Biomedical Engineering Reference
In-Depth Information
whereas Fas and TNFR
receptors both activate
the apoptotic cascade and carry out compensa-
tory or redundant functions, each receptor
mediates a unique set of biological responses
[
1
126
]. Treatment of human articular chondro-
cytes with FasL in vitro causes apoptosis.
Because the Fas system is present in growth-
plate chondrocytes in vivo, it may play a role in
chondrocyte apoptosis during endochondral
development [
]. Thus failure to initiate the programmed
cell death of one or another population of
immune cells that mediate the transition of the
specifi c stages of an immune response leads to
a variety of systemic autoimmune pathologies
[
229
]. In previous studies, carti-
lage cells within the fracture callus [
6
,
83
] have
been shown to express Fas, and articular chon-
drocytes will undergo programmed cell death
in response to TNF-
224
]. In essence, these cytokines act as the
central arbitrators of a tissue's microenviron-
ment during immune activation. They do so
by promoting the survival of one population
of cells while causing another to undergo
apoptosis.
The TNF-
204
]. The relationship
between the apoptotic process and the normal
progression of endochondral development can
be observed in pathological conditions such as
rickets, as well as in the numerous genetically
engineered defects that affect growth-cartilage
development. The hallmark of almost all of
these defects is either a foreshortening or an
expansion of the growth plates. Two examples
of factors causing an expansion of the growth
plate are vitamin D defi ciency in growing
animals and the genetically engineered abla-
tion of matrix metalloproteinase
α
[
69
family of cytokines has been the
primary focus of many immune function
studies, but the death receptor family also plays
a pivotal regulatory role in many developmen-
tal processes [
α
]. It is interesting that during
postnatal tissue repair and regeneration these
cytokines directly and indirectly regulate many
nonimmune cell types downstream from an
initial immune response [
43
9
(MMP-
9
)
[
]. Ablation of the PTHrP gene, on the other
hand, causes an osteochondrodysplasia,
primarily manifested in an accelerated hyper-
trophy and removal of the chondrocytes. A
phenomenon common to these very different
pathologies of the endochondral process is that
in all three the timing or rate of chondrocyte
apoptosis has been altered. The consequence of
an abnormally timed apoptosis is that the
microenvironment of the endochondral tissue
is altered by retention or loss of the chondro-
cytes. This is important because osteogenesis,
vascular invasion, and marrow formation
follow in sequence as the chondrogenic cells
hypertrophy and undergo apoptosis [
210
]. The signaling
functions by immune cell cytokines during
postnatal tissue repair derive from functions
carried out during embryogenesis. Alterna-
tively, these cells may initiate postnatal repair
or regenerative processes that replace mecha-
nisms that functioned during embryological
development. TNF-
82
thus functions within
skeletal tissues either during the course of
normal skeletal homeostasis or in response to
tissue injury [
α
]. It does so by acting on both
apoptotic and nonapoptotic events within mes-
enchymal cell types found in skeletal tissues.
This includes specifi c types of mesenchymal
precursors [
158
].
Thus, in analogy with their role during the
immune response, the death receptors and
ligands during endochondral development
promote the removal of one cell population
(chondrocytes) and are permissive for osteo-
genic and marrow cell populations to move
into the space previously occupied by the car-
tilage tissue.
120
78
], osteogenic cells [
1
], and syno-
vial fi broblasts [
].
Recent studies have shown that activation of
TNF-
64
,
137
B can affect tissue repair,
response to injury, and arthritic pathology by
specifi cally inducing the expression of mor-
phogenetic factors of the TGF-
α
and/or NF
κ
]. It
may also alter second signal activity of SMADs
that mediate bone morphogenetic protein
(BMP) signaling [
α
family [
64
].
It is now well established that cartilage cells
undergo apoptosis during normal endochon-
dral development and during arthritic disease
[
21
,
36
,
57
2.2.1.2 Role of the TNF-
Family of
Cytokines in Bone Remodeling
As just discussed, embryologic development
and postnatal growth are regulated by ontoge-
netic and systemic hormonal mechanisms.
α
]. Currently, three members of the
TNF family of cytokines have been implicated:
Fas ligand (FasL), TNF-
3
,
4
,
5
,
56
,
72
α
, and TRAIL [
6
,
39
,
83
,
