| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Institutes of Molecular Animal Breeding (A.H., S.N., H.L., E.W.), Animal Physiology (M.E.), and Veterinary Pathology (R.W.), Ludwig-Maximilian University, 81377 Munich, Germany; Lilly Germany GmbH (W.F.B.), 61350 Bad Homburg, Germany; Institute of Clinical Chemistry (H.J.K.), Clinic Harlaching, 81545 Munich, Germany; and Institute of Animal Breeding and Genetics (G.B.), University of Veterinary Sciences, 1210 Vienna, Austria
Address all correspondence and requests for reprints to: Prof. Dr. Eckhard Wolf, Institute of Molecular Animal Breeding/Gene Center, Ludwig-Maximilian University, Feodor-Lynen-Strasse 25, 81377 Munich, Germany. E-mail: ewolf{at}lmb.uni-muenchen.de
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Effects of IGFBP-2 overexpression have been studied in a variety of in vitro models, with a wide spectrum of consequences, from growth inhibition (7, 8, 9, 10) to growth stimulation (11, 12 ; for review, see 6). Overexpression of IGFBP-2 in transfected 293 human embryonic kidney cells reduced cell proliferation. The same effect was seen for IGF-responsive colon carcinoma cell lines cultured in conditioned media containing high levels of IGFBP-2. In both systems, the proliferation-inhibiting effect of IGFBP-2 could be overcome by addition of exogenous IGFs, Long R3 IGF-I being markedly more effective than IGF-I (8). On the other hand, long-term overexpression of IGFBP-2 in transfected mouse adrenocortical tumor cells (Y-1) was associated with increased cell proliferation and tumorigenic potential. These effects were independent of exogenous IGFs (12).
To understand the function of IGFBP-2 in vivo, the IGFBP-2 gene has been inactivated in mice by gene targeting. However, only minor phenotypic changes, i.e. increased liver weights and reduced spleen weights, in adult males were observed. In this model, the serum activities of IGFBP-1, IGFBP-3, and IGFBP-4 were increased, eventually compensating for the lack of IGFBP-2 (13, 14).
To investigate the consequences of elevated IGFBP-2 in vivo, we generated transgenic mice overexpressing IGFBP-2 under the control of the CMV-promoter. These mice displayed reduced postweaning body weight gain, which was mostly caused by a reduction in carcass weight, identifying IGFBP-2, for the first time, as a growth inhibitor in vivo (15). Because the phenotype of IGFBP-2 transgenic mice was, in many aspects, opposite to that of IGF-I-overexpressing transgenic mice, we concluded that IGFBP-2 might inhibit IGF-I effects.
To further clarify this point, we studied consequences of IGFBP-2 overexpression under conditions of increased levels of GH and IGF-I. Transgenic mice overexpressing homologous or heterologous GH provide unique models for studying long-term effects of elevated GH and IGF-I. These models have been extensively studied, with respect to body (16, 17), skeletal (18, 19, 20), and organ growth (16, 21, 22, 23, 24). In addition to markedly stimulated growth, long-term GH overproduction in transgenic mice causes a spectrum of pathological lesions, which develop primarily in kidney and liver (for review, see 25, 26, 27) and result in a dose-dependent shortened life-span (28).
To study effects of elevated IGFBP-2, in the context of GH excess, we crossed hemizygous CMV-IGFBP-2 transgenic mice with hemizygous PEPCK-bGH transgenic mice, generating four groups of offspring harboring either the CMV-IGFBP-2 (B) or the PEPCK-bGH transgene (G), both transgenes (GB), and nontransgenic controls (C). Analysis of a large panel of growth parameters revealed that elevated IGFBP-2 can indeed partially block GH-stimulated growth processes. Interestingly, the growth-inhibiting activity of IGFBP-2 was even more pronounced in high-GH/IGF-I mice than in mice with normal GH and IGF-I levels.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
PEPCK-bGH transgenic mice, originally generated on a C57BL/6 x SJL genetic background (29), were kindly provided by Dr. T. E. Wagner, Edison Biotechnology Center, Ohio University, Athens, OH. Hemizygous PEPCK-bGH transgenic mice used in this study were derived from the 12th generation of sequential crossing with NMRI outbred mice (Charles River Laboratories, Inc.-Wiga, Sulzfeld, Germany). PEPCK-bGH transgenic mice were identified by PCR using 5' CGG ACC GTG TCT ATG AGA AGC 3' sense and 5' GGA AAG GAC AGT GGG AGT GG 3' antisense oligonucleotides (30).
Female hemizygous CMV-IGFBP-2 transgenic mice were mated with male hemizygous PEPCK-bGH transgenic mice to generate four different genetic groups of offspring, of which only male mice were investigated in the present study: animals harboring both transgenes (GB), the GH (G) or the IGFBP-2 (B) transgene, and nontransgenic controls (C).
All mice were maintained under standard (nonbarrier) conditions and had free access to a standard diet (V1534; Ssniff, Soest, Germany) and tap water.
Measurement of serum bGH, IGFBPs, and IGF-I
Blood samples were obtained from 15-week-old mice by
puncture of the retroorbital sinus in ether anesthesia. Serum was
separated by centrifugation, and IGFBP-2 and IGF-I concentrations were
quantified by specific RIAs as described previously
(31, 32, 33). For all assays, dilution curves of mouse serum
samples were linear and paralleled those of human standards. Serum GH
was quantified by an enzyme-linked immunosorbent assay specific for bGH
(34). Serum samples were analyzed for IGF-binding activity
by Western ligand blot (WLB) analysis as previously described
(15). Data were analyzed by ANOVA as described below.
IGFBP-2 levels in different tissues
IGFBP-2 levels in different tissues were determined by Western
immunoblot analysis as described previously (15). Briefly,
tissue samples were homogenized in extraction buffer [10
mM Na2HPO4, pH
7.0; 0.2% (wt/vol) SDS; 10% (vol/vol) glycerin] using a cell
homogenizer (ART, Mühlheim, Germany). Thirty micrograms of
protein were boiled (5 min) and separated under reducing conditions 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. IGFBP-2 was identified using a
specific antiserum raised in rabbit (15). Bound antibodies
were detected with peroxidase-coupled antibodies against rabbit IgG
(Dianova Germany, Hamburg, Germany) using an ECL detection
kit (Amersham Pharmacia Biotech, Freiburg, Germany). Three
mice per genetic group were analyzed at 5 and 15 weeks of age.
Analysis of body and organ growth
Body weight of all mice was recorded, in weekly intervals, to
the nearest 0.1 g. To estimate average growth of the individual
groups, data were transformed to a weighing age of n x 7 days, by
linear interpolation, as described previously (17). At the
age of 15 weeks, mice were ether-anesthetized and killed by bleeding
from the retroorbital sinus. In addition, mice from each genetic group
were analyzed at the age of 5 weeks. Nose-rump-length (NRL) was
measured as the distance between nose and base of the tail, as
described before (17). 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 abdominal
fat tissue. For the analysis, organs were removed, blotted dry, and
weighed to the nearest milligram. Carcasses were weighed, after removal
of the organs, without skin, head, and tail. Data for body growth and
organ/tissue weights were analyzed by ANOVA, taking the effect of group
into account. Means were compared by using LSD post hoc
tests [SPSS, Inc. (Chicago, IL) program package]. To
compare the effects of IGFBP-2 transgene expression, under conditions
of normal vs. increased GH/IGF-I levels, relative
differences between B and C mice, as well as GB and G mice, were
calculated for all parameters. Therefore, values recorded for B and GB
mice were divided by the corresponding means calculated for C and G
mice, respectively. The relative effects (percent difference in body
weight, organ/tissue weights, or NRL) of IGFBP-2 overexpression in a
high (GB vs. G) and a normal (B vs. C) GH/IGF-I
background were compared using Student’s t test.
Histology
Livers from 6 G, 6 GB, 3 B, and 6 C mice were selected for
histological analysis. Immediately after determination of liver weight,
the organ was fixed by immersion in 10% neutral buffered formalin for
48 h at room temperature. Approximately 3-mm-thick slices of the
left, the median, and the right lobes were routinely processed and were
embedded in paraffin wax. Histological sections were cut at 4 µm and
stained with hematoxylin and eosin according to standard methods.
Histological analyses were carried out on coded slides to avoid
knowledge of the nature of the experimental group.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
).
|
).
The activities of other serum IGFBPs were determined by WLB analysis,
which showed an increased signal for proteins of 39/43 kDa (IGFBP-3)
and of 24 kDa (nonglycosilated IGFBP-4) in the PEPCK-bGH
transgenic groups. The increase in immunoreactive IGFBP-2 in the B and
GB groups was confirmed by WLB, demonstrating functional activity of
the transgene-encoded IGFBP-2 (Fig. 2).
|
).
IGFBP-2 levels in different tissues
Western immunoblot analysis did not reveal obvious differences in
tissue IGFBP-2 levels between 15-week-old B and GB mice. IGFBP-2 levels
were highest in pancreas, followed by skeletal muscle and heart,
kidney, brain, skin, and spleen. No elevation of IGFBP-2 was found in
the liver (Fig. 3). Analysis of tissue
samples from 5-week-old mice led to similar results (data not
shown).
|
).
Body weight of B vs. C mice was reduced (13%,
P < 0.05), confirming our first report on the
consequences of IGFBP-2 overexpression in transgenic mice
(15). However, the growth-inhibiting effect of IGFBP-2 was
also evident on the background of GH overexpression and increased
levels of IGF-I. Body weight of GB vs. G mice was reduced by
17% (P < 0.001).
|
). IGFBP-2 overexpression in GB mice abolished the effect of the
PEPCK-bGH transgene on NRL in 5-week-old mice and reduced it
significantly (P < 0.001) in 15-week-old animals. In
addition, there was a significant (P < 0.05) reduction
in NRL in 15-week-old B vs. C mice. The NRL-body
weight1/3-ratio was not different between the
groups at 5 weeks of age. Although the relative NRL was significantly
(P < 0.05) increased in 15-week-old G mice, IGFBP-2
overexpression in GB mice completely reduced normalized body size in
the condition of GH excess (Fig. 4C), strongly supporting an enhanced
IGFBP-2 effect in the context of high levels of GH and IGF-I.
Organ and tissue weights
These parameters were investigated in 5-week-old mice
because this was the age when the first significant differences in body
weight were observed. The absolute weights of spleen (127%), liver
(70%), skin (41%), kidneys (35%), heart (33%), and pancreas (23%)
were already significantly (at least P < 0.05)
increased in G vs. C mice (Table 1). The carcass weight of G mice was, as
a tendency, increased (13%, P = 0.158), compared with
C mice.
|
). Pancreas weights of GB mice
were even lower than those of C mice. Liver weights of GB mice were
also significantly reduced vs. G mice (P <
0.001) but were still higher (P < 0.05) than in C and
B mice. Interestingly, a reduction (P < 0.05) in brain
weight was seen in B and GB mice vs. C and G mice. These
data show that elevated IGFBP-2 potently reduces effects of GH
overexpression at the age of 5 weeks.
|
). Whereas the relative weights of
carcass and brain were significantly (P < 0.05)
reduced in G and GB vs. C and B mice, GH overexpression
resulted in an overproportionate increase of spleen and liver weights.
These effects were similar to those observed in 15-week-old mice (see
below). However, in contrast to the older age class, relative pancreas
weights were not yet increased in 5-week-old GH-overexpressing mice but
were reduced (P < 0.05) in GB mice vs. all
other groups. The relative kidney weight was increased
(P < 0.01) in B mice vs. all other
groups.
|
). However, coexpression of the
CMV-IGFBP-2 transgene in GB mice reduced the effect of GH excess on the
weights of carcass (27%, P < 0.001), kidneys (21%,
P < 0.001), pancreas (17%, P <
0.05), liver (15%, P < 0.001), brain (12%,
P < 0.001), heart (12%, P < 0.05),
spleen (11%, P = 0.07), and skin (9%,
P < 0.05; Fig. 5B). In contrast, a significant
reduction in B vs. C mice was seen only for the weights of
carcass (21%, P < 0.001) and brain (15%,
P < 0.001).
|
). However, the GH transgenic groups (G,
GB) displayed an overproportionate increase in the weights of liver
(P < 0.001), skin (P < 0.001), spleen
(P < 0.001 vs. C; P < 0.05
vs. B), and pancreas (P < 0.01
vs. C; P < 0.05 vs. B). In
contrast, the relative weights of brain (P < 0.001)
and carcass (P < 0.01) were significantly reduced in G
and GB vs. C and B mice. Effects of the CMV-IGFBP-2
transgene were also seen on relative organ weights. The relative weight
of the carcass was decreased (P < 0.001), whereas the
relative weight of the skin was increased (P < 0.05)
in GB vs. G mice. Furthermore, B mice displayed reduced
relative carcass weights (P < 0.001) but increased
relative spleen and liver weights (P < 0.05), compared
with C mice. As a proportion of body weight, the abdominal fat weight
was, as a tendency, reduced in G vs. C mice and in GB
vs. B mice. A significant (P < 0.05)
difference was found between B and G mice.
|
In 5-week-old mice, the reduction in spleen, pancreas, kidney, and skin
weights, as well as NRL of GB vs. G mice, was significantly
(P < 0.05) greater than the effect observed in B
vs. C mice. A tendency (P < 0.1) of an
enhanced inhibitory effect of IGFBP-2 overexpression in giant GH
transgenic mice was seen for body weight and the weights of heart,
abdominal fat, liver, and brain (Fig. 5A).
In 15-week-old mice, the relative reduction in liver weights of GB
vs. G mice was significantly (P < 0.05)
greater than in B vs. C mice, and a tendency
(P < 0.1) of an augmented IGFBP-2 effect in
high-GH/IGF-I mice was seen for kidney weight and NRL. Opposite effects
of IGFBP-2 overexpression were seen for spleen weight, which was, as a
tendency, reduced in GB vs. G mice but increased in B
vs. C mice (Fig. 5B).
Histology of the liver
Because overexpression of IGFBP-2 markedly reduced growth
effects of GH excess, we studied pathological alterations of the liver
that are a well known consequence of GH excess in transgenic mice.
Histologically, liver lesions were consistently found in both
15-week-old G and GB mice, and the pattern of histological liver
alterations was similar in these groups (Fig. 6). The most striking feature was the
presence of abnormally large hepatocytes with karyomegaly. The
megalocytic change was restricted to hepatocytes and was commonly more
pronounced in the centrilobular areas. Significant enlargement and
pleomorphism of almost all the hepatocytes and their nuclei were
observed in two out of six G mice and in one out of six GB mice.
Hypertrophic liver cell nuclei frequently demonstrated pseudoinclusions
resulting from enfolding of the nuclear membrane by cytoplasmic
material. Further changes consistently observed in livers from G and GB
mice, respectively, included single liver cell necroses and mild
degrees of oval cell proliferation. Livers from B and C mice (Fig. 6)
were indistinguishable by light microscopy and demonstrated
slight variation in the size of liver cell nuclei and low numbers of
lymphoid cells in scattered portal tracts.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Serum GH levels of both G and GB mice were in the range of 2 µg/ml,
which is consistent with our previous reports on PEPCK-bGH transgenic
mice (28, 35) and indicates that phenotypic differences
between G and GB mice are not attributable to altered PEPCK-bGH
transgene expression by coexpression of the CMV-IGFBP-2 transgene in GB
mice. Conversely, GH overexpression did not affect the expression of
the CMV-IGFBP-2 transgene, as shown by similar tissue levels of IGFBP-2
in B and GB mice (Fig. 3). Serum IGFBP-2 levels of B and GB mice,
investigated in the present experiment, were higher than those observed
in our previous study (15). This is most likely
attributable to the different genetic background produced by our
crossing experiment.
GH overproduction caused a marked increase in all organ weights except for the brain. In 15-week-old mice, the increase was proportionate to body weight for kidney and heart but overproportionate for skin, pancreas, liver, and spleen. An overproportionate growth of liver and spleen, but not of skin and pancreas, was seen in 5-week-old G mice, demonstrating organ- and time-specific sensitivity of different organs to GH excess. The weights of carcass and especially of brain were less increased than total body weight both in 5- and 15-week-old G mice.
The effects seen for elevated IGFBP-2 in the absence of GH overexpression largely confirmed our previous study. However, presumably because of the higher IGFBP-2 expression levels, the weight of the brain and the NRL were significantly reduced in B vs. C mice, in addition to the previously described significant reduction in carcass weight (15).
Interestingly, the growth-inhibiting effect of IGFBP-2 overexpression
was even more marked in high-GH/IGF-I mice, as indicated by several
observations: 1) At 5 weeks of age, GB mice displayed a significant
reduction of all growth parameters except for the weight of abdominal
fat, compared with G mice; whereas only brain weight was significantly
reduced in B vs. C mice (Table 1); 2) In 15-week-old
animals, a significant reduction in all growth parameters, except for
spleen and abdominal fat weights, was seen in GB vs. G mice;
whereas only NRL and the weights of carcass and brain were
significantly reduced in B vs. C mice (Table 3); 3) IGFBP-2
overexpression in GB mice completely reduced normalized body size
(NRL-body weight1/3-ratio) in the condition of GH
excess (Fig. 4C); and 4) A direct comparison of the relative effects
(percent difference in body weight, organ/tissue weights or NRL) of
IGFBP-2 overexpression in a high (GB vs. G) and a normal (B
vs. C) GH/IGF-I background showed statistically significant
differences in both 5- and 15-week-old mice (Fig. 5, A and B).
Theoretically, there are three major routes to explain the enhanced inhibitory activity of IGFBP-2 in giant GH transgenic mice: 1) IGFBP-2 blocks IGF-I-mediated effects of GH excess; 2) IGFBP-2 impairs direct effects of GH overexpression; or 3) IGFBP-2 inhibits growth in a GH/IGF-I independent manner, but this effect is via yet-unknown mechanisms augmented in high-GH/IGF-I mice.
Several reasons argue for an IGF-I-dependent mechanism of growth inhibition by IGFBP-2 overexpression in giant GH transgenic mice. The essential role of IGF-I, to stimulate growth in vivo, has been shown by elegant studies in transgenic and knockout mouse models. Whereas overexpression of IGF-I in GH-deficient transgenic mice restored normal somatic growth (36), treatment with GH was inefficient in stimulating growth of IGF-I-deficient mice (37). Furthermore, the growth of organs that were particularly affected by IGFBP-2 overexpression has previously been shown to be regulated by IGF-I. For instance, the weights of the spleen, pancreas, and kidneys were most markedly reduced in 5-week-old GB vs. G mice. In IGF-I-overexpressing transgenic mice, spleen and pancreas were among the organs showing the greatest increase in weight (38). Furthermore, a specific increase in weights of spleen and kidney was observed in GH-deficient rats treated with IGF-I (39, 40, 41). In contrast, markedly reduced serum IGF-I levels in mice lacking hepatic Igf1 gene expression were associated with significantly reduced kidney weights, in spite of elevated GH levels (42).
The weight of the carcass, which consists mainly of skeletal muscle tissue, was most markedly reduced by IGFBP-2 overproduction in 15-week-old mice, both in the absence and presence of the PEPCK-bGH transgene. In hypophysectomized rats, skeletal muscle was the tissue that showed the greatest increase (9.7-fold) in IGF-I mRNA levels after GH treatment (43). Furthermore, transgenic mice overexpressing IGF-I displayed an increase in body weight by 1.3-fold, which was primarily explained by increased muscle and/or connective tissue growth (38). In contrast, lack of IGF-I expression in Igf1 knockout mice results in generalized muscle hypoplasia (44) and dystrophy that is most prominent in the diaphragm (45), causing a high incidence of perinatal death attributable to respiratory failure. These findings underline the importance of IGF-I for muscle development and growth.
A role of IGF-I for the growth of the heart has been demonstrated
by cardiac-specific overexpression, in transgenic mice, of a human
IGF-I cDNA under the control of the 
myosin heavy chain
promoter. These mice developed cardiomegaly because of an increased
number of cells in the heart (46). Also, for brain, IGF-I
seems to be an important growth factor. Increased brain weights were
found in IGF-I-overexpressing transgenic mice (38, 47),
even in the near absence of GH (36). In contrast, reduced
brain growth was a common finding in several transgenic mouse models
overexpressing IGFBP-1 (48, 49, 50, 51, 52, 53, 54 ; for review, see
55), which seems to inhibit IGF-dependent cellular
growth and differentiation (1, 56).
However, there are also indications that IGFBP-2 might inhibit direct growth effects of GH excess or act as a growth inhibitor independent of GH or IGF-I. A number of studies suggested that liver growth is directly stimulated by GH and does not depend on IGF-I. First, transgenic mice overexpressing a human IGF-I cDNA under the control of the mouse metallothionein I promoter were characterized by 3-fold-increased IGF-I peptide levels in the liver but did not show increased liver growth (38). Second, expression of the same transgene in mice lacking somatotrophic cells completely normalized linear growth and weights of most organs but not the weight of the liver, which was still lower than in pituitary-intact controls (36). Third, liver-specific inactivation of the Igf1 gene in mice eliminated IGF-I production in the liver and decreased circulating IGF-I levels by 75%; however (possibly as a consequence of elevated GH levels), the weight of the liver was increased in these animals (42, 57). Our study demonstrated a significant reduction of liver weight in GB vs. G mice, at both the ages of 5 and 15 weeks, suggesting that IGFBP-2 overexpression inhibits liver growth by partially blocking the GH stimulus or directly via a yet-unknown mechanism. The latter is supported by the fact that male mice lacking IGFBP-2 expression displayed increased liver weights (14). However, relative liver weights of G and GB mice were not different, both being disproportionately increased, compared with C and B mice. Therefore, the reduction of absolute liver weight in GB vs. G mice might be a general size effect, i.e. the expected organ size change, given a certain overall weight change and a particular coefficient of growth allometry (for review, see 21). Importantly, characteristic pathological lesions observed in GH transgenic mice (16, 25, 26, 58) were also seen in GH/IGFBP-2 double transgenic mice. The influence of IGFBP-2 on long-term effects of GH on liver growth and pathology, including tumorigenesis (59, 60), deserves further investigation.
The effects of elevated IGFBP-2, to reduce body and organ growth,
parallel those observed in transgenic mice overexpressing IGFBP-1 in
several aspects. In phosphoglycerate kinase promoter-rat IGFBP-1
transgenic mice, the birth weight was significantly reduced, to
approximately 83–92% of the weight of wild-type animals
(49). The growth retardation persisted in the postnatal
period, particularly after weaning. Except for brain weight (which was
disproportionately reduced) and spleen weight (which was heavier), the
absolute weights of individual organs were reduced in transgenic mice,
but similar to those of control mice when considered as a function of
body weight. The specific increase in spleen weight, in this transgenic
model, has been discussed as a consequence of IGF-independent effects
of elevated IGFBP-1. Overexpression of human IGFBP-1 under the
control of the 1 antitrypsin promoter in transgenic mice resulted in
growth retardation within the first weeks of postnatal life. Body
weight of adult mice was negatively correlated with plasma IGFBP-1
concentration (50). In contrast, no major effects on total
body weight were observed in MT-hIGFBP-1 transgenic mice
(61). These different findings may be attributable
to differences in level and tissue specificity of transgene expression
in the various models (for review, see 55). Other
alterations, such as altered glucose homeostasis and impaired female
fertility, which were seen in part of the IGFBP-1-overexpressing
transgenic mouse models (49, 50, 62), were not obvious in
CMV-IGFBP-2 transgenic mice (15), although detailed
analyses of metabolic and reproductive functions in this model remain
to be done.
In summary, our study demonstrates that IGFBP-2 is an inhibitor of normal and GH-stimulated growth of mice, and that growth inhibition by IGFBP-2 overexpression is more effective in high-GH/IGF-I mice. This may be attributable to inhibition of indirect (IGF-I-mediated) or direct effects of GH excess by elevated IGFBP-2 or may represent a direct effect of IGFBP-2 that might be potentiated in high-GH/IGF-I mice. The crossing experiment used for this study provides a unique model system to understand tissue-specific effects and interactions between members of the GH/IGF system and to identify, by expression profiling, other factors involved in growth regulation of specific organs.
|
Acknowledgments |
|---|
Received January 2, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  M. Bielohuby, J. Roemmler, J. Manolopoulou, I. Johnsen, M. Sawitzky, J. Schopohl, M. Reincke, E. Wolf, A. Hoeflich, and M. Bidlingmaier Chronic Growth Hormone Excess Is Associated with Increased Aldosterone: A Study in Patients with Acromegaly and in Growth Hormone Transgenic Mice Experimental Biology and Medicine, August 1, 2009; 234(8): 1002 - 1009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bielohuby, M. Sawitzky, I. Johnsen, D. Wittenburg, F. Beuschlein, E. Wolf, and A. Hoeflich Decreased p44/42 Mitogen-Activated Protein Kinase Phosphorylation in Gender- or Hormone-Related But Not during Age-Related Adrenal Gland Growth in Mice Endocrinology, March 1, 2009; 150(3): 1269 - 1277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kiepe, A. Van Der Pas, S. Ciarmatori, L. Standker, B. Schutt, A. Hoeflich, U. Hugel, J. Oh, and B. Tonshoff Defined Carboxy-Terminal Fragments of Insulin-Like Growth Factor (IGF) Binding Protein-2 Exert Similar Mitogenic Activity on Cultured Rat Growth Plate Chondrocytes as IGF-I Endocrinology, October 1, 2008; 149(10): 4901 - 4911. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G Miquet, L. Gonzalez, M. N Matos, C. E Hansen, A. Louis, A. Bartke, D. Turyn, and A. I Sotelo Transgenic mice overexpressing GH exhibit hepatic upregulation of GH-signaling mediators involved in cell proliferation J. Endocrinol., August 1, 2008; 198(2): 317 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. E. DeMambro, D. R. Clemmons, L. G. Horton, M. L. Bouxsein, T. L. Wood, W. G. Beamer, E. Canalis, and C. J. Rosen Gender-Specific Changes in Bone Turnover and Skeletal Architecture in Igfbp-2-Null Mice Endocrinology, May 1, 2008; 149(5): 2051 - 2061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Martin and R. C. Baxter Expression of Insulin-Like Growth Factor Binding Protein-2 by MCF-7 Breast Cancer Cells Is Regulated through the Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Pathway Endocrinology, May 1, 2007; 148(5): 2532 - 2541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Moerth, M. R. Schneider, I. Renner-Mueller, A. Blutke, M. W. Elmlinger, R. G. Erben, C. Camacho-Hubner, A. Hoeflich, and E. Wolf Postnatally Elevated Levels of Insulin-Like Growth Factor (IGF)-II Fail to Rescue the Dwarfism of IGF-I-Deficient Mice except Kidney Weight Endocrinology, January 1, 2007; 148(1): 441 - 451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W Frommer, K. Reichenmiller, B. S Schutt, A. Hoeflich, M. B Ranke, G. Dodt, and M. W Elmlinger IGF-independent effects of IGFBP-2 on the human breast cancer cell line Hs578T. J. Mol. Endocrinol., August 1, 2006; 37(1): 13 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Russo, P. D. Gluckman, E. L. Feldman, and G. A. Werther The Insulin-Like Growth Factor System and Its Pleiotropic Functions in Brain Endocr. Rev., December 1, 2005; 26(7): 916 - 943. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. S. Thorey, B. Hinz, A. Hoeflich, S. Kaesler, P. Bugnon, M. Elmlinger, R. Wanke, E. Wolf, and S. Werner Transgenic Mice Reveal Novel Activities of Growth Hormone in Wound Repair, Angiogenesis, and Myofibroblast Differentiation J. Biol. Chem., June 18, 2004; 279(25): 26674 - 26684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Palermo, P. Manduca, E. Gazzerro, L. Foppiani, D. Segat, and A. Barreca Potentiating role of IGFBP-2 on IGF-II-stimulated alkaline phosphatase activity in differentiating osteoblasts Am J Physiol Endocrinol Metab, April 1, 2004; 286(4): E648 - E657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Firth and R. C. Baxter Cellular Actions of the Insulin-Like Growth Factor Binding Proteins Endocr. Rev., December 1, 2002; 23(6): 824 - 854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. HOEFLICH, M. M. WEBER, T. FISCH, S. NEDBAL, C. FOTTNER, M. W. ELMLINGER, R. WANKE, and E. WOLF Insulin-like growth factor binding protein 2 (IGFBP-2) separates hypertrophic and hyperplastic effects of growth hormone (GH)/IGF-I excess on adrenocortical cells in vivo FASEB J, November 1, 2002; 16(13): 1721 - 1731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. V. Silha and L. J. Murphy Minireview: Insights from Insulin-Like Growth Factor Binding Protein Transgenic Mice Endocrinology, October 1, 2002; 143(10): 3711 - 3714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. K. Goh, T. Zhu, W.-Y. Leong, and P. E. Lobie c-Cbl Is a Negative Regulator of GH-Stimulated STAT5-Mediated Transcription Endocrinology, September 1, 2002; 143(9): 3590 - 3603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Tonner, M. C. Barber, G. J. Allan, J. Beattie, J. Webster, C. B. A. Whitelaw, and D. J. Flint Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice Development, January 10, 2002; 129(19): 4547 - 4557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hoeflich, R. Reisinger, H. Lahm, W. Kiess, W. F. Blum, H. J. Kolb, M. M. Weber, and E. Wolf Insulin-like Growth Factor-binding Protein 2 in Tumorigenesis: Protector or Promoter? Cancer Res., December 1, 2001; 61(24): 8601 - 8610. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
