice overexpressing IGFBP-3 exhibit a reduction in birth weight and early postnatal skeletal growth of ϳ10% despite elevated circulating IGF-I levels (43).…”

“…The other observation regarding the role of IGFBP-3 in the growth process derives from the growth pattern of transgenic mice overexpressing IGFBP-3 (43). Transgenic mice overexpressing IGFBP-3 exhibit a reduction in birth weight and early postnatal skeletal growth of ϳ10% despite elevated circulating IGF-I levels (43). This observation might be consistent with the report that circulating levels of IGF-I do not seem to have an effect on postnatal growth (44) or with our hypothesis that IGFBP-3 has an IGF-independent effect on growth.…”

Insulin-like Growth Factor-binding Protein-3 (IGFBP-3) Blocks the Effects of Asthma by Negatively Regulating NF-κB Signaling through IGFBP-3R-mediated Activation of Caspases

“…IGFBP-3 transgenic mice were generated and maintained as described previously (24). All experimental animals used in this study were treated according to guidelines approved by the Institutional Animal Care and Use Committee of the Chonbuk National University Medical School.…”