Biomedical Engineering Reference
In-Depth Information
vated: the Wnt/
-catenin (canonical) pathway,
the Wnt/Ca
2
+
pathway, and the Wnt/polarity
pathway. The latter two are defi ned as nonca-
nonical [
β
110
a expression was analyzed in
a murine knockout model, severe skeletal
defects were observed [
]. When Wnt
3
91
,
198
]. Studies of the
]. It is of interest that a given Wnt
protein can activate more than one signaling
cascade. The canonical pathway involves stabi-
lization of
11
direct effects of Wnt
on mesenchymal stem
cells (MSCs) demonstrated that exogenous
addition of Wnt
3
to murine MSCs inhibited
osteogenic differentiation and decreased matrix
mineralization; however, the suppression of
osteogenesis can be fully reversed when Wnt
3
-catenin, followed by translocation
to the nucleus where transcription genes are
activated via the TCF/LEF
β
1
family of transcrip-
3
a
tion factors [
].
The noncanonical signaling is not as well
understood, though studies in
Drosophila
and
C. elegans
are being continued. The Wnt/Ca
2
+
pathway is thought to induce an increase in
intracellular Ca
2
+
and activation of PKC, but
further signaling steps have not yet been iden-
tifi ed. Genetic studies in
Drosophila
indicate
that the c-Jun N-terminal kinase (JNK) pathway
is involved in the Wnt/polarity pathway, which
in turn regulates cell polarity by controlling
cytoskeletal organization, utilizing at some
stage the disheveled (Dsh) scaffold protein [
24
is removed.
The noncanonical effects of Wnt signaling
have been examined through studies of Wnt
5
.
In contrast to the inhibitory effects of Wnt
3
a,
Wnt
appeared to promote osteogenic differ-
entiation of the MSCs. These fi ndings suggest
that canonical Wnt signaling functions to
maintain an undifferentiated, proliferative
MSC population, whereas the noncanonical
Wnts stimulate osteogenic differentiation [
5
24
].
Interestingly, ectopic expression of Wnt
a
delayed chondrocyte maturation and collagen
type X expression, processes involved in carti-
lage formation [
5
11
].
The exact mechanism by which the LRP-
5
and
].
Many questions remain on the functional
role of the Wnts, their receptors, their intracel-
lular signaling, and their possible interaction
with other morphogenic factors, such as the
TGF-
81
,
109
-
coreceptors function is not understood, but
they are essential for appropriate signaling.
Loss of function of Arrow, the
Drosophila
analog to the vertebrate LRP receptor, mimics
the wingless mutation that was fi rst observed
in the early
6
β
family.
s and therefore provides
evidence for the synergism between these
receptors [
1980
].
The roles Wnt signaling plays during skeletal
development and postnatal bone repair were
recognized as a result of mutations in humans.
One is the autosomal recessive disorder osteo-
porosis pseudoglioma, characterized by low
bone mass, frequent deformations and frac-
tures, and defects in eye vascularization, all of
which are linked to mutations in LRP-
200
2.3 Origins of Postnatal
Skeletal Stem Cells,
Cytokines, and
Morphogenetic Signals
During Bone Repair
].
Children with osteoporosis pseudoglioma
have normal endochondral growth and bone
turnover, but their trabecular bone volume
is signifi cantly decreased [
5
[
73
Bone is unique in that after fracture or surgery,
it can regenerate the original structure and bio-
mechanical competency of the damaged tissue.
Bone repair involves four stages that overlap
and cause the various tissue types to interact,
as shown in Fig.
]. Furthermore,
gain-of-function experiments in humans and
in mouse models have shown that organisms
with an activated LRP-
106
5
mutation exhibit a
high bone mass [
].
Because the canonical signal transduction
pathway is fairly well known, Wnt
12
. The fracture line in the
bone determines the spatial relationships of the
morphogenetic fi elds during tissue regenera-
tion. This is evidenced by the development of
two circular centers of cartilage (ECB) that
form symmetrically with respect to the fracture
line and taper proximally and distally along the
2
.
1
a was
studied in transgenic mice. Previous studies
had shown that Wnt
3
a acts in the apical ecto-
dermal ridge of the limb bud to keep cells in an
undifferentiated and proliferative state [
3
108
,
