Biomedical Engineering Reference
In-Depth Information
the skeleton. Studies in which both the
c-fos
and the
v-fos
genes were virally introduced
have shown that
fos
expression generated osteo-
sarcomas [
PTHrP in their growth plates, which are made
up mainly of hypertrophic chondrocytes. Con-
versely, animals lacking PTHrP have very small
zones of proliferating chondrocytes and exhibit
a premature transition to cellular hypertrophy
and mineralization [
].
C-fos
knockout mice
develop osteochondrodysplasia, overproduce
hypertrophic cartilage, and cannot replace
bone. This condition in some ways looks like
osteopetrosis [
74
,
180
,
181
]. Interestingly, if
the Ihh-ablated mice are engineered to have a
constitutively active PTH
136
,
194
]. Other studies have also
shown increases in
c-fos
proto-oncogene in
bone from patients with fi brous dysplasia in
whom bone formation is overexpressed or bone
forms ectopically [
213
R receptor, prema-
ture chondrocyte hypertrophy is prevented,
but proliferation of the chondrocytes in the
growth zones is still diminished. These fi nd-
ings suggest molecular mechanisms that are
regulated by Ihh and not activated by PTHrP
control cell proliferation [
1
]. Studies examining dif-
ferent members of the basic leucine zipper
protein family have demonstrated that both
ATF-
31
].
A further understanding of the developmen-
tal role of PTHrP has been gained from studies
in two different human chondrodysplasias.
One type of chondrodysplasia is a nonlethal,
autosomal dominant disorder that was fi rst
identifi ed by Jansen in
103
and hXBP are expressed in skeletal
tissues [
2
leads to a
defect in endochondral ossifi cation with a his-
topathology similar to human hypochondro-
plasia [
40
,
173
]. Ablation of ATF-
2
173
].
]. It has subse-
quently been characterized at a molecular level
as a constitutively activating mutation in the
PTH
1934
[
95
2.2.4.3 The Role of PTHrP in
Endochondral Development
The discovery of PTHrP as the primary factor
in malignant hypocalcemia constituted a
major advance in understanding the systemic
effects of many malignancies. However, the
subsequent characterization of PTHrP as an
essential autocrine/paracrine factor in skeletal-
tissue development was equally important.
Initial animal studies demonstrated that PTHrP
mRNA was fully expressed in perichondral
cells and in the chondrocytes found in the
proliferating zones of endochondral growth
plates. The PTHrP receptor was expressed
progressively more fully as endochondral
chondrocytes matured toward their terminal
hypertrophic state. Missense expression studies
of PTHrP in developing avian embryo growth
plates and studies in transgenic animals with
the targeted ablation of PTHrP have demon-
strated a complex negative feedback loop that
involves Indian hedgehog (Ihh) regulation of
the progression of chondrocyte development
during endochondral bone formation [
]. The patients are charac-
terized by short limbs caused by severe abnor-
malities in their growth plates and associated
hypocalcemia. The second type of chondrodys-
plasia was identifi ed by Blomstrand et al. [
1
R receptor [
186
].
It is a prenatal lethal chondrodysplasia charac-
terized by abnormal bone ossifi cation and
shortened limbs. In these fetuses, the limbs
show very advanced endochondral develop-
ment, and the disease is characterized by an
autosomal recessive pattern of inheritance.
Molecular analysis of these patients suggested
the disease is due to an inactivating mutation
in the PTH
22
1
R receptor [
97
].
2.2.4.4 PTH as a Therapeutic for
Osteoporosis and Augmentation
of Fracture Healing
Numerous recent studies have focused on the
systemic effects and potential therapeutic appli-
cations of PTH [
102
,
122
,
]. The continuous
infusion of PTH into mammals induces cata-
bolic events, increases bone remodeling, and
leads to a loss of skeletal bone mass. On the
other hand, intermittent dosing seems to have
anabolic effects and results in increased bone
mass [
48
,
159
,
169
208
]. These studies demonstrate that Ihh posi-
tively regulates PTHrP expression, as a result
of which cells are maintained in an undifferen-
tiated state, with Ihh promoting proliferation
and thereby expanding the population. The
increased output of PTHrP causes Ihh expres-
sion to be down-regulated by expanding the
pool of proliferating immature chondrocytes.
Ihh-ablated transgenic mice have no detectable
116
,
151
,
199
]. Clinical trials utilizing the
1
PTH peptide have increased bone mineral
density and reduced the risk of vertebral and
nonvertebral fractures in postmenopausal
-
34
