Biomedical Engineering Reference
In-Depth Information
acids and have a coil domain that is separated
by a hinged region from a fi brinogen-like
domain. Angiopoietins exist as multiple splic-
ing variants and only interact with the Tie
ablation strategies to assess the contribution of
vessel formation to new bone formation.
Administration of a soluble VEGF receptor
1
-
2
immunoadhesin, mFlt(
)-IgG, completely
blocked new vessel formation in the growth
plates of mice and impaired chondrocyte apop-
tosis and trabecular bone formation [
1
-
3
receptor.
Angiopoietins bind to Tie
receptors,
a tyrosine kinase with immunoglobulin and
epidermal growth factor homology domains.
Ligand binding induces receptor dimerization,
which causes autophosphorylation of the recep-
tor, thereby activating its kinase signaling [
1
and
2
66
].
Studies by Gerber et al. (
) have identifi ed
VEGF as the key factor that regulates capillary
invasion, growth-plate morphogenesis, and
cartilage remodeling. In mice, systemic inhibi-
tion of VEGF during periods of rapid growth
has led to inhibition of angiogenesis and to a
decrease in the number of chondroclasts/osteo-
clasts/osteoblasts at the growth plates. Chon-
droclasts/osteoclasts belong to the monocyte
cell lineage, express VEGFR, and migrate in
response to VEGFR
66
143
].
Other studies have shown that the Tie
recep-
tor is proteolytically modifi ed when endothe-
lial cells interact with VEGF. This suggests
some coordination between the signaling
events that are mediated by angiopoietins and
VEGF. Interestingly, although the Tie receptors
are tyrosine kinases, they do not signal through
the MAP kinase system used by VEGF, but
appear to recruit various phosphatases selec-
tively, including SHP
1
1
-selective ligands. This
indicates that VEGFR
1
has a role in monocyte
migration [
]. Because osteoblasts express
both VEGF receptors and neuropilin
15
, a factor that promotes
cell migration by altering activities of focal
adhesion kinases.
2
], the
decrease in osteoblasts at the growth plates in
anti-VEGF-treated mice refl ects an impairment
of VEGFR or neuropilin signaling. This in turn
has impaired recruitment and/or differentia-
tion of these cell types. Thus, VEGF contrib-
utes importantly not only to angiogenesis, but
also to osteogenesis. In mice lacking the VEGF
gene, the long bones demonstrate a disturbed
vascular pattern at birth, consistent with
reduced bone growth [
1
[
80
2.2.3.3 The Role of Angiogenic Factors in
Bone Development
Angiogenesis is important during intramem-
branous and endochondral bone formation.
Vascularization of the growth plate contributes
to the coupling of chondrogenesis and osteo-
genesis. Chondrocyte apoptosis and osteoclast
recruitment and activation are essential termi-
nal stages of cartilage hypertrophy. The osteo-
clasts resorb the mineralized cartilage and
thereby permit bone formation by osteoblasts.
Morphological evidence suggests that chon-
drocyte apoptosis occurs readily following the
invasion of endothelial cells [
]. Osteoblast and
hypertrophic chondrocyte development are
also impaired [
140
].
VEGFs play an important role in regulating
bone remodeling. They do so by attracting
endothelial cells, osteoblasts, and osteoclasts
[
140
] and by autocrine regulation of chon-
drocyte function [
46
,
147
]. Local administration of
VEGF also enhances osteoclast number [
33
].
Further linkage between VEGF and bone for-
mation was recently described by studies in
which hypoxia was shown to drive BMP expres-
sion through VEGF [
100
] and that
chondrocyte death is induced by diffusible
factors that arise either from the vasculature or
from hematopoietic elements brought in during
angiogenesis [
56
,
90
]. A number of recent
studies have also shown that BMPs stimulate
the expression of VEGF by osteoblasts and
osteoblast-like cells [
27
]. The newly developing
blood vessels in addition establish the conduit
for the cells that form primary bone following
resorption of the mineralized trabeculae of
cartilage [
71
,
72
]. Finally, the tissue-
specifi c regulation of VEGF expression during
bone development seems to be dependent on
the expression of Cbfa
47
,
222
].
The interrelationship between blood-vessel
formation and osteogenesis has been studied
by various approaches aimed at inhibiting
VEGF signaling. Because mice whose VEGF
has been ablated die as embryos, studies have
utilized inhibitors of VEGF signaling or select
59
, known as the
key transcriptional factor that regulates the
commitment of mesenchymal cells to the skel-
etal-cell lineage [
1
/Runx
2
]. Taken together, these
fi ndings provide a considerable body of evi-
dence in support of the concept that VEGF
226
