Biomedical Engineering Reference
In-Depth Information
women. Intermittent treatment also has im-
proved the bone mass in osteoporotic men [
current family of closely structurally related
proteins is encoded by at least
85
].
genes. Four
distinct FGF receptors each a unique gene
product, mediate activity through tyrosine
kinase activity. Each receptor appears to be
activated by all members of the FGF ligand
family. The ligands in general have heparin-
binding activity and, when complexed with
heparin, have improved activity. FGF ligands
regulate a wide variety of cellular functions
and can act as mitogens, chemoattractants,
and mediators of cellular differentiation. FGF
receptor activity appears to directly regulate
the expression of a number of different pro-
teins,
22
) as an ana-
bolic treatment for osteoporosis has been a
major impetus to the use of PTH in bone
healing. PTH administration has enhanced
early fracture healing in parathyroidectomized
rats [
The recent approval of PTH(
1
-
34
63
], with PTH doses ranging from
10
to
200
µ
g/kg having signifi cantly improved the
mechanical and histological aspects of normal
fracture repair in the rat [
]. PTH
analogs have also been shown to reverse the
inhibition of bone healing in ovariectomized
rats [
7
,
88
,
155
112
] and in corticosteroid-treated rabbits
[
) is reported to increase bone
ingrowth and pullout strength in porous metal-
lic implants [
25
]. PTH(
1
-
34
including
metalloproteinases
and
morphogens [
].
The roles played by FGF in skeletal develop-
ment have been elucidated by identifying auto-
somal dominant mutations that constitutively
activate the FGF receptors [
142
,
164
,
165
].
One drawback of the rat studies is that the
hormone doses were much higher than would
be tolerated in humans. To evaluate the clinical
potential of PTH for fracture healing, patient-
appropriate doses of recombinant human para-
thyroid hormone [PTH(
193
]. Mutations
in the receptors lead two types of disorders.
One, in FGFR
191
,
219
, affects axial long-bone
development and leads to the dwarfi ng chon-
drodysplasia syndromes. These include hypo-
chondroplasia [
3
); teriparatide;
Forteo
TM
] were used in a well-established rat
model. As early as day
1
-
34
of this study, calluses
from the group treated with
21
18
], achondroplasia [
191
], and
g/kg of PTH
showed signifi cant increases over controls in
terms of torsional strength, stiffness, bone
mineral content (BMC), bone mineral density
(BMD) and cartilage volume. By day
30
µ
thanatophoric dysplasia [
178
]. The second
group of mutations, in FGFR
, causes a variety
of craniosynostosis syndromes, including the
Apert syndrome [
2
215
] and the Crouzon syn-
35
, both
drome [
]. To date, changes in growth due
to inactivating mutations in individual FGF
ligands have not been identifi ed. This suggests
that the developmental functions of the FGF
ligands involve collaboration among various
molecules.
FGF family signaling pathways play multiple
and essential roles in the early stages of skeletal
patterning and in the recruitment and ultimate
apoptosis of mesenchymal cells. They also
seem to participate in the control of endochon-
dral growth in the axial skeleton and of cranial
bone growth at suture lines. During early limb-
bud development, FGF signaling plays a role in
mesenchymal epithelia [
93
the
g/kg PTH-treated groups
showed signifi cant increases in BMC, BMD, and
total osseous tissue volume; the experimental
groups also showed signifi cant decreases in
void space and cartilage volume. At day
5
-
µ
g and the
30
-
µ
, tor-
sional strength was also signifi cantly increased
in the group treated with
35
30
µ
g of PTH. Even
after
84
days, the group that had received
30
µ
g
of PTH for
days, with treatment discontin-
ued thereafter, exhibited increases in torsional
strength and BMD over comparable control
values. Thus, daily systemic administration of
a low dose of PTH(
21
) enhanced fracture
healing and induced an anabolic effect through-
out the entire remodeling phase.
1
-
34
14 4
]. As a result, FGF-
10
b
in the apical ectodermal ridge. Cells in the
latter then express FGF-
is produced and acts on the FGF receptor
2
8
, which signals back
2.2.5 Other Growth Factors Within
Skeletal Tissues
2.2.5.1 Fibroblast Growth Factor (FGF)
FGFs were originally isolated as oncogenes and
shown to stimulate cell proliferation [
to FGFR
c in the limb mesoderm.
The role of FGF signaling in endochondral
growth has been made apparent by activating
mutations in FGFR
1
. However, the exact effect
of the signaling pathways involved in endo-
chondral development and the downstream
FGF signaling on chondrocytes and osteoblasts
3
196
]. The
