Biomedical Engineering Reference
In-Depth Information
matrix was capable of inducing endochondral bone for-
mation when implanted ectopically into soft tissues of
experimental animals
[24]
. Urist and colleagues sub-
sequently discovered that lowMW glycoproteins isolated
from bone were responsible for the osteogenic activity
observed earlier and were capable of inducing bone for-
mation when delivered to ectopic or orthotopic loca-
tions. Wozney
et al.
and Celeste
et al.
subsequently
cloned the first bone morphogenetic proteins: BMP-2,
BMP-3, and BMP-4. Ozkaynak
et al.
, using similar tech-
niques, cloned BMP-7 and BMP-8. At least 15 BMPs have
been identified, many of which can induce chondro-
osteogenesis in various mammalian tissues. The BMPs are
homodimeric molecules (MW: 25-30 kDa) that regulate
various cellular functions such as bone induction, mor-
phogenesis, chemotaxis, mitosis, hematopoiesis, cell
survival, and apoptosis. With the exception of BMP-1,
which is a protease that possesses the carboxy-terminal
procollagen peptide, BMPs are part of the transforming
growth factor (TGF)-b superfamily and play a major role
in the growth and development of several organ systems,
including the brain, eyes, heart, kidney, gonads, liver,
skeleton, skeletal muscle, ligaments, tendons, and skin.
Although the sequences of members of the TGF-b su-
perfamily vary considerably, all are structurally very sim-
ilar. The BMPs are further divided into subfamilies based
on phylogenetic analysis and sequence similarities: BMP-2
and -4 (dpp subfamily); BMP-3; BMP-5, -6, -7, -8A, and
-8B (60A subfamily). And BMP-6 is characteristically
expressed in prehypertrophic chondrocytes during em-
bryogenesis. Several investigators have reported that
BMP-6 plays a role in chondrocyte differentiation both
in vivo
and
in vitro.
When involved in osteoinduction,
BMPs have three main functions. First, BMPs act as a
chemotactic agent, initiating the recruitment of progenitor
and stem cells toward the area of bone injury. Second,
BMPs function as growth factors, stimulating angiogenesis
and proliferation of stem cells from surrounding mesen-
chymal tissues. Third, BMPs function as differentiation
factors, promoting maturation of stem cells into chon-
drocytes, osteoblasts, and osteocytes.
in vivo,
such as embryonic development, angiogenesis,
osteogenesis, chondrogenesis, and wound repair. The
FGF superfamily consists of 23 members, all of which
contain a conserved 120-amino-acid core region that
contains six identical, interspersed amino acids. The su-
perfamily members act extracellularly through four ty-
rosine kinase FGF receptors, with multiple specificities
noted for almost all FGFs. The FGFs are considered to
play substantial roles in development, angiogenesis, he-
matopoiesis, and tumorigenesis. Human FGF-2, other-
wise known as basic FGF, HBGF-2, and EDGF, is an 18
kDa, non-glycosylated polypeptide that shows both in-
tracellular and extracellular activity. The FGFs are stored
in various sites of the body under interactions with
GAGs such as heparin and heparan sulfate in the ECM.
And FGF-2 binds to heparin and heparan sulfate with
a high affinity. These GAGs stabilize FGF-2 by
protecting from inactivation by acid and heat as well as
from enzymatic degradation. Also, heparin enhances the
mitogenic activity of FGF-2 and serves as a cofactor to
promote binding of FGF-2 to high affinity receptors.
7.2.7.1.3 VEGF
Of many unknown angiogenic factors, VEGF is unique in
that it is the only known cytokine with mitogenic effects
primarily confined to endothelial cells. The VEGF is
produced by a variety of normal and tumor cells. Its ex-
pression correlates with periods of capillary growth during
embryologic development, wound healing, and the female
reproductive cycle, as well as with tumor expansion. In
addition, suppression of VEGF expression in adult mice
or neutralization of VEGF receptors suppresses tumor
growth, while VEGF
mice are mortal
in utero.
Conse-
quently, VEGF is thought to be a major promoter of both
physiologic and pathologic angiogenesis. Furthermore,
VEGF has been shown to be an anti-apoptosis survival
factor for endothelial cells even during periods of micro-
vessel stasis. In addition, VEGF can enhance tissue se-
cretion of a variety of pro-angiogenic proteases, including
uPA, MMP-1, and MMP-2. It has also been shown that
inhibition of VEGF or the VEGF-R2 receptor can sup-
press expression of MMP-2 and MMP-3.
The development of blood vessels includes two pro-
cesses. Vasculogenesis is the embryonic formation of
blood islands, the earliest vascular system, by the dif-
ferentiation from mesoderm of angioblasts and hemato-
poietic precursor cells (HPCs). Angiogenesis is the
sprouting of pre-existing vessels to form the vascular
tree. In addition to a key role in embryonic development,
angiogenesis is essential in such things as wound healing
and tumor growth. While many growth factors exhibit
angiogenic activity (FGFs, PDGF, TGF-a, HGF, and
P/GF), most evidence points to a special role for VEGF.
The VEGF is a dimeric glycoprotein that stimulates en-
dothelial
7.2.7.1.2 FGFs
The function of FGFs is not restricted to cell growth.
Although some of the FGFs induce fibroblast pro-
liferation, the original FGF (FGF-2 or basic FGF) is now
known also to induce proliferation of endothelial cells,
chondrocytes, smooth muscle cells, melanocytes, as well
as other cells. It can also promote adipocyte differenti-
ation, induce macrophage and fibroblast IL-6 production,
stimulate astrocyte migration, and prolong neural sur-
vival. The FGFs are potent modulators of cell pro-
liferation, motility, differentiation, and survival, and play
an important role in normal regeneration processes
cells,
induces
angiogenesis
and increases
