Endocrinology Vol. 140, No. 11 5178-5184
Copyright © 1999 by The Endocrine Society
Insulin-Like Growth Factor I Is Essential for Postnatal Growth in Response to Growth Hormone
Jun-Li Liu1 and
Derek LeRoith
Clinical Endocrinology Branch, The National Institute of Diabetes
and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, Maryland 20892-1758
Address all correspondence and requests for reprints to: Dr. Derek LeRoith, CEB/National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 8D12, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892-1758. E-mail:
Derek{at}helix.nih.gov
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Abstract
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Insulin-like growth factor I (IGF-I) is essential for cell growth and
intrauterine development while both IGF-I and GH are required for
postnatal growth. To explore the possibility of direct GH action on
body growth, independent of IGF-I production, we have studied the
effects of GH in an IGF-I-deficient mouse line created by the Cre/loxP
system. The IGF-I null mice are born with 35% growth retardation and
show delayed onset of peripubertal growth, grow significantly slower,
and do not attain puberty. Their adult body weight was approximately
one third and body length about two thirds that of their wild-type
litter mates. Injection of recombinant human GH (rhGH, 3 mg/kg, twice
daily, sc) between postnatal day 14 (P14) to P56 failed to
stimulate their growth as measured as both body weight and length. In
contrast, wild-type mice receiving the same doses of rhGH exhibited
accelerated growth starting at P21 that continued until P56, when their
body weight was increased by 30% and length by 12% compared with
control mice treated with diluent. Despite the lack of response in
growth, IGF-I null mice have normal levels of GH receptor expression in
the liver and increased liver Jun B expression and liver size in
response to rhGH treatment. Our results support an essential role for
IGF-I in GH-induced postnatal body growth in mice.
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Introduction
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GH IS a small protein hormone of 191 amino
acids that causes growth of almost all tissues of the body by
increasing cell size and cell number and by promoting differentiation
of bone and muscle cells (1). Deficiency in either GH or the GH
receptor causes severe postnatal growth retardation and proportionate
dwarfism in humans and mice (2, 3). Insulin-like growth factor I
(IGF-I), expressed by many cells and tissues throughout
development, is an essential factor in cell growth, intrauterine
development, and postnatal growth (4, 5, 6, 7). IGF-I deficiency in humans
and mice causes severe intrauterine and postnatal growth retardation,
perinatal lethality, and developmental defects in the bone, muscle, and
reproductive systems.
Several modes of GH action on postnatal body growth have been proposed
(8, 9). GH may act on a major target organ, namely the liver, to
stimulate the synthesis and secretion of IGF-I, which reaches its
skeletal targets as a true endocrine reagent (the somatomedin
hypothesis) (10). GH may stimulate longitudinal bone growth directly
through local production of IGF-I (modified somatomedin hypothesis)
(11, 12, 13). In addition, GH may have a direct mitogenic action on target
tissues such as the chondrocyte precursor cells, or GH action may be
mediated by growth factors other than IGF-I (14, 15, 16). For example, GH
was found to stimulate synthesis of the bone morphogenetic proteins in
the presence of IGF-I antiserum (14). A recent report from our
laboratory has demonstrated that liver-derived "endocrine" IGF-I is
not essential for postnatal growth and has challenged the classical
somatomedin hypothesis (17). In this study, to test the direct effect
of GH, we created viable dwarf mice with IGF-I deficiency by the
Cre/loxP system and studied the effect of GH administration on their
body growth. Our results demonstrate an essential role for IGF-I in
GH-induced postnatal body growth in mice and hence support the modified
somatomedin hypothesis.
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Materials and Methods
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Animal production
IGF-I null mice were generated while studying EIIa-cre-induced
gene recombination in IGF-I floxed (flanked by loxP repeats) mice (18).
Briefly, mice (F1) carrying one allele of igf-1/flox and
EIIa-cre transgene (L/+, Cre/+) were intercrossed to generate
homozygous igf-1/flox mice that were also EIIa-cre positive
(F2, L/L, Cre/+) (Fig. 1
). At that stage,
Cre-induced recombination of the igf-1 locus had occurred
(18). F2 mice were further intercrossed to generate mice (F3, L/-)
with an allele of igf-1/flox and an allele of
igf-1 null (germ line transmission from F2) which had
segregated the Cre transgene. These L/- mice were assigned to multiple
mating pairs to generate IGF-I null (-/-) mice. Among the three
genotypes generated [L/L, L/-, and -/-] and used in the current
study, L/L and L/- are virtually normal in IGF-I gene expression,
development, and growth and are treated as wild-type mice. On the other
hand, -/- (IGF-I null) mice have no IGF-I expression and demonstrate
a severe defect in intrauterine development and postnatal growth. The
animals were kept in a designated breeding room and were observed
closely throughout the experiment. Genotyping by PCR and Southern blot
analysis has been reported (18). The Animal Care and Use Committee of
the NIDDK, National Institutes of Health (Bethesda, MD) approved all of
the animal manipulations.

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Figure 1. Breeding strategy for the production of IGF-I null
mice. See details in text of Animal Production in Materials and
Methods.
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Growth response to GH
Wild-type (WT) and IGF-I null mice were treated with recombinant
human GH (rhGH, Genentech, Inc., South San Francisco, CA),
3 mg/kg twice daily, sc, from postnatal day 14 (P14) to P56.
Control mice of both genotypes received an equal volume of normal
saline (diluent). Their body weights were measured daily. At the end of
the study (8 weeks of age), mice were anesthetized using 0.2% avertin
and bled via periorbital puncture; their body length (nose to anus) was
measured, and organs (brain, heart, liver, kidney, and spleen) were
removed and weighed. Liver RNA was extracted, using RNAzol B reagent
(Tel-Test, Friendswood, TX), to determine the level of GH
receptor messenger RNA (mRNA) using ribonuclease (RNase) protection
assay.
Effect of GH on Jun B gene expression
To study the effect of GH on the expression of immediate early
genes, liver expression of Jun B mRNA was analyzed. Mice of wild-type
and knockout genotypes, at 6 weeks of age, were fasted overnight and
injected with rhGH (3 mg/kg, ip) or diluent. After 30 min, they were
anesthetized and bled. Total RNA was extracted from the liver to
determine the level of Jun B mRNA by RNase protection assay.
RNase protection assay
The expression of IGF-I from various tissues and expression
of Jun B and GH receptor from the liver were studied using the
RNase protection assay (19). 32P-labeled riboprobes were
made from mouse IGF-I exon 4 (18), pTRI-Jun (B)-mouse (Ambion, Inc., Austin, TX), and mouse GH receptor exon 4
(BamHI/AvaI fragment, provided by Dr. John J
Kopchick, Ohio University, Athens, OH) (2).
Hormone assay, serum chemistry, and statistics
The serum concentration of total IGF-I (Diagnostics Systems Laboratories, Inc. Webster, TX), insulin (Linco,
St-Charles, MO), and GH (Amersham Pharmacia Biotech,
Arlington Heights, IL) were determined by RIA kits available
commercially. Glucose was measured with a Glucometer Elite (Bayer Corp., Elkhart, IN). Serum chemistry was performed by the
Pathology Department at the Clinical Center of the NIH. Statistical
significance was determined by the two-tailed t test using
the program SigmaStat 2.03 (Access Softek, Inc., San Rafael, CA).
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Results
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Characterization of the IGF-I deletion mutant
To study IGF-I-independent, direct GH action on body growth, we
generated IGF-I null mice by inbreeding multiple pairs of L/- mice
(with an allele of igf-1/flox and an allele of
igf-1 null) (Fig. 1
). Southern blot analysis was performed
on tail DNA to identify the genotype of the offspring (data not shown).
RNase protection assay on several tissues was employed to assess the
level of IGF-I gene expression and serum IGF-I level was determined by
RIA. As shown in Fig. 2
, wild-type mice
have varying amounts of IGF-I mRNA in the liver, heart, and kidney,
while IGF-I null mice have undetectable IGF-I mRNA. Their circulating
IGF-I concentration was below the detection limit (Table 1
). As such, the gene deletion was
confirmed at the level of tissue DNA, mRNA, and circulating
peptide.

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Figure 2. IGF-I gene expression in wild-type (lanes 14)
and IGF-I null mice (lanes 58). Total RNA was prepared from liver (10
µg), heart (50 µg), and kidney (10 µg) of adult mice and analyzed
by RNase protection assay using probes for IGF-I exon 4 and 18S
ribosome RNA.
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As a consequence of a diminished negative feedback control by IGF-I, we
anticipated finding an increased release of GH from the pituitary in
IGF-I null mice. Indeed, in 5-week-old mice, serum GH concentration
increased 12.4-fold (Table 1
). Consistent with GH hypersecretion, adult
IGF-I null mice show specific and significant increases in the relative
weight of the following organs: brain (+113%), liver (+41%), heart
(+37%), and kidney (+21%). No change was found in the weight of the
spleen (Table 2
).
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Table 2. Changes of organ weight (as a % of body weight) and
body length (in cm) after 6-week course of rhGH treatment
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The serum glucose level (24 h fasted) in IGF-I null mice was decreased
by 50% (P < 0.001), whereas serum insulin
concentrations tended to be higher in these mice (Table 1
). This
finding is similar to a report on severe IGF-I deficient (midi) mice
created by an insertional mutation (20). In the standard serum
chemistry assay, there was a dramatic 58% reduction in alkaline
phosphatase (Table 1
), associated with the reduction in bone
growth.
Postnatal survival and growth rates
While the overall phenotype of the IGF-I null mice generated in
this study remains similar to those previously reported (4, 7),
demonstrating severe defects in prenatal development and postnatal
growth, our IGF-I null mice demonstrate improved postnatal survival
rate, which enables a more detailed postnatal study. At birth, viable
IGF-I null pups weigh 65% of their wild-type litter mates, which
decreased to 50% after 2 weeks, and then the growth curve flattened
and body weight decreased to approximately 30% of wild-type litter
mates as adults (Fig. 3
). Thus, while
IGF-I is essential for both intrauterine and postnatal development, the
growth defect becomes more profound postnatally.
A study of 27 mating pairs and 116 litters revealed that IGF-I null
pups were born at a ratio of 18.5%, which is lower than the expected
25%. With 639 pups of L/L and L/- genotypes (expected combined ratio
75%), there should be 213 (25%) of IGF-I null pups born. Instead, we
received only 145, representing a possible 31% prenatal lethality. Of
those delivered, many die within 24 h, resulting in a postnatal
survival rate of 42% (Table 3
). This
rate is relatively high but within the reported range (5% in C57BL/6J,
10% in 129/sv, 16% in C57BL/6J and 129/sv mix, and 68% in MF1 and
129/sv mix) (4, 7).
Effect of GH on postnatal growth
The effect of GH on body growth was studied in wild-type and
IGF-I null mice by injecting rhGH from 2 to 8 weeks of age. In
wild-type mice, we observed two phases of postnatal growth: an early
phase of rapid growth in the first 23 weeks of life, which cannot be
further stimulated by GH injection (data not shown), and a peripubertal
growth spurt from 3 weeks, which can be further increased by GH
injection (Fig. 4
). From 2 weeks on, the
IGF-I null mice grow more slowly and have delayed onset of the
prepubertal growth and do not undergo pubertal changes. Their final
body weight becomes approximately one third and body length about two
thirds of their wild-type litter mates as adults. As shown in Fig. 4
and Table 2
, continuous injection of rhGH did not affect their growth
rate at all, when measured both by weight and length. In contrast,
wild-type mice receiving the same doses of rhGH exhibited accelerated
growth starting at P21 and continuing to P56, where they showed a 29%
increase in body weight and 12% in body length in comparison to those
treated with diluent alone.

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Figure 4. Postnatal growth curves of IGF-I null and
wild-type mice treated with rhGH. As in Fig. 3 , the mean body weight
was plotted against the age in weeks. Wild-type mice: n = 7, *,
P < 0.05; **, P < 0.01. IGF-I
null mice: n = 910.
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Changes in organ weight caused by IGF-I deficiency and GH
injection
At the end of the 6-week injection, we measured the weight of
several organs. In wild-type mice, GH induced a significant, 27%
increase in relative liver weight, decreased the relative weight of the
brain (-20%) and kidney (-22%) (due to the increase in body weight,
because the absolute weights of organs other than liver were
unchanged), but had no effect on the relative weight of the heart and
the spleen (Table 2
). As stated earlier, IGF-I null mice have enlarged
brain, liver, heart, and kidney and GH injection caused a further
increase of 16% in liver weight (P < 0.05) (Table 2
).
Therefore, GH induced liver enlargement despite the IGF-I
deficiency.
GH receptor expression in the liver
To exclude the possibility that the lack of growth responsiveness
to GH is due to a decrease in GH receptor expression in the face of
IGF-I deficiency, we performed RNase protection assays from mouse liver
at the end of the period of GH injections. As shown in Fig. 5
, hepatic GH receptor mRNA level was
affected neither by IGF-I deficiency nor by GH treatment.

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Figure 5. Levels of hepatic GH receptor-mRNA in wild-type
and IGF-I null mice after a 6-week treatment with or without rhGH.
Total liver RNA (50 µg) was hybridized to probes containing exon 4 of
the GH receptor gene and 18S ribosomal RNA (rRNA). A representative
blot is illustrated from a study of seven wild-type and five IGF-I null
mice treated and untreated with GH. No significant variation was
revealed by densitometry analysis.
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Effect of GH on Jun B expression in the liver
In addition to chronic effects on body growth, GH induces
immediate early gene expression (including Fos, Jun, and Jun B) (21, 22). After injection of a single dose (3 mg/kg) of rhGH to overnight
fasted, 6-week-old mice, we measured hepatic Jun B-mRNA levels at 30
min. GH stimulated Jun B expression by about 2.9-fold in the wild-type
as well as in the IGF-I null mice (Fig. 6
). Thus, GH actions (on Jun B expression
and liver enlargement) are not affected by IGF-I deficiency. It further
demonstrates that GH was functional in IGF-I null mice although it
failed to increase body growth.

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Figure 6. Effect of acute rhGH injection on hepatic Jun B
expression. Mice (6 weeks of age) were injected with a single dose of
GH (3 mg/kg) for 30 min, and liver total RNA was isolated and subject
to RNase protection assay with probes for Jun B and 18S ribosomal RNA
(rRNA). A representative blot was illustrated from two experiments.
Despite lack of IGF-I, Jun B expression was stimulated approximately
2.9-fold by GH in mice of both genotypes.
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Discussion
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The current study used mice with IGF-I gene deficiency similar to
those described in two previous reports (4, 7), although the target
region used is unique due to the removal of the selection marker and
different genetic strains of mice studied. We have replaced the entire
exon 4 with a loxP site, representing a larger portion of the gene,
rather than targeting only a part of the exon or exon 3 (4, 7, 18). The
neomycin gene cassette was removed by Cre expression, because of
concerns that it may interfere with the cognate intron/exon structures
and create a microenvironment of gene activity. The adverse effect
caused by the selection marker gene used in gene targeting has been
reported (23, 24). In addition, our mice were bred on a mixed genetic
background of 129/sv, C57BL/6J, and FVB/N, which may also add to some
different aspects of the phenotype described below.
In addition to the previously reported phenotype of pre- and postnatal
growth retardation, perinatal lethality, and infertility, in our
IGF-I-deficient mice, we propose a 30% prenatal lethality, which
suggests that some IGF-I null fetuses did not survive due to
developmental retardation. We further demonstrate, in these IGF-I null
mice, GH-resistant dwarfism and marked serum GH elevation. In addition,
there is enlargement of multiple organs (brain, liver, kidney, and
heart). Finally, IGF-I null mice have normal liver GH receptor
expression and liver Jun B response to GH.
The rate of growth retardation of the IGF-I null mice started at 35%
at birth and worsened to approximately 65% as adults, in terms of body
weight. This may indicate that the fetal development of the IGF-I null
mice is partially compensated by IGF-I produced from the placenta or
possibly the presence of IGF-II and insulin. The placenta produces a
large number of hormones, including GH, IGF-I, and IGF-II, that may
reach the fetus (25, 26). Deficiency in either IGF-II or insulin
contributes to intrauterine growth retardation. Birth weights of IGF-II
knockout mice are 60% and IGF-I/II double knockout are only 30% of
their wild-type litter mates (27, 28), while insulin-1 and -2 double
knockouts also induce 1520% growth retardation in mouse embryos
(29). After birth, a further growth retardation was observed, since the
pups were no longer influenced by placental IGF-I, mouse IGF-II level
diminishes quickly, and the role of insulin on postnatal growth is
apparently very limited (29).
According to the somatomedin hypothesis, production of IGF-I from the
liver and other tissues is regulated by GH release from the pituitary.
Like many other physiological systems, overproduction of IGF-I sends a
signal to inhibit GH production via a long loop (involving GHRH and
somatostatin) and a short loop (directly on somatotrophs) negative
feedback mechanism (30, 31, 32). It is well established that exogenous
IGF-I, when administered in vivo, suppresses GH secretion,
while IGF-I deficiency is accompanied by GH hypersecretion (20, 23, 33). In a separate study, when IGF-I production was abolished
exclusively from the liver (using albumin-Cre/loxP system), we
effectively decreased serum IGF-I level by 75% without affecting the
growth and development of extrahepatic tissues. Serum GH increased
6.4-fold in these mice, suggesting that circulating IGF-I affects GH
secretion (17). The current study abolished both endocrine and
paracrine IGF-I production and thereby increased serum GH level even
further to 12.4-fold. The fold increase in serum GH concentration
correlates well with serum IGF-I levels under these circumstances.
Therefore, our studies demonstrate the presence of a potent negative
feedback on GH secretion by IGF-I.
A central issue in the somatomedin hypothesis is that GH acts through
IGF-I production from the liver or local tissues in stimulating body
growth. There have been suggestions that GH exerts some direct effects
on target tissues that are not mediated by IGF-I (15, 16, 25, 34). The
current study demonstrates that IGF-I null mice are selectively
resistant to GH in terms of body growth, directly confirming that GH
works exclusively via IGF-I production in this aspect. This is
consistent with an earlier report on the ineffectiveness of GH on
weight gain of IGF-I null mice (35). As for the role of IGF-I in the
circulation or as a paracrine growth factor, our study on
liver-specific IGF-I gene deletion demonstrated that liver-derived
endocrine IGF-I is not essential for postnatal growth (17, 36). These
studies, as well as those by other investigators (37), demonstrate that
IGF-I, most probably produced by nonhepatic tissues, is essential for
GH-stimulated postnatal growth.
One exception to the above conclusion is that the profound defect in
development and metabolism caused by IGF-I deficiency may have impaired
the ability of GH and its other growth mediators to promote body
growth. To address this question, we have demonstrated that IGF-I null
mice have normal levels of GH receptor mRNA in the liver and that rhGH
caused a significant increase in liver size. Furthermore, in an
acute experiment, we tested the effect of rhGH on liver Jun B
expression. Early response genes encode for transcription factors
including Fos, Jun, Jun B, and Myc, which can be induced by GH and are
involved in activating DNA synthesis, downstream gene expression, and
cell proliferation (21, 22). As expected, Jun B expression was
activated within 30 min of an in vivo rhGH injection in
wild-type mice. The response in IGF-I null mice was virtually
identical, further demonstrating the presence of a functional GH
signaling system. The current study therefore does not support direct
GH action on growth and indicates that those IGF-I-independent
mechanisms of GH at least in mice, are not involved in body
growth regulation.
Defects in GH receptor or downstream targets (such as STAT5b, HNF-1
,
and IGF-I) cause GH insensitivity (GHIS) or Laron Syndrome. Patients
with GH receptor gene mutations show normal prenatal development,
severe postnatal growth retardation, high serum GH, and low levels of
serum IGF-I that cannot be corrected by GH injection (38). A second
class of Laron type dwarfism, induced by HNF-1
deficiency in mice,
demonstrates normal GH receptor level, elevated serum GH, and
diminished IGF-I and insulin concentrations (23). These HNF-1
null
mice are viable and sterile and develop non-insulin-dependent diabetes
mellitus. Deficiency in STAT5b (signal transducer and activator of
transcription 5b), another transcription factor downstream of GH, also
causes Laron type of dwarfism with virtually identical features to
HNF-1
(hepatocyte nuclear factor 1
) null mice (39).
Defects in IGF-I production are rare, probably due to intrauterine
lethality. The only case of IGF-I deficiency reported features growth
failure before and after birth, high GH level, and resistance to GH
treatment (6). In agreement with the report on patients, our
data demonstrate a dramatic increase in serum GH level and the
inability of GH to promote body growth in the face of IGF-I deficiency.
It clearly defines a new class of GH-resistant dwarfism (similar to
GHIS) and proves that IGF-I is essential for GH-stimulated postnatal
growth. This mouse model provides a valuable tool with which to explore
the relationship of the GH-IGF-I axis and to provide therapeutic
modalities to treat such dwarfism.
The finding of multiple organ enlargement (relative weight) in IGF-I
null mice is an extension of previously observed weight increases of
the brain and the liver and may be the result of a sustained GH
hypersecretion (7, 40). To exclude the influence of an overall change
in body weight, we expressed the organ weight as per body weight and
found that IGF-I null mice have a 21113% increase in the weight of
the kidney, heart, liver, and brain. GH further induced changes in both
wild-type and IGF-I null mice. In wild-type mice, chronic rhGH
administration increased the weight of the liver by 27% but decreased
the relative weights of the brain and the kidney. In IGF-I null mice, a
15% increase in liver weight, caused by GH treatment, and no change in
other organs were observed.
The relationship of GH with organ growth has been well studied. For
example, prolonged excessive secretion of GH by GH3 tumor cells in rats
induced widespread visceromegaly affecting the liver, kidney, spleen,
heart, and adrenals that was associated with an increase in DNA
synthesis (41); transgenic mice overexpressing GH have selective
splanchnomegaly coupled with glomerular sclerosis and hepatomegaly
(42); pulsatile administration of GH in broiler pullets induced
hepatomegaly due largely to cellular hypertrophy (43); and
GH-transgenic mice have accelerated liver, kidney, and skeletal growth
(44). Because the IGF-I null mice have no IGF-I production and a marked
increase in GH secretion, we propose an IGF-I-independent, direct GH
action on hepatocyte growth and proliferation under conditions of both
IGF-I-deficient status and when GH was exogenously
administered.
Analysis of a standard serum chemistry profile revealed a marked
decrease in alkaline phosphatase and glucose concentrations among IGF-I
null mice. Alkaline phosphatase from the bone and other tissues is
essential for normal skeletal mineralization and growth (45, 46, 47). IGF-I
has been found to influence alkaline phosphatase activity as part of
the mechanism of stimulating bone formation. For example, locally
infused IGF-I into mouse femurs can stimulate expression of alkaline
phosphatase and bone formation; the age-dependent decline in bone
formation can be attributed in part to a decline in local IGF-I
expression and response (48); and IGF-I stimulates alkaline phosphatase
activity and type I procollagen mRNA expression in osteoblastic cells
in vitro (49). The current study demonstrates severe
hypophosphatasia due to IGF-I deficiency and suggests that alkaline
phosphatase activity may be an important downstream target of IGF-I
action on postnatal skeletal growth.
In conclusion, using the Cre/loxP system, we have generated IGF-I null
mice that have a 42% postnatal survival rate and enable an in-depth
postnatal study. These mice exhibited multiple organ enlargement
accompanied by decreased serum alkaline phosphatase and glucose
concentrations. The increase in serum GH concentration and failure of
GH in stimulating body growth in these IGF-I null mice clearly
demonstrate GH resistance (with respect to body growth) and the role of
IGF-I in feedback control of GH secretion.
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Acknowledgments
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The authors wish to thank Dr. John Kopchick (Ohio University,
Athens, OH) for providing the GH receptor probe; Dr. Peter Rotwein
(Oregon Health Sciences University, Portland, OR) for the IGF-I exon 4
probe; Bernice Samuels (NIDDK, NIH, Bethesda, MD) for performing
insulin RIA; Genentech, Inc. (South San Francisco, CA) for
providing the rhGH; and Drs. Matthew Rechler, Mark Sperling, Michael
Karas, Liliana Uribe, and David Kleiner for helpful communications.
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Footnotes
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1 Supported by a fellowship from the Medical Research Council of
Canada. 
Received June 10, 1999.
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