Biomedical Engineering Reference
In-Depth Information
Fracture and skeletal tissue healing after
surgery, on the other hand, are initiated in
response to regulatory mechanisms associated
with infl ammation and the innate immune
response [
extreme differences in the avascular microen-
vironment of cartilage and bone. Indeed, the
interactions of hematopoietic/lymphopoietic
and osteogenic microenvironments in regulat-
ing bone remodeling are emerging as a major
area of research, and changes in cytokines
that alter lymphopoiesis affect both bone
homeostasis and immune function [
]. Two discrete types of resorp-
tion take place during fracture repair. The fi rst
occurs at the end of the endochondral period,
in the course of which mineralized cartilage is
removed and primary bone is formed. TNF-
16
,
54
30
,
105
,
α
and its receptors remain largely unexpressed
during the initial periods of endochondral dif-
ferentiation, but are expressed as the cartilage
cells hypertrophy and tissue resorption begins.
During this same period, there is an increase
in the concentration of RANKL and osteopro-
tegrin (OPG) (two members of the TNF-
175
,
206
].
2.2.2 The Bone Morphogenetic
Proteins (BMPs)
2.2.2.1 BMPs and Signaling
On the basis of their distinct structural charac-
teristics, BMPs (with the exception of what has
been named BMP-
α
superfamily) as well as macrophage colony-
stimulating factor (M-CSF), all key regulatory
factors in osteoclastogenesis [
]. However,
other cytokines that are associated with bone
remodeling, including interleukin
118
) are members of the trans-
forming growth factor
1
) superfamily.
This family also includes activins, inhibins,
and growth and differentiation factors (GDFs).
BMP-
β
(TGF-
β
1
α
(IL-
1
α
),
IL-
], are not expressed. The
other type of resorption occurs during second-
ary bone formation, which follows the endo-
chondral phase. These events are comparable
to the process of coupled remodeling seen in
normal bone homeostasis. During this period,
expression of IL-
1
β
, and IL-
6
[
115
belongs to the astacin family of
metalloendopeptidases and exhibits BMP-like
activity by proteolytically activating mixtures
that contain the proforms of BMP.
The TGF-
1
superfamily of pre-proproteins
displays extensive amino acid sequence homol-
ogy across species and can carry out a wide
diversity of biological functions. The proteins
share a characteristic pattern of seven con-
served cysteine residues within the carboxy-
terminal mature region that are essential for
the formation of cysteine knot domains. This
tertiary protein structure is thought to be criti-
cal for receptor interaction [
β
increases, whereas
the levels of OPG, M-CSF, and RANKL
decline.
These data suggest that the processes medi-
ating endochondral resorption and the more
prolonged phase of secondary bone remodeling
differ and that the resorption of the mineral-
ized cartilage is more dependent on the activi-
ties of M-CSF, OPG, and RANKL. In contrast,
bone remodeling appears to depend on the
levels of RANKL and to be coregulated by the
activities of the cytokines IL-
1
and IL-
6
]. The mature-
region cysteines are also important in the
formation of intermonomeric disulfi de bonds
necessary for the formation of physiologically
functional dimers [
220
1
, IL-
6
, and TNF-
α
found in bone marrow. Differences between
bone and cartilage remodeling are apparent
from studies of RANKL (TRANCE)-defi cient
mice and of mice whose RANKL expression
was rescued by engineering RANKL expression
in their lymphocytes. When RANKL was
expressed by lymphocytes in the knockout
mice, their osteopetrosis was overcome and
osteoclast development was promoted. However,
it was not possible to correct the chondrodys-
plasia of the epiphyseal and metaphyseal
regions. The authors therefore concluded that
cartilage and bone possess different mecha-
nisms that induce RANKL expression [
]. As in most secreted
proteins, there are numerous potential N-
linkage glycosylation sites located throughout
the amino acid sequence. Most BMPs induce
some level of glycosylation, which varies among
species, with mouse BMP inducing the lowest
and bovine BMP inducing the highest degree of
glycosylation [
119
].
As an example of a typical BMP structure,
BMP-
183
,
212
2
is translated as a
396
-amino-acid pre-
p r o p r ot e i n t h a t c o nt a i n s a
-amino-acid signal
sequence for targeted secretion, a
19
263
-amino-
acid proregion, and a
-amino-acid mature
segment. Within the mature region of BMP-
114
].
In this context it is interesting to note the
114
,
seven cysteines and one N-linked glycosylation
2
