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

Endocrinology ◽  
2001 ◽  
Vol 142 (5) ◽  
pp. 1958-1967 ◽  
Author(s):  
Tomislav Modric ◽  
Josef V. Silha ◽  
Zengdun Shi ◽  
Yaoting Gui ◽  
Adisak Suwanichkul ◽  
...  
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Phosphoglycerate Kinase ◽  
Serum Levels ◽  
Postnatal Growth ◽  
Insulin Like Growth Factor ◽  
Liver Size ◽  
Igf I ◽  
Igfbp 3

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 5.8μ 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 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.

No evidence for reduced spontaneous or growth-hormone-stimulated serum levels of insulin-like growth factor (IGF)-I, IGF-II or IGF binding protein 3 in women with spinal osteoporosis

1994 ◽  
Vol 131 (2) ◽  
pp. 150-155 ◽  
Author(s):  
M Kassem ◽  
K Brixen ◽  
W Blum ◽  
L Mosekilde ◽  
EF Eriksen
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Binding Protein ◽  
Serum Levels ◽  
Insulin Like Growth Factor ◽  
Spinal Osteoporosis ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Igfbp 3

Kassem M, Brixen K, Blum W, Mosekilde L, Eriksen EF. No evidence for reduced spontaneous or growth-hormone-stimulated serum levels of insulin-like growth factor (IGF)-I, IGF-II or IGF binding protein 3 in women with spinal osteoporosis. Eur J Endocrinol 1994;131:150–5. ISSN 0804–4643 To test the hypothesis that a dysfunctional growth hormone (GH)–insulin-like growth factor (IGF) axis may play a role in the pathogenesis of osteoporosis, we compared the levels of IGF-I, IGF-II and IGF binding protein 3 (IGFBP-3) in 15 women with spinal osteoporosis (i.e. at least one non-traumatic vertebral fracture) and 15 normal age-matched women. Furthermore, the response to 3 days' treatment with recombinant human GH (r-hGH) (0.2 IU kg−1·day−1) was determined. The basal levels of IGF-I, IGF-II and IGFBP-3 were similar in patients and controls (mean ± sem): IGF-I, 16.5 ± 1.3 versus 16.0 ± 1.3 nmol/l (NS); IGF-II, 79.9 ± 3.6 versus 72.5 ± 4.1 nmol/l (NS); and IGFBP-3, 125.7 ± 6.5 versus 130.3 ± 7.8 nmol/l (NS). Stimulation with r-hGH elicited increased levels of IGF-I, IGF-II and IGFBP-3 within both groups (p < 0.001). The maximal values expressed as a percentage of baseline were: IGF-I, 341 ± 26% versus 369 ± 22%, IGF-II, 125 ± 4% versus 119 ± 5%, IGFBP-3, 141 ± 5% versus 147 ± 7% in osteoporotic patients and controls, respectively. No significant differences were observed between patients and controls in either their maximal response or in the area under the response curves. Our results do not support the hypothesis of a dysfunctional GH–IGF axis in women with spinal osteoporosis. Kim Brixen, University Department of Endocrinology and Metabolism, Aarhus Amtssygehus, Tage-Hansens gade 2, DK-8000 Aarhus C, Denmark

Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3

1998 ◽  
Vol 275 (2) ◽  
pp. E321-E331 ◽  
Author(s):  
Phil G. Campbell ◽  
Susan K. Durham ◽  
Adisak Suwanichkul ◽  
James D. Hayes ◽  
David R. Powell
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Binding Domain ◽  
Insulin Like Growth Factor ◽  
Heparin Binding ◽  
Binding Studies ◽  
Igf I ◽  
Heparin Binding Domain ◽  
Igfbp 3

Limited proteolysis lowers affinity of insulin-like growth factor (IGF)-binding protein (IGFBP)-3 for bound IGFs, resulting in greater IGF bioavailability. Plasmin is one of many proteases that cleave IGFBP-3, and the plasmin system may regulate IGFBP-3 proteolysis and IGF bioavailability in cultured cells in vitro. A role for the plasmin system in IGFBP-3 proteolysis in vivo is suggested by data presented here showing that IGFBP-3 binds plasminogen (Pg; Glu-Pg) with a dissociation constant ( Kd) ranging from 1.43 to 3.12 nM. IGF-I and Glu-Pg do not compete for IGFBP-3 binding; instead, the binary IGFBP-3/Glu-Pg complex binds IGF-I with high affinity ( Kd= 0.47 nM) to form a ternary complex. Competitive binding studies suggest that the kringle 1, 4, and 5 domains of Glu-Pg and the heparin-binding domain of IGFBP-3 participate in forming the IGFBP-3/Glu-Pg complex, and other studies show that Glu-Pg in this complex is activated at a normal rate by tissue Pg activator. Importantly, IGFBP-3/Glu-Pg complexes were detected in both human citrate plasma and serum, indicating that these complexes exist in vivo. Binding of IGFBP-3 to Glu-Pg in vivo suggests how Glu-Pg activation can specifically lead to IGFBP-3 proteolysis with subsequent release of IGFs to local target tissues.

scholarly journals The phosphorylation status of insulin-like growth factor-binding protein-1 in prepubertal obese children

1999 ◽  
pp. 585-589 ◽  
Author(s):  
T Kamoda ◽  
H Saitoh ◽  
S Nakahara ◽  
M Inudoh ◽  
T Hirano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Serum Levels ◽  
Insulin Like Growth Factor ◽  
Obese Children ◽  
Factor Binding ◽  
Igf I ◽  
The Status ◽  
And Control ◽  
Igfbp 3

OBJECTIVE: We measured the total and nonphosphorylated insulin-like growth factor-binding protein (IGFBP)-1 concentrations in obese children to determine the effect of obesity on the status of IGFBP-1 phosphorylation. We also measured the serum levels of insulin, total and free IGF-I, and IGFBP-3 to investigate their relationships to the IGFBP-1 phosphorylation status in obese subjects. SUBJECTS AND METHODS: Nineteen prepubertal obese and 15 age-matched control children were included in the study. The serum levels of total and nonphosphorylated IGFBP-1 were determined by noncompetitive RIAs. RESULTS: The serum levels of total and nonphosphorylated IGFBP-1 were significantly lower in the obese group (48.7+/-5.6 microgram/l, P<0.001 and 11.1+/-1.9 microgram/l, P<0.01 respectively) than in the controls (86.7+/-9.0 microgram/l and 28.8+/-6.2 microgram/l respectively). However, the ratio of nonphosphorylated IGFBP-1 to total IGFBP-1 did not differ significantly between the obese and control groups. The circulating free IGF-I level was significantly higher in the obese children than in the controls (P<0.05), while the serum levels of insulin, total IGF-I and IGFBP-3 were not significantly different between the two groups. A stepwise regression analysis of the combined group revealed that only the total IGFBP-1 level was an independent predictor of the free IGF-I concentration (P<0.001). CONCLUSION: The present study shows that both total and nonphosphorylated IGFBP-1 concentrations are decreased in obese children and the increased free IGF-I level in obese children is related to the reduced total IGFBP-1 level, but unrelated to the change in the IGFBP-1 phosphorylation status.

Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease

1994 ◽  
Vol 142 (3) ◽  
pp. 407-415 ◽  
Author(s):  
P Cohen ◽  
D M Peehl ◽  
H C B Graves ◽  
R G Rosenfeld
Keyword(s):  
Growth Factor ◽  
Prostate Specific Antigen ◽  
Binding Protein ◽  
Biological Effects ◽  
Specific Antigen ◽  
Independent Effect ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Igfbp 3

Abstract Prostate specific antigen (PSA) is an insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) protease found in seminal plasma and produced by prostatic epithelial cells (PC-E) in vivo. We examined the effects of PSA-proteolysis of IGFBP-3 on the affinity of IGFBP-3 fragments for IGFs and on the mitogenic action of IGFs on PC-E. Recombinant human IGFBP-3 was cleaved by PSA, then incubated with 125I-IGF-I or -II in the presence of varying concentrations of unlabelled peptides, and then cross-linking electrophoresis and densitometric analysis were performed. While the affinity of IGF-II for the PSA-generated IGFBP-3 fragments fell slightly compared to intact IGFBP-3, the affinity of the PSA-generated IGFBP-3 fragments for IGF-I fell by ten fold. The addition of IGF-I or -II to PC-E in serum-free culture conditions resulted in a two-fold stimulation of cell number compared to control. The presence of IGFBP-3 in the media blocked the IGF-induced stimulation, but had no independent effect in the absence of IGFs. When PSA was added to PC-E cultures to which both IGF-I or -II and IGFBP-3 were added, the inhibitory effects of IGFBP-3 on IGF mitogenesis were reversed. We conclude that PSA decreases the affinity of IGFBP-3 for IGF and can potentiate IGF action in the presence of inhibitory IGFBP-3. This phenomenon may contribute to normal and malignant prostate growth. Journal of Endocrinology (1994) 142, 407–415

Stimulation of hepatic insulin-like growth factor-binding protein-1 and -3 gene expression by octreotide in rats

1995 ◽  
Vol 147 (3) ◽  
pp. 545-551 ◽  
Author(s):  
A Flyvbjerg ◽  
A G P Schuller ◽  
J W van Neck ◽  
C Groffen ◽  
H Ørskov ◽  
...  
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Somatostatin Analogue ◽  
Insulin Like Growth Factor ◽  
Human Hepatoma Cells ◽  
Factor Binding ◽  
Igf I ◽  
Clinical Experiments ◽  
Igfbp 3

Abstract It has recently been demonstrated in various clinical experiments that native somatostatin and its long-acting analogues increase circulating levels of insulin-like growth factor-binding protein-1 (IGFBP-1) within 1–2 h, independent of effects on circulating insulin or glucose levels. Using human hepatoma cells in vitro the somatostatin analogue, octreotide, has been shown to increase IGFBP-1 mRNA within 24 h indicative of a direct stimulatory effect of octreotide on IGFBP-1 synthesis. In order to ascertain whether octreotide acutely stimulates IGFBP-1 mRNA in vivo, placebo or two doses of octreotide were injected subcutaneously into three groups of rats. One hour after saline or octreotide administration, liver, kidney and serum were obtained for the measurement of IGFBPs-1 to -6 mRNA in tissue and IGFBPs and IGF-I in serum. Octreotide increased liver IGFBP-1 (562%) and IGFBP-3 (23%) mRNA expression with a concomitant rise in the circulating 30 kDa (106%) and 38–42 kDa (23%) IGFBPs. No detectable changes were seen in other liver IGFBP transcripts, other circulating IGFBPs or in any of the kidney IGFBP transcripts. Serum IGF-I increased by 37% in the animals receiving the high octreotide dose. No concomitant changes were observed in glucose or insulin levels. These data show that octreotide acutely stimulates hepatic IGFBP-1 and -3 mRNA in vivo in rats. The stimulating effect on IGFBP-3 presents a possible hitherto unknown form of regulation of IGFBP-3 whilst the effect on IGFBP-1 indicates that the stimulatory effect of octreotide on circulating IGFBP-1 described in clinical trials may be due to increased hepatic production. The present findings may be of importance in the clinical use of octreotide. Journal of Endocrinology (1995) 147, 545–551

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