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In Depth Tutorials and Information
Consistent with the effects of IGF-1
in vitro
, mice
with osteoblast-specific overexpression of IGF-1 have
increased trabecular bone resulting from increased bone
formation rate.
57
Conversely, osteoblast-specific dis-
ruption of IGF-1R markedly impairs mineral apposi-
tion rate and increases mineralization lag time.
58
Also
consistent with
in vitro
observations, the ability of GH
to induce osteoblast proliferation
in vivo
appears to
require IGF-1, as daily GH administration increased
osteoblast numbers in control mice, but failed to do so
in mice with osteoblast-specific deletion of IGF-1R.
53
Interestingly, the effects of these genetic manipulations
are most pronounced during the pubertal growth spurt,
likely owing to an interaction of IGF-1 and the sex ste-
roids.
59
A number of humans bearing mutations in IGF-1
or related genes also highlights the importance of IGF-1
in normal bone formation. A 15-year-old patient with
homozygous deletion of exons 4 and 5 of the
IGF1
gene
displayed severe intrauterine growth retardation and
postnatal growth failure, including delayed bone devel-
opment.
22
Patients with mutations in the
IGFALS
gene,
which encodes ALS found in the IGF ternary complex,
displayed moderate postnatal growth retardation with
an apparent delay in bone growth.
60
These patients had
undetectable levels of ALS and low IGF-1 in the presence
of normal GH levels.
Mice with GH deficiency arising from spontane-
ous mutations of the GHRH receptor (
lit/lit
or little
mouse), Prop-1 (Ames dwarf), Pit 1 (Snell dwarf)
61
and
the GH-insensitive Laron mouse
62
are all indistinguish-
able from wild-type animals through the first 2 weeks of
postnatal life. By postnatal day 40, however, all of these
GH-deficient or -insensitive mice have only achieved 50%
of wild-type growth,
61
highlighting the predominance of
GH-dependent IGF-1 in driving growth during postna-
tal life. This is, of course, in contrast to the
Igf1
and
Igf1r
mutants that demonstrate severe intrauterine growth
defects and illustrate that, in the prenatal context, IGF-1
actions are independent of GH.
63,64
Additionally,
lit/lit
mice and global
Ghr
null mice, with no GH and low IGF-1
levels, have reduced cortical bone, but normal trabecular
bone.
65,66
Decreased cortical bone in these GH-deficient
mice is attributed to the reduced systemic IGF-1 levels, as
liver-specific deletion of
Igf1
or
Igfals
(or combined dele-
tion) also reduces systemic IGF-1 and results in reduced
cortical bone.
67
It has been suggested that the IGF ter-
nary complex may function in a compartment-specific
fashion (i.e., in cortical rather than trabecular bone).
67
Interestingly, osteoblast-specific GHR knockout mice gen-
erally phenocopy mice with osteoblast-specific deletion of
IGF-1R, with an added, transient decrease in cortical bone
(DiGirolamo, unpublished data).
Much like the effects of mutations leading to GH
deficiency or insensitivity in mice, humans with severe
isolated GH deficiency (GHD), GHRH receptor muta-
tions, GH insensitivity due to GHR mutations and
STAT5b mutations all demonstrate significant growth
impairment.
68-73
The growth pattern of these patients
with GH deficiency/insensitivity is similar to that of
primary IGF-1 deficiency,22
22
highlighting again the domi-
nance of GH-dependent IGF-1 in postnatal growth pre-
viously noted in mice. Correcting for body size, bone
mineral apparent, or volumetric, density (BMAD, g/cm
3
)
is not significantly affected by childhood-onset GHD,
GHD in adults of all ages, severe GH resistance or IGF-1
gene mutations.
74
Minimal gains in BMAD are detectable
after years of GH or IGF-1 treatment, however.
74
Despite
the lackluster effect of GH treatment on bone density in
these patients, there may be additional benefits of GH/
IGF-1 treatment resulting from increased muscle mass
and secondary bone geometry changes (i.e., periosteal
expansion) that could ultimately contribute to increased
bone strength and fracture reduction. This is an espe-
cially attractive idea in the context of considering GH for
the treatment of OI.
CLINICAL TESTING FOR GROWTH
HORMONE AND IGF-1
IGF-1 levels can be helpful in determining whether a
patient may be growth hormone deficient, but the inter-
pretation of these levels is dependent on many factors
and must be evaluated cautiously. Consistent levels of
IGF-1 are maintained throughout the day and can be eas-
ily measured in the serum. Normal levels tend to exclude
a diagnosis of GH deficiency. However, IGF-1 levels have
a broad range of normal in younger children, and there
is a significant degree of overlap between normals and
those with GH deficiency.75
75
IGF-1 levels are low in young
children and have a puberty-dependent rise, becoming
more accurate as a child gets older (for review see
76
). In
addition, these levels are affected by nutritional status
and are therefore lower in malnutrition and in chronic
disease. IGF-1 correlates with pubertal status and is typi-
cally interpreted relative to pubertal status/bone age
rather than chronologic age during puberty. Insulin-like
binding protein type 3 (IGFBP-3), a major human serum
carrier protein for IGF peptides, is age dependent and
can also be a reflection of GH status; it is less nutrition-
ally dependent than IGF-1.
Although IGF-1 and IGFBP-3 levels are helpful, pro-
vocative GH testing is the standard of care for diagnosis
of GH deficiency. Random growth hormone levels are
uninterpretable unless a peak happens to be obtained
because the pituitary gland produces growth hormone
in pulsatile bursts occurring in 3-5 hour intervals with
the greatest secretory bursts occurring during deep
