Biomedical Engineering Reference
In-Depth Information
16 CHAPTER 2. CARTILAGE AGINGAND PATHOLOGY
In the sclerotome (the most medial segment of the somites after splitting into three segments)
and the mesenchyme, cells first commit to becoming cartilage cells, causing the surrounding cells to
express Pax1 and scleraxis. These two transcription factors then activate cartilage-specific genes [
100
,
101
]. The cells condense into nodules and differentiate into chondrocytes. The chondrocytes divide
rapidly and secrete cartilage-specific matrix, forming cartilage tissue (Figure 2.1).
Figure 2.1:
Condensation and chondrogenesis. Cells first condensate (red) and differentiate into chon-
drocytes. Boundaries are defined as the perichondrium forms (in yellow), and chondrocytes can further
undergo hypertrophy (green cells) to eventually mineralize to result in bone formation through endo-
chondral ossification.
In response to sonic hedge hog protein (shh), bone morphogenetic proteins (BMPs) regulate
Hox genes [
102
,
103
] to initiate mesodermal cell proliferation and differentiation [
104
]. Msx-1 and
Msx-2 are also involved at this stage as transcriptional repressors [
105
,
106
]. The differentiation
is additionally mediated by epithelial-mesenchymal interactions by TGF-
β
[
107
,
108
]. TGF-
β
participates in condensation by regulating fibronectin [
109
], which in turn regulates N-CAM [
110
],
which was initially thought to be required in maintaining condensation along with the adhesion
molecule N-cadherin [
111
-
113
]. Note that N-CAM is not required in initiating condensation [
110
],
but instead in its maintenance. Also, recent data obtained using organ culture have shown that N-
cadherin-deficient limb buds were capable of mesenchymal condensation and chondrogenesis [
114
],
indicating that N-CAM is not necessary in chondrogenesis, albeit an important player within normal
cartilage development. Within the condensate, cell proliferation and adhesion is modulated by
Hox genes (regulated by BMPs). Other transcription factors that regulate proliferation include
CFKH-1, which regulates TGF-
β
, MFH-1, and osf-2, which is regulated by BMP-7 and vitamin
D3. Syndecan, a receptor that binds to tenascin [
115
] and fibronectin [
116
], inactivates these to
result in inactivated N-CAM, thus setting the boundaries for condensation. Around the condensate,
noggin then binds to BMPs to slow or stop cell proliferation, halting condensate growth [
117
,
118
].
From this point, the cells transition to differentiation via transcriptional activation of Hoxd-11-
13 [
119
]. Within Figure 2.1, the molecular events that transpired above correspond to the point of
chondrogenesis and perichondrium formation. This is a brief presentation of the intricate events
