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Department of Pediatric Endocrinology (S.C.v.B.-O., J.G.K., M.G.G., C.M.H., R.J.B., J.A.K.), University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands; and Laboratory of Pediatrics (M.v.K., D.J.L.-K., S.L.S.D., J.W.N.), Subdivision of Molecular Endocrinology, Erasmus University, 3015 GD Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: S. C. van Buul-Offers, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Department of Pediatric Endocrinology, Room KC3.063.0, P.O. Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: s.vanbuul{at}wkz.azu.nl
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Abstract |
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Treatment with IGF-I alone induced a significant increase in body length (108% of control) and weight (112%) as well as an increase in weight of the submandibular salivary glands (135%), kidneys (124%), femoral muscles (111%), testes (129%), and spleen (126%) compared with saline-treated controls. IGFBP-1 alone induced a significant increase in weight of the kidneys (152% of control). Coadministration of IGF-I with IGFBP-1 neutralized the stimulating effects of IGF-I on body length and weight as well as on the femoral muscles and testes. In contrast, the weights of the submandibular salivary glands (143%) were not significantly different from those of IGF-I-treated animals, whereas the weights of the kidneys (171%) and spleen (156%) were significantly increased compared with IGF-I-treated mice. The effect of IGFBP-1 plus IGF-I on kidney weight was not significantly greater than the effect of IGFBP-1 alone.
Western ligand blotting showed induction of the IGFBP-3 doublet as well as IGFBPs with molecular masses of 24 kDa, most probably IGFBP-4, by human GH, IGF-I alone, and IGF-I in combination with IGFBP-1.
Our data show that coadministration of IGFBP-1 inhibits IGF-I-induced body growth of GH-deficient mice but significantly stimulates the growth promoting effects of IGF-I on the kidneys and the spleen. These data warrant further investigation because differences in concentrations of IGFBP-1 occurring in vivo may influence IGF-I-induced anabolic processes.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The physiological role of IGFBP-1 in vivo is still unclear. It has been shown that recombinant nonphosphorylated IGFBP-1 inhibits growth stimulation by IGF-I and GH in hypophysectomized rats (13); and coadministration of amniotic fluid-derived hIGFBP-1, in which the nonphosphorylated form predominates, inhibited IGF-I-induced hypoglycemia in rats (14, 15). Also, in transgenic mice overexpressing IGFBP-1, somatic growth retardation has been observed (16, 17, 18). In all these studies, a molar excess of IGFBP-1 above IGF-I was present in serum. These data strengthen the view that IGFBP-1 functions primarily as a competitor of IGF receptors.
In vivo studies showing potentiation of IGFs by IGFBP-1 are limited to the promotion of wound healing by local application to skin incisions in rats (19) and to dermal ulcers in both normal rabbits and in rabbits with diabetes (20). Results were dependent on the molar ratio of IGF-I to IGFBP-1 used and on the phosphorylation state of IGFBP-1.
Little is known, however, about the effects of IGFBP-1 on IGF-I-induced organ growth in GH deficiency. This is of importance because elevated levels of serum IGFBP-1 may influence IGF-I-induced anabolic processes, as suggested by a case of short stature associated with high circulating levels of IGFBP-1 (2.2 µg/ml) (21). Therefore, we investigated the effects of amniotic fluid-derived hIGFBP-1 alone and in combination with IGF-I (1:1 molar ratio) on total body growth and growth of specific organs in the Pit-1 deficient Snell dwarf mice (22). In addition, serum IGFBP-1 and IGF-I, antibody formation against IGF-I and IGFBP-1, and serum IGFBP profiles were investigated to obtain more insight into the observed growth responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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hIGFBP-1 was purified from amniotic fluid from pregnant women (midterm), which was obtained for diagnostic purposes and approved by the ethical committee. This source of IGFBP-1 eliminated the risk of contamination by endotoxin. Amniotic fluid was filtrated, followed by an ammonium sulfate precipitation (1.8 M) of the supernatant overnight at room temperature. After centrifugation, the pellet was washed, centrifuged again, and dissolved in water. Precipitation occurred in methanol at a final concentration of 65%. After 30 min at room temperature, the solution was centrifuged. The resulting supernatant was separated on a C18 column using a 65%–35% methanol gradient. The IGFBP-1 fractions were pooled and precipitated with 0.6 vol aceton overnight at -20 C. After centrifugation of the aceton precipitate, the pellet was dissolved in 10 mM NH4HCO3 (pH 7.5) and vacuum dried. The resulting hIGFBP-1 had a purity of greater than 95%, as determined by reversed phase HPLC, and SDS-PAGE (Coomassie Blue and silver stain), mass spectrometry, and N-terminal sequencing. By nondenaturing electrophoresis, approximately 50% of this preparation was phosphorylated (3–4 phosphoisomers) and 50% nonphosphorylated (data not shown).
Animals and experimental design
Snell dwarf mice were bred and kept under standardized
laboratory conditions as described earlier (23). Because growth
patterns of males and females were similar, groups consisted of both
males and females (age, 6–8 weeks). At the start of the experiment,
mean lengths and weights and the SD in the groups were
identical (24). hGH, IGF-I, and IGFBP-1 were dissolved in PBS, pH 7.4.
For the coadministration experiments, IGF-I and IGFBP-1 were incubated
overnight in equimolar amounts in PBS (pH 7.4) at 4 C (25). The
solutions were used for 4 weeks and stored in the dark at -20 C.
In 2 independent long-term experiments, dwarf mice (age, 6–8 weeks at the start of the experiment) received hGH (16.6 mU/day), IGF-I (30 µg/day), IGFBP-1 (105 µg/day), IGF-I + IGFBP-1 (30 + 105 µg/day), or PBS for 4 weeks. An IGF-I dose was chosen, which had induced significant organ growth in previous experiments (22). The IGFBP-1 dose was equimolar to the IGF-I dose and was comparable with the amounts of IGFBP-1 administered to hypophysectomized rats (13) and athymic mice (26, 27). To avoid hypoglycemia, 10% glucose was added to the drinking water, starting 1 week before the experiment. Dwarfs (n = 5 per group in each experiment) were injected sc in the neck with 0.1 ml hormone solution or vehicle, three times daily, 5 days a week. All animals were weighed, and the total length was measured under ether anesthesia, once a week, by the method of Hughes and Tanner (28). The animals were killed by decapitation 2 h after the last injection. Blood was collected, and the sera were pooled per group to collect sufficient amounts for all serum determinations (see below) and stored at -20 C. Organs were removed and weighed to the nearest milligram. Because the data of both experiments were very comparable, the 2 independent replicate experiments were treated as one experiment. For body growth and organ growth, the number of animals was 10 for each group (from the 2 experiments), except for the testes (n = 4–6). Glucose was determined in individual serum samples (n = 10), and the average was determined for each treatment group. For IGF-I and IGFBP-1 measurements, the serum samples from the animals in each group (n = 5) had to be pooled.
Serum determinations
Serum IGF-I and IGF-II were routinely measured by heterologous
RIAs after acid Sep-Pak C18 (Waters Corp., Milford,
MA) chromatography as described previously (29).
hIGFBP-1 levels were determined by RIA using IGFBP-1 purified from human amniotic fluid and a mouse monoclonal antibody against hIGFBP-1 (30). Displacement studies with purified hIGFBP-1 or serum indicated that 125I-labeled-hIGFBP-1 (as prepared by either the chloramine-T, iodogen, or lactoperoxidase method) was not suitable as a tracer. Instead, we used a covalent complex of native 125I-labeled-hIGF-I and hIGFBP-1, which was prepared essentially according to the method described by Baxter and Martin (31). Unreacted iodo-IGF-I was separated from the 125I-labeled-hIGF-I-IGFBP-1 complex by successive adsorption to charcoal at neutral and acid pH (pH 3.0), respectively. An excess of hIGF-I was added to the assay mixture (see below) to prevent possible interference from free 125I-labeled-hIGF-I contaminating the radioactive complex in the RIA. The RIA buffer was composed of 0.1 M sodium phosphate (pH 6.5), 0.05% (wt/vol) Tween-20, 0.2% BSA, and 0.02% NaN3. Standards were prepared from purified hIGFBP-1 and stored at -70 C. Standard dilutions ranged from 0.19–15 ng per tube. Duplicates of serum samples were diluted 1:3 with assay buffer. The incubation mixture consisted of 100 µl assay buffer, 50 µl standard or diluted sample, 50 µl IGF-I solution (100 ng/ml), 50 µl antibody (1:650,000), and 50 µl tracer (10,000 cpm). After incubation for 18 h at 4 C in polystyrene tubes, 100 µl Sac-Cel solid-phase antimouse-coated cellulose suspension (IDS; Boldon, UK) was added. Complexation was complete after 30 min at 20 C, and 0.6 ml distilled water was added to the samples, which were subsequently centrifuged at 1000 x g for 3 min. Pellets were washed once with 0.6 ml distilled water and counted. The sensitivity of the assay was approximately 1 ng/ml. The intraassay variation was 7.9% at 31.6 ng/ml and 12% at 8.7 ng/ml. The interassay variation was 10% at 27.4 ng/ml.
To rule out the possibility of antibody formation to IGF-I or IGFBP-1 during treatment of the dwarf mice, sera were incubated with 125I-labeled-IGFBP-1 or 125I-labeled-IGF-I at different dilutions, followed by precipitation by either a polyethyleneglycol mixture (Immuno Nuclear Corp., Merck, Amsterdam, The Netherlands) in the case of IGF-I, or the Sac-Cel solid-phase antimouse/rat suspension in the case of IGFBP-1. The incubation conditions were similar to those described for the regular RIAs for IGF-I and IGFBP-1, respectively (29).
Serum IGFBPs were analyzed by Western ligand blotting, according to Hossenlopp (32), as described previously (29). Quantification of the blots was performed by phosphorimaging using a GS-363 Molecular Imager System with Molecular Analyst software (Bio-Rad Laboratories, Inc., Hercules, CA).
hIGFBP-1 in the sera was analyzed by Western immunoblotting using the mouse monoclonal IGFBP-1 antibody described above and was visualized by enhanced chemiluminescence, (Amersham International, Buckinghamshire, UK). In the immunoblot procedure, the primary antibody was diluted 1:8,000; whereas the second antibody, goat-antimouse IgG conjugated with peroxidase, was diluted 1:10,000.
Blood glucose levels were measured in each animal using a Lifescan One-touch II glucose analyzer (Johnson & Johnson, Amersfoort, The Netherlands).
Statistical analysis
For comparison of multiple groups, we used ANOVA, as described
by Scheffé (33). Student’s t test was applied for
testing differences between two groups.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IGF-I stimulated total body length and
weight significantly, confirming our previously published data (23, 29). IGFBP-1 alone did not affect body length, whereas a slight
nonsignificant decrease was observed for body weight. IGFBP-1 in
combination with IGF-I significantly inhibited the IGF-I-induced
growth stimulation. hGH, at the dose tested, was more stimulatory than
IGF-I.
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shows body length and
weight and the weights of several organs after 4 weeks of treatment.
Fig. 2 shows a selection of organs to
illustrate the differences between treatments in a relative manner
(weights expressed as percentage of control treatment). Similar to hGH,
IGF-I stimulated growth of the muscles quadriceps femoris and the
testes, whereas IGFBP-1 alone had no effect on these organs. As for
body length and body weight, coinjection of IGFBP-1 and IGF-I abolished
the growth-stimulatory effect of IGF-I on these organs. As observed for
muscles and testes, the weights of the kidneys, the submandibular
salivary glands, and the spleen significantly increased by treatment
with hGH and IGF-I compared with controls. For the latter three organs,
however, IGFBP-1 alone was stimulatory, although significance was
reached only for the kidneys. The growth-promoting effect of
IGFBP-1 on the kidneys was significantly higher than with IGF-I alone
(Fig. 2). The combination of IGF-I and IGFBP-1 shows additive effects
with respect to weight increase of kidneys and spleen, compared with
the effects obtained with both peptides administered alone (Fig. 2, Table 1). The growth stimulatory effect of IGF-I on the submandibular
salivary glands was not abolished by coinjection of IGFBP-1.
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Serum glucose, IGFs, and IGFBPs
Serum glucose levels were significantly decreased by IGF-I alone
(5.7 ± 0.7 mM, n = 10), compared with the
controls (8.0 ± 0.3 mM, n = 10). hGH and IGFBP-1
alone did not influence serum glucose levels. IGFBP-1, in combination
with IGF-I, slightly decreased serum glucose levels compared with
controls (to 6.9 ± 0.6 mM, n = 10), although
significance was not reached.
Serum hIGFBP-1 levels in both experiments were higher after
administration of IGFBP-1 alone (12.0 µg/ml, two pools) than after
treatment with the combination of IGF-I and IGFBP-1 (4.1 µg/ml, two
pools). The relatively high value measured in PBS-treated mice (0.5
µg/ml, two pools) probably is attributable to interference with mouse
-globulins, because a mouse-monoclonal was used. Absorption of serum
with protein A Sepharose abolished this interference, whereas spiking
of this stripped serum with hIGFBP-1 resulted in a recovery of 100%.
The presence of hIGFBP-1 was confirmed by Western immunoblotting (data
not shown).
Serum IGF-I concentrations were markedly increased after injection of IGF-I (417.2 ng/ml, two pools), whereas only a slight rise was observed after hGH administration (23.2 ng/ml, two pools), compared with PBS-treated controls (13.4 ng/ml, two pools). IGF-I values of the other treatment regimes were unreliable, caused by interference of IGFBP-1 in the IGF-I RIA (data not shown).
The inhibition of IGF-I-induced growth by IGFBP-1 of total body growth and growth of distinct organs cannot be explained by antibody formation against either IGF-I or IGFBP-1. Antibodies against hIGF-I in the IGF-I-treated mice were undetectable, and antibodies against IGFBP-1 could not be detected after 2 weeks of treatment. After 4 weeks of treatment, antibodies against IGFBP-1 were detectable, but the titer of the serum was extremely low; by using a serum dilution of 1:30, 8% and 24% binding of the 125I-IGFBP-1 tracer was obtained with the sera of mice treated with IGFBP-1 and IGF-I + IGFBP-1, respectively. For comparison, a rabbit polyclonal antiserum (35) had to be diluted 1:150,000 to achieve similar binding of the tracer.
Western ligand blotting of the sera, using
125I-labeled IGF-II as tracer, showed induction
of the IGFBP-3 doublet (42 and 38 kDa) (Fig. 3). This was more pronounced in the group
treated with IGF-I (5.9-fold increase compared with control) or IGF-I +
IGFBP-1 (8.4-fold) than in the group treated with hGH (3.8-fold).
IGFBP-1 alone had no effect. IGFBP-1 was present in high amounts at 30
kDa, confirming the RIA data. With respect to the 24-kDa band, most
probably representing IGFBP-4, we observed an increase of the intensity
after treatment with hGH (1.5-fold) and after administration of
IGFBP-1 (3.3-fold), IGF-I (3.1-fold), and the combination of IGF-I
+ IGFBP-1 (4.6-fold).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Regarding organ growth, we observed a differential pattern. Both GH and IGF-I are growth stimulatory for many organs, in accordance with data reported before (29, 39). As with body length and body weight, we observed inhibition of IGF-I-induced growth by IGFBP-I in muscles and testes. IGFBP-1 alone had no effect on the growth of these organs. Kidneys, submandibular salivary glands, and spleen, however, reacted differently. The growth stimulatory effect of IGF-I on the submandibular salivary glands was not abolished by coinjection of IGFBP-1. Coadministration of IGFBP-1 and IGF-I even resulted in additive effects on growth of the spleen and the kidneys, compared with the effects obtained with both peptides when administered alone. In addition, IGFBP-1 by itself was stimulatory for the weights of the kidneys, and this effect was even significantly higher than with IGF-I alone.
The effects obtained by administration of IGFBP-1 differ from those observed with IGFBP-3 by us and others. We have previously compared the growth-promoting effects of IGF-I alone and in combination with IGFBP-3 in Snell dwarf mice, using amounts of IGF-I and IGFBP similar to those used in this study (34). Whereas IGFBP-1 stimulates kidney growth and inhibits growth of the thymus, IGFBP-3 has no effect on these organs (34). Similarly, coinjection of IGFBP-3 diminished IGF-I-induced growth in the kidneys, whereas IGFBP-1 showed an additive effect together with IGF-I. With respect to body length and weight and the other organs studied, both IGFBP-1 and IGFBP-3 have no effect when administered alone, and they both neutralize IGF-I-induced body growth. In several other studies, IGFBP-3 has been shown to enhance the anabolic and growth-promoting activity of IGF-I. For example, the effects of IGF-I on wound healing and bone formation in rats and humans could be improved by coadministration of IGFBP-3 (40, 41, 42). Short-term coadministration of IGFBP-3 in hypophysectomized rats either enhanced the growth promoting activity of IGF-I or had no additional effect, depending on the mode of administration (43). The discrepancies between our results and results found by others for IGFBP-1 and IGFBP-3 could be caused by differences in experimental design.
In Fig. 4, the relationship between
kidney weight and body weight is plotted to illustrate these
differences between treatment with IGFBP-1 and IGFBP-3 for the kidneys.
These data demonstrate that in vivo IGFBP-1 may either
inhibit or stimulate weight of organs in a tissue-specific manner.
Although IGFBP-3 shows similar actions, the organ specificity is
different. Differences between IGFBP-1 and IGFBP-3 actions are also
found in IGFBP-3 and IGFBP-1 transgenic mice. In IGFBP-3 transgenic
mice, total body growth is unaffected; selective organomegaly is
demonstrated for the spleen, liver, and heart. However, no effect is
observed for the kidneys (44). In transgenic mice overexpressing
IGFBP-1 under control of the metallothionein or phosphoglycerate
promoter, growth is slightly affected, and growth of the brain is
markedly retarded; whereas weights of the kidneys are unaffected, and
splenomegaly is only observed in the phosphoglycerate IGFBP-1
transgenic mice (18, 36). In contrast, lesions of the glomeruli of the
kidneys are reported in transgenic mice overexpressing IGFBP-1 under
the control of the liver-specific 
1-antitrypsin promoter (17).
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Complex formation with IGFBP-1 results in inhibition of the IGF-I-induced hypoglycemia. IGFBP-1 alone does not cause hyperglycemia, confirming the results in normal and diabetic rats (46) as well as in hypophysectomized rats (13). In one report, a rise in plasma glucose levels was observed upon IGFBP-1 administration in normal rats (14).
The observed changes of IGF-I and IGFBPs in serum may be important in defining the local concentrations of these peptides and therefore contribute to tissue-specific growth regulation. The marked heterogeneity in the effects of IGFBP-1 on different organs is in line with the observations that tissues synthesize and secrete IGFBPs in a tissue-specific fashion (3, 22, 47). Therefore, one can presume that the net effect of IGFs and IGFBPs in our dwarf mice differs per tissue, resulting in either enhancement or inhibition of IGF actions. These diverse actions of IGFBP-1 in our dwarf mice may complicate its use as a therapeutic agent, as suggested, for instance, for the inhibition of tumor growth in vitro and in vivo (27).
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Acknowledgments |
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Received March 9, 1999.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
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), IGFBP-1 (105 µg/day; 
), IGF-I +
IGFBP-1 (30 + 105 µg/day; 
), and hGH (16.6 mU/day; •). The
mean ± SEM is given. Number of animals for all
treatments, n = 10. Significant differences (P
< 0.05) compared with PBS-treated controls, after 4 weeks of
treatment, were determined by Scheffé’s test (**) or Student’s
t test (*).
0.05) between IGFBP-1 or IGF-I +
IGFBP-1 treatment and the other treatments (PBS, IGF-I, IGFBP-3, and
IGF-I + IGFBP-3).