Biomedical Engineering Reference
In-Depth Information
mediates bone formation by direct stimulation
of osteogenesis and indirectly by its effects on
vascularization.
healing studies, showed that during fracture
healing Ang
was the factor with the highest
expression. Unlike the VEGF family, which
promotes new vessel formation by stimulating
endothelial cell division, Ang
2
promotes desta-
bilization and regression of blood vessels in the
absence of VEGF A or bFGF [
2
2.2.3.4 The Role of Angiogenic Factors in
Tissue Healing
Fracture healing and bone or tissue repair
result in an up-regulation of blood fl ow, so that
bone regeneration can occur within the callus
or repair tissues [
87
,
135
,
141
].
Recent fi ndings have suggested that Ang
,
along with VEGF, promotes new vessel forma-
tion by inducing remodeling of the capillary
basal lamina and by stimulating endothelial-
cell sprouting and migration [
2
]. The importance
of vascularization during fracture repair was
confi rmed by studies showing that broad-
spectrum angiogenic inhibitors completely
prevented fracture healing, callus formation,
and the formation of periosteal woven bone
[
10
,
52
,
179
141
]. This sug-
gests that Ang
expression plays a role similar
to that of VEGF in bone repair. By itself, Ang
2
2
inhibits blood-vessel formation, but in combi-
nation with VEGF it stimulates new vessel for-
mation and plasticity in existing vessels.
These studies also pointed to collaborative
interactions between VEGI (vascular endothe-
lial growth inhibitor)-induced angiogenesis
and the TNF-
]. In contrast, treatment of healing frac-
tures with VEGF improved bone healing and
led to more rapid mineralization of the callus
and regaining of mechanical strength [
84
,
195
].
The role angiogenesis plays in osteogenesis
following distraction rupture has been exten-
sively studied with the aid of an artifi cially pro-
duced gap following osteotomy. When this
technique is used, new bone forms primarily
via an intramembranous mechanism with
extensive revascularization of the regenerated
bone. Within the marrow space, venous sinu-
soids are formed that parallel the newly grown
trabeculae. Analysis of experimental models of
osteogenesis following distraction has revealed
an early intense vascular response, with the
newly formed vessels maturing into sturdier
vessels capable of withstanding the tensile
forces that are generated in the distraction gap
[
195
family of regulators. Interac-
tion of VEGI with death receptor
α
and the
primary regulator of the progression of vascu-
larization refl ects a dual role: maintaining
growth arrest of endothelial cells in G
4
1
interfaces, while at the same time inducing
apoptosis in cells that enter the S phase [
0
/G
79
,
225
,
227
]. Taken together, these results suggest that,
after injury, vessels are dissociated into a pool
of nondividing endothelial cells through the
actions of Ang
. They are then are held in this
state through the actions of VEGI, which stim-
ulates apoptosis of all cells that enter the S
phase. When endochondral remodeling is
initiated, VEGF levels rise, stimulating cell
division and allowing endothelial cells to con-
tribute to neoangiogenic processes. The concept
of controlled cell regression and growth is also
consistent with the role that angiopoietin is
thought to play in blood-vessel formation [
2
].
As discussed above, angiogenesis appears to
involve two separate pathways: a VEGF-depen-
dent pathway and an angiopoietin-dependent
pathway. Interestingly, both Ang
129
,
179
2
have been identifi ed in bone cells during devel-
opment [
1
and Ang
87
].
] and in bone cells that arise in
osteogenesis following distraction and fracture
healing [
89
2.2.4 Parathyroid Hormone (PTH)/
Parathyroid Hormone-Related
Peptide (PTHrP) and
PTHrP Signaling
2.2.4.1 PTH Versus PTHrP: Endocrine Versus
Paracrine Effects
PTH, a peptide, is an hormone that is synthe-
sized by the parathyroid gland. The mature
]. Indeed, in studies of mice
that had undergone distraction fracture, Ang
34
,
127
,
128
1
,
Ang
, and their Tie receptors were expressed
throughout healing at the same time that VEGF
A and VEGF C were expressed. These regula-
tors of angiogenesis were expressed throughout
the chondrogenic phase of healing, reaching
maximum levels during the late phases of
endochondral remodeling and during bone
formation. These studies, as well as fracture-
2
