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Linear growth patterns have been found to be consis-
tent with what would be predicted based on the severity
of the OI type.
1-3,8,18
Children with mild OI (type I) were
found to have average birth sizes, but the height percen-
tiles gradually decreased to the subnormal range in child-
hood with final height being slightly below the normal
height range for adults. In moderate OI (type IV), birth
weights were again normal with growth decelerating into
the subnormal range by 1-2 years, slow growth until age
3-4 years, and then growth that is parallel but below the
curve through the rest of childhood; final height is com-
promised to a moderate degree. In severe OI (type III),
the infants are small to normal with poor growth veloci-
ties and extremely compromised heights as adults. Vetter
et al. examined 127 children (40 type I, 39 type II and 48
type IV) and found that the birth weights and lengths of
type III patients were significantly lower than in types I
and IV
2
which raises questions as to whether the nega-
tive impact on growth in severe OI begins
in utero
. In
addition, although there does not seem to be a difference
in height Z-score between genders in childhood, adult
women have lower height Z-scores than men. This raises
issues as to whether the pubertal growth patterns may be
impacted differently between genders in OI.
Translational studies of linear growth in OI through
evaluation of genotype-phenotype correlations for
heights have provided important information (for
review, see
9
). Rauch et al. examined 192 OI patients
ranging in age from infancy to almost 17 years of age
and found that patients with haploinsufficiency muta-
tions on average were taller (height Z-score of −1.3) than
patients with helical mutations in the alpha 1 or alpha 2
chains (height Z-score of −5.5 and −5.3, respectively).
19
In a study by Rauch et al. of 161 patients with OI who
had glycine mutations in the triple helical domain of
collagen type I, it was found that mutations in
COL1A1
and
COL1A2
had similar and average height Z-scores.
20
Interestingly, there was an inverse relationship between
the height and the location of the mutation in the tri-
ple-helical domain of the alpha 2 chain with the results
implicating that a mutation closer to the carboxy-termi-
nal end of the triple-helical domain of the alpha 2 chain
was more detrimental to height. For mutations in the
alpha 1 chain no correlation to height was found. The
result from the analysis of the alpha 2 chain is consistent
with the thought that mutations at the carboxy terminal
end of the alpha 2 chain cause more disruption to the tri-
ple helix formation and therefore lead to a more severe
phenotype.
9
Rauch et al. also found that height is affected by the
specific substituting amino acid, not only by the location
of the glycine substitution.
20
The most common type of
mutations in both the alpha 1 and alpha 2 chains are ser-
ine substitutions which seem to lead to a shorter average
stature when the alpha 1 chain is affected.
20
The second
most frequent mutations in the alpha 1 chain are arginine
substitutions, and patients with these changes have less
severe short stature than those with serine substitutions.
For the alpha 2 chain, aspartate substitutions are the sec-
ond most frequent mutations and seem to lead to severe
short stature overall.
Therefore, the investigations of the genotype-
phenotype correlations over the past several years have
provided an important avenue through which an under-
standing of linear growth in OI may even be determined
at the molecular and cellular level.
ACTION OF THE GROWTH HORMONE-
IGF-
1 AXIS IN SKELETAL GRO
WTH
Growth hormone and IGF-1 are critically important
growth factors for the development and maintenance
of the musculoskeletal system. Growth hormone and
IGF-1 were first identified nearly 60 years ago in experi-
ments performed by Salmon and Daughaday examin-
ing the role of pituitary-regulated growth stimulating
substances,
21
and the importance of this hormonal axis
in regulating longitudinal growth is easily appreciated
in patients with insufficient activity (e.g., GH deficiency)
or overactivity (e.g., acromegaly). GH and IGF-1 exert
profound growth promoting actions in postnatal life,
although IGF-1 (and IGF-2) is also a key player in embry-
onic growth, independent of GH.
22
The availability of
sophisticated genetic mouse models in recent years has
offered insight into the precise effects of GH and IGF-1
in the growth and maintenance of the musculoskeletal
system. The use of GH to treat growth and skeletal dis-
orders, by contrast, predates vastly our understand-
ing of its molecular mechanisms of action and was first
described in 1958 for the treatment of pituitary dwarf-
ism.
23
Although our discussion will focus on the skel-
eton, the anabolic effects of GH and IGF-1 in skeletal
muscle bear mentioning when considering GH treatment
for OI. Numerous studies of GH therapy for childhood-
or adult-onset GH deficiency demonstrated that muscle
augmentation preceded and exceeded bone mass gains
(if any).
24-27
These results present the interesting pos-
sibility that GH deficiency may primarily affect muscle
mass, with reduced muscle-generated force leading to
secondary bone loss. Since bone strain generated by
muscle force acts to stimulate periosteal formation and
expansion, one might presume bone loss in GH defi-
ciency would occur in the cortex and not trabeculae, and,
indeed, evidence supports this supposition.
28-30
Growth hormone is a member of a large family of
cytokine peptides and is produced by the somatotroph
cells of the anterior pituitary gland in response to both
central and peripheral signals.
31
Growth hormone is pro-
duced in response to GH-releasing hormone (GHRH)
