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Institute of Molecular Animal Breeding (A.H., M.W., H.L., E.W.) and Laboratory of Molecular Biology (T.F., G.J.A.), Gene Center, and Institute of Veterinary Pathology (R.W.), Ludwig-Maximilian University, 81377 Munich, Germany; Musculoskeletal Diseases Center (S.M.), Loma Linda, California 92357; Endocrinology Laboratory (J.F.), University Child Hospital, 72070 Tübingen, Germany; and Institute of Clinical Chemistry (H.J.K.), Clinic Harlaching, 81545 Munich, Germany
Address all correspondence and requests for reprints to: Dr. Andreas Hoeflich, Institute of Molecular Animal Breeding/Gene Center, Ludwig-Maximilian University, Feodor-Lynen-Strasse 25, 81377 Munich, Germany. E-mail: hoeflich{at}lmb.uni-muenchen.de
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Introduction |
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Disruption of the IGFBP-2 gene in mice resulted in only minor phenotypical changes and increased expression of other IGFBPs, suggesting functional redundancy of the IGFBPs (12, 13). However, there is at least indirect evidence for an inhibitory effect of increased levels of IGFBP-2 on IGF actions. Transgenic rabbits expressing high levels of recombinant human IGF-I in their mammary glands did, unexpectedly, not show any phenotypic alterations, such as increased milk yield, changes of milk composition, hyperplasia, or even tumors of the mammary gland. Ligand blot analysis of milk from these transgenic rabbits revealed a marked increase in the activity of IGFBP-2, which might have buffered effects of excess IGF-I (14). In addition, reduced growth of mice selected for low body weight was associated with increased hepatic IGFBP-2 mRNA expression and elevated serum IGFBP-2 levels (15), further suggesting IGFBP-2 as a negative growth regulator in vivo. Increased IGFBP-2 expression was also found in several experimental models of growth retardation in rat and swine (16, 17, 18).
Recently, we have shown that IGFBP-2 overexpression in transfected embryonic kidney fibroblasts (293 cells) inhibits cell proliferation. Furthermore, conditioned media of these cells inhibited IGF-dependent growth of several colon carcinoma cell lines (19).
To evaluate the specific role of IGFBP-2 in vivo, we generated transgenic mice overexpressing homologous IGFBP-2 under the control of the cytomegalovirus (CMV)-promoter. The present study evaluates level and tissue-specificity of transgene expression, effects on other components of the IGF system, and consequences for body and organ growth. IGFBP-2 transgenic mice displayed reduced postweaning body weight gain, which was mainly explained by reduced carcass weights. Increased serum and tissue levels of IGFBP-2 are therefore likely to reduce the bioavailability of IGF-I.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
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Analysis of IGFBP expression
IGFBP-2 mRNA expression was analyzed by Northern blot
hybridization, as described previously (19). In brief, tissues were
homogenized in guanidinium thiocyanate, and RNA was pelleted in 5.7
M CsCl by ultracentrifugation. Ten micrograms of total RNA
were separated by formaldehyde gel electrophoresis. For hybridization,
fluorescein-labeled IGFBP-2 cRNA probes were used as for Southern
blot hybridization. Serum samples and extracts from different tissues
were analyzed by Western ligand blot analysis, as previously described
(19), to demonstrate the molecular weight of the transgene product and
its capacity to bind human IGF-II. Briefly, tissue samples were
homogenized in extraction buffer [10 mM
Na2HPO4, pH 7.0; 0.2% (wt/vol) SDS; 10%
(wt/vol) glycerin] using a cell homogenizer (ART, Mühlheim,
Germany). Fifty micrograms of protein were boiled (5 min) and
electrophoresed on a 5% stacking/12% separating SDS-polyacrylamide
gel using the Mini Protean II system (Bio-Rad Laboratories, Inc., Munich, Germany). Separated proteins were transferred to a
nitrocellulose membrane (Millipore Corp., Eschborn,
Germany). The blots were blocked with 1% fish gelatin and incubated
with [125I]-IGF-II (106 cpm per blot).
Binding proteins were visualized and quantified on Phosphor-Imager
Storm (Molecular Dynamics, Inc., Krefeld, Germany). All
incubations and washing steps were performed at 4 C.
An IGFBP-2 specific antiserum was generated by immunization of rabbits using a synthetic peptide (amino acids 117–132: KRRVGTTPQQVADSDD) of mouse IGFBP-2. Specificity of the antiserum was analyzed by two-dimensional Western blotting of pancreatic protein extracts from IGFBP-2 transgenic mice. Mass spectrometry of the spot detected by two-dimensional Western blotting revealed a complete identity with murine IGFBP-2 (data not shown). For Western immunoblotting, membranes were prepared, as described above, with the only exception being that the proteins were separated under reducing conditions. Membranes were incubated with peptide-induced antibodies (dilution 1:1000) for 1 h, and bound antibodies were detected with peroxidase-coupled antibodies against rabbit IgG [Dianova (Germany), Hamburg, Germany] and subsequent addition of 3,3‘-diaminobenzidine tetrahydrochloride (Sigma, Munich, Germany).
Histology and immunohistochemistry
Pancreata of two IGFBP-2 transgenic mice (one male, one female)
and two nontransgenic littermate controls (one male, one female) were
used for histological and immunohistochemical investigations. The
animals were killed by cervical dislocation, under ether anesthesia, at
an age of 5.5 months. The entire pancreas (with attached spleen,
stomach, and intestine) was rapidly excised and fixed by immersion in
4% formaldehyde in PBS (pH 7.4), for 48 h, at room temperature.
After fixation, the pancreas was trimmed free of surrounding tissues,
placed in a tissue capsule, routinely processed, and embedded in
paraffin wax. From each organ, several serial paraffin sections were
cut, at a nominal thickness of 3 µm, and were mounted on
aminopropyltriethoxysilane-treated glass slides. The first two sections
from each series were routinely stained with hematoxylin and eosin.
Subsequent sections were taken for IGFBP-2 immunohistochemistry using
an indirect immunoperoxidase technique (20).
For immunohistochemistry, sections were deparaffinized in xylene and rehydrated in a graded series of ethanol. After blocking of endogenous peroxidase, by treatment with 1% hydrogen peroxide in PBS for 15 min and rinsing in PBS (2 x 10 min), sections were treated with normal swine serum for 30 min. Subsequently, sections were incubated with the primary antibodies (affinity-purified rabbit antibodies against murine IGFBP-2, as described above, diluted 1:100 in PBS) at 4 C for 24 h. After a rinse in PBS (2 x 10 min), sections were incubated with peroxidase-labeled swine antirabbit Ig (DAKO Corp. Diagnostika, Hamburg, Germany; diluted 1:100 in PBS containing 5% normal mouse serum) for 1 h at room temperature. After another rinse in PBS (2 x 10 min), peroxidase activity was visualized with 3,3‘-diaminobenzidine tetrahydrochloride (Fluka Feinchemikalien, Neu-Ulm, Germany), 10 mg in 20 ml of PBS containing 0.01% hydrogen peroxide, 5–10 min at room temperature. Sections were finally counterstained with Mayer’s hematoxylin, rinsed in water, dehydrated in a graded series of ethanol, cleared with xylene, and mounted in mounting medium (Eukitt, Kindler, Freiburg, Germany). For negative controls, the primary antibody was substituted by PBS or normal rabbit serum diluted 1:100 in PBS.
Measurement of IGFBP-2, IGF-I, and IGF-II
IGFBP-2, IGF-I, and IGF-II serum levels were quantified by
specific RIAs, as described previously (10). For all assays, dilution
curves of mouse serum samples were linear, and they paralleled those of
human standards. For the statistical analysis, Student’s unpaired
t test was used.
Serum insulin and glucose levels
Blood glucose concentrations were determined in both
overnight-fasted and 5-h-refed animals using the Precision QID system
(Medi-sense, Taufkirchen, Germany). The corresponding
serum insulin levels were measured using a commercial insulin RIA
(Insulin-CT, CIS-Bio International, Gif-sur-Yvette,
France), as described previously (10). For the statistical analysis,
the unpaired Student’s t test was performed.
Analysis of body and organ growth
Mice were weighed, twice weekly, to the nearest 0.1 g. To
estimate average growth of the individual groups, data were transformed
to a weighing day of n x 3, by linear interpolation, as described
previously (21). Then 5.5-month-old mice were ether anesthetized and
killed by bleeding from the retroorbital sinus. Nose-rump length was
measured, as the distance between nose and base of the tail, as
described before (21). For the nose-rump length measurement, the
animals were gently stretched (25 g). The weight of mesentery and fat
tissue surrounding the genital organs and kidneys, which is correlated
with total body fat content, was determined as the amount of
intraabdominal fat tissue. For the analysis, organs were removed,
blotted dry, and weighed to the nearest mg. Carcasses were weighed,
after removal of the organs, without skin, head, and tail. Data for
body weight were analyzed by the General Linear Models procedure
(SAS Institute, Inc., Cary, NC). The statistical
model included group (transgenic vs. control), sex, and age.
Least-squares means for group x sex were calculated per
weighing age and compared using the unpaired Student’s t
test. Organ and carcass weights were analyzed by ANOVA, taking effects
of group and sex into account.
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Results |
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). Absolute
quantitation by TaqMan technology revealed two copies integrated in
strain 1 and nine copies integrated in strain 2 (not shown).
IGFBP-2 mRNA expression was investigated by Northern blot
hybridization, which revealed a transgene-specific band (1.6 kb) in a
number of organs (including heart, stomach, kidney, jejunum, spleen,
skeletal muscle, colon, and lung; Fig. 2). In addition, transgenic IGFBP-2 mRNA
was detected in brain, salivary glands, adipose tissue, and adrenal
glands (data not shown). In contrast, no transgene-specific transcript
could be detected in liver (Fig. 2). A transcript of the same length
has been described previously in 293 cells transfected with the same
expression vector (19). An endogenous signal was visible at 1.4 kb in
spleen, colon, lung, and liver (Fig. 2). Increased IGFBP-2 protein
levels were demonstrated in pancreas, heart, skeletal muscle, brain,
and stomach in 2 independent transgenic strains, as shown by Western
ligand blotting (Fig. 3). Increased
IGFBP-2 protein levels were also detected in kidney, small intestine,
spleen, salivary glands, lung, and adrenal glands (data not shown). In
spite of endogenous IGFBP-2 mRNA expression in the liver, IGFBP-2
protein was undetectable in liver samples of both transgenic animals
and controls (Fig. 3). In both transgenic strains, the transgene
expression varied considerably between animals, consistently at
elevated levels, compared with controls. Overall, the highest transgene
expression was found in pancreas, followed by stomach, heart, colon,
and adipose tissue (Fig. 4). By Western
ligand blotting, a single band at 32 kDa was detected (Fig. 4A). Under
reducing conditions, using IGFBP-2 specific peptide-induced antibodies,
a single band was detected at 34 kDa (Fig. 4B). No signal was present
in nontransgenic littermates demonstrating marked overexpression of
IGFBP-2 and the specificity of the peptide-induced antiserum for
IGFBP-2. To test whether the transgene was active during the first
weeks of postnatal life, we determined serum and pancreatic IGFBP-2
levels by Western ligand blot analysis in 2-day- and in 2- and
4-week-old mice. Increased IGFBP-2 serum levels (Fig. 5A) and strong transgene expression in
the pancreas (Fig. 5B) were found at all timepoints investigated.
Endogenous IGFBP-2 serum levels were high 2 days after birth in control
animals and declined thereafter.
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). The immunohistochemical staining
pattern within the islets suggests transgene expression in ß-cells.
In contrast, no IGFBP-2 immunoreactivity was found in pancreatic tissue
from control mice (Fig. 6B).
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). In contrast, total serum IGF-I (Fig. 7B) and IGF-II (Fig. 7C) levels were not affected by IGFBP-2
overexpression in transgenic mice.
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).
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).
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). Body weights in the second transgenic
strain were similarly reduced (data not shown). Body weight of
CMV-IGFBP-2 transgenic mice was still reduced in the period between
days 150 and 240 and did not seem to be compensated with time (data not
shown).
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). However, in male and female
transgenic mice, 10/14 and 8/14 parameters investigated, respectively,
displayed slightly reduced values, compared with controls. In total,
the organ weights analyzed were reduced by only about 3% in both sexes
in transgenic mice, compared with their nontransgenic littermates. When
relative organ weights were calculated, significant (P
< 0.01) increases were found for kidneys, lung, stomach, and colon of
female transgenic mice (Fig. 10B). Significantly decreased
(P < 0.05) absolute carcass weights (Fig. 11) were measured in IGFBP-2 transgenic
mice (10.6 ± 1.1 g), compared with nontransgenic controls
(12.1 ± 1.2 g), corresponding to approximately 13%
reduction. Importantly, a significant (P < 0.05)
reduction of the relative carcass weights was present in transgenic
mice (40.0 ± 3.5%), compared with controls (45.4 ± 3.8%),
which represents a similar reduction of about 12% (Fig. 11). During
the dissection of the mice, no obvious pathological alterations were
found.
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Discussion |
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Transgene expression
Transgenic mice displayed transgene expression on mRNA and protein
level in nearly every organ tested, with exception of the liver. The
spectrum of tissues expressing the transgene was almost identical to
that of a high-expressing transgenic strain of mice harboring a
CMV-chloramphenicol expression vector (22). The only exception was the
pancreas. In our model, the pancreas represented the organ with highest
transgene expression of the organs investigated, whereas the pancreatic
expression level in the CMV-chloramphenicol transgenic model was
intermediate. In addition, expression was restricted to the islets and
probably to the ß-cells. The intron used in the expression vector was
derived from the rat insulin II gene. It is tempting to speculate, and
worth further investigation, whether the intron used is responsible for
the strong transgene expression within the ß-cells of the pancreas
observed in our transgenic mouse strains. Transgene expression was
characterized by a relatively high variation between individual animals
in both transgenic strains. However, the overall transgenic IGFBP-2
secretion seemed similar in the different individuals, resulting in a
reproducible 3-fold increase of IGFBP-2 serum levels and a consistent
phenotype of reduced body weight gain. No expression of
transgene-specific mRNA was found in the liver, and no IGFBP-2 protein
was detected in protein extracts from the liver. The liver is known to
express and secrete endogenous IGFBP-2. It is most likely that
endogenous IGFBP-2 was below the detection limit because of IGFBP-2
secretion by the liver. Nevertheless, the liver (besides pancreas,
spleen, salivary glands, and brain) was among those organs displaying
more pronounced weight reductions, indicating endocrine vs.
auto- or paracrine mechanisms of IGFBP-2 action in the liver.
Glucose homeostasis
The levels of IGFBP-2 within the pancreatic islets of CMV-IGFBP-2
transgenic mice were extremely high. This finding is particularly
interesting in the context of potential effects on glucose homeostasis
in IGFBP-2 transgenic mice. Interestingly, glucose levels were, as a
tendency, reduced in IGFBP-2 transgenic mice. However, fasted glucose
serum level differences did show only borderline significance
(P = 0.051). In addition, fasted insulin serum levels
were slightly (but not significantly) reduced in transgenic mice,
compared with controls (P = 0.111). After refeeding,
serum levels of both insulin and glucose were in the same range in both
genetic groups. A role of insulin in the regulation of IGFBP-2 has been
suggested from several studies in which diabetic children displayed
increased IGFBP-2 levels (7, 23). In contrast, insulin therapy tended
to reduce IGFBP-2 levels (24). Moreover, nutritional regulation of
IGFBP-2 expression has been well documented (10, 25, 26, 27). In a sharp
contrast to IGFBP-2 transgenic mice, an increase of relative pancreas
weight, as well as of serum glucose and insulin levels, have been
observed in IGFBP-1 transgenic mice (28, 29). Because, in IGFBP-2
transgenic mice, neither hyperglycemia nor hyperinsulinemia have been
observed, and the pancreas was among the organs of the more severe
weight reductions, distinct roles in the control of growth and
metabolism for IGFBP-1 and IGFBP-2 are likely to suppose. Further
studies are required to study a potential involvement of IGFBP-2 in
glucose homeostasis.
Expression of other components of the IGF system
IGFBP-2 serum levels were markedly (about 3-fold) increased in
transgenic mice. Interestingly, no effect on IGF-I or -II serum levels
was demonstrated in transgenic mice. IGFBP-2 is supposed to have higher
affinity for IGF-II than for IGF-I (2). In a goat model, iv injection
of IGFBP-2 resulted in increased plasma clearance of IGF-I and -II
(30). It was concluded that IGFBP-2 targets the IGFs to distinct
tissues. Such effects were not seen in CMV-IGFBP-2 transgenic mice,
which may be attributable to differences in the levels of serum IGFBP-2
reached or to unknown species-specific factors. Because serum IGF-I
levels (which monitor GH serum levels and, therefore, GH growth
control) were unaffected by IGFBP-2 overexpression, reduced weight gain
of CMV-IGFBP-2 transgenic mice is most likely attributable to local
inhibition of IGF actions at the tissue level by IGFBP-2.
Body and organ weights
Body weight of IGFBP-2-overexpressing mice was significantly
reduced at days later than postnatal day 23, a fact which is
surprising, because transgene expression was active from postnatal day
2. However, we found very high endogenous IGFBP-2 serum levels in the
early postnatal period. Therefore, differences in IGFBP-2 serum levels
between transgenic and control mice were relatively small, which might
be a reason for the absence of a clear phenotype during the first weeks
of life. Similarly, the impairment of body weight gain in two different
transgenic mouse models overexpressing IGFBP-1 (29, 31) occurred mainly
between 3 and 8 weeks of age. Accordingly, it is possible that
increased IGFBP-2 expression could substantially decrease the
GH-induced IGF-I action during pubertal growth spurt.
Whereas IGFBP-2 transgenic mice displayed a significant reduction of body weight, organ weights were only partly and slightly reduced, with the spleen of male transgenic mice being the only organ significantly reduced in weight. However, although not significant, those organs (spleen, pancreas, brain, kidney, and liver) that were most markedly increased in IGF-I-overexpressing transgenic mice (32) showed the clearest tendency of reduced weight in IGFBP-2-overexpressing mice. This inverse phenotype of IGF-I- and IGFBP-2-overexpressing mice suggests an inhibitory effect of IGFBP-2 on IGF-I. It is known that IGF-I represents a postnatal regulator of growth in mice; in contrast, IGF-II is important for fetal growth (33, 34), whereas its expression is almost completely shut down in adult tissues.
Although there were slight reductions in absolute organ weights of
CMV-IGFBP-2 transgenic mice, the difference in the sum of organ weights
(accounting for about 20% of total body weight), between transgenic
and control mice, corresponded to only about 3% and could thus not
explain the overall 10% difference in total body weight. If calculated
relative to body weight, we found significant increases in the weight
of kidneys, lung, stomach, and colon in female transgenic mice. We
conclude that the organs contributed to the overall body weight
reduction only to a limited extent. Therefore, we determined the
carcass weight, which accounts for 40–45% of total body weight, in
six CMV-IGFBP-2 transgenic and in six control mice. The mean carcass
weight was significantly (P < 0.05) smaller in
transgenic (10.6 ± 1.1 g) than in control mice (12.1 ±
1.2 g), resulting in a difference of about 13%. A similar
reduction (
12%) was also evident when relative carcass weights were
calculated, a fact which strongly suggests the carcass as a main target
of direct or indirect IGFBP-2 actions in vivo. Various cell
types comprising the carcass, including osteoblasts, chondroblasts, and
myoblasts, are target tissues of IGF-I (35, 36) and are therefore
likely to be sensitive to IGFBP-2-mediated inhibition of IGF-I.
Conversely, carcass weight was increased by 20% in transgenic mice
overexpressing IGF-I (32).
Our data suggest that IGFBP-2 is capable of inhibiting the biological actions of IGF-I in vivo via endocrine or paracrine mechanisms, resulting in reduced postnatal weight gain.
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Acknowledgments |
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Received March 29, 1999.
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