Biomedical Engineering Reference
In-Depth Information
ment, but its function is redundant with that of
other BMPs, since knockout animals survive
through gestation. However, BMP-
extraskeletal sites induces de novo formation
of cartilage and bone [
]. This seminal obser-
vation led to investigations culminating in the
extensive purifi cation of the osteoinductive
activity of demineralized bone matrix (DBM)
and the sequencing and cloning of the individ-
ual BMPs [
203
-defi cient
mice die shortly after birth because their
kidneys do not develop normally [
7
]. In situ
hybridization analysis has shown that the
absence of BMP-
86
affects the expression of
molecular markers of nephrogenesis, such as
Pax-
7
]. The subsequent expres-
sion of BMPs in recombinant systems permitted
their use in a variety of animal models, in par-
ticular to demonstrate their stimulating effects
on the repair of fracture and skeletal defects
[
35
,
166
,
217
2
and Wnt-
4
, between
12
.
5
and
14
.
5
days
postcoitum [
-defi cient
mice have defects in the eye that appear to
originate during lens development. Skeletal
patterning defects affect the rib cage, the skull,
and the hind limbs; this shows the wide infl u-
ence BMPs have in mammalian development
[
138
]. In addition, BMP-
7
]. Even though exogenous BMPs may
enhance fracture healing, our understanding
of their role in skeletal repair and regeneration
remains incomplete.
Using reverse-transcriptase polymerase
chain reaction (PCR) amplifi cation, Nakase
et al. were the fi rst to demonstrate the temporal
and spatial distribution of BMP-
53
,
67
,
221
]. The importance of BMPs, however, is
restricted neither to skeletal development nor
to prenatal development. BMP-
138
expression has
been reported to be critical for both extraem-
bryonic and embryonic development [
2
4
in fracture
101
], with
healing [
]. In an investigation using a mono-
clonal antibody against BMP-
157
BMP-
shown to be essential for cranial neural
crest production. Without it, the skeletal and
neural derivatives failed to develop. The im-
portance of BMPs during development has
been most extensively studied in
Xenopus
. If
BMP-
2
,
Bostrom et al. delineated the expression of
these BMPs over a
2
and BMP-
4
4
-week period of fracture
healing [
] have
shown that specifi c members of the TGF-
26
]. Recently, Cho et al. [
38
β
superfamily, including the BMPs, may act in
combination to promote the various stages of
intramembranous and endochondral bone for-
mation observed during fracture healing.
Using ribonuclease protection analysis, this
study demonstrated that BMP-
signaling is disrupted transgenically by
expression of a dominant negative form of its
receptor, the ventral mesoderm is converted to
a dorsal mesoderm [
4
]. In situ hybridization
in
Xenopus
showed that BMP-
197
is expressed in
a spatially and temporally restricted manner.
Disruption of the pattern of BMP-
4
2
has an early
expression
by localized microinjections of rhBMP-
4
peak in expression on day
1
of fracture healing.
4
severely disturbed embryonic development
[
This suggests that BMP-
may be the most
upstream mediator in the cascade of BMP
expression. BMP-
2
]. These experiments make it clear that
BMP-
49
appeared to be preferen-
tially associated with intramembranous bone
formation, whereas BMP-
3
regulates dorsal-ventral patterning in
terms of both location and temporal expres-
sion. As a morphogen, BMP-
4
may
function in osteoblast recruitment during both
intramembranous and endochondral ossifi ca-
tion. Taken together, these studies suggest that
the coordinated expression of multiple BMPs
and their receptors during fracture healing is
important in both skeletal development and
skeletal repair. However, the roles of specifi c
BMPs during fracture healing need to be
investigated.
4
, -
7
, and -
8
modulates meso-
dermal patterning by establishing concentration
gradients that cells detect during migration.
Further evidence of the signifi cant role active
BMPs play in the control of differentiation
comes from experiments that have examined
the regulation and responsive expression of
specifi c BMP antagonists, such as Noggin [
4
44
,
49
]. The coordinated expression of BMP antag-
onists interferes with BMP function in somite
and limb development [
172
,
190
].
2.2.3 Angiogenic Factors
2.2.2.3 BMP Function in Skeletal Repair
In
Angiogenesis is the process by which new blood
vessels are formed from pre-existent vessels.
It is important for almost all embryological
, Marshall R. Urist demonstrated that
the implantation of demineralized bone at
1965
