Biomedical Engineering Reference
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predominantly in mesenchymal condensations
5
and prehypertrophic condrocytes
6
where
α
1(II)
collagen is also expressed. The coexpression of Sox9 and
α
1(II) collagen, an early and abundant
marker of chondrocyte differentiation, implicated that Sox9 may play a role in specifying
chondrocytic lineage. Subsequently, Sox9 was found to bind directly to chondrocytic specific
cis-acting elements in the
α
1(II) and
α
2(XI) collagens and to control the expression of these
genes in cells of the chondrocytic lineage,
7,8
thus providing a direct evidence that Sox9 may be
a regulator of chondrogenesis. The most convincing evidence that Sox9 is required for the
formation of mesenchymal condensation came from mouse genetic studies. Indeed, in chimaeric
mouse embryos, Sox9 -/- embryonic stem (ES) cells but not wild type (wt) ES cells are ex-
cluded from the mesenchymal condensations indicating that Sox9 is required for their forma-
tion. Moreoever, teratomas derived from Sox9 -/- ES cells, but not from wt ES, failed to de-
velop cartilage in mouse chimaeras.
8,9
Interestingly, although Sox9 heterozygous deficient mice
are phenotypically similar to human patients, the severity of the phenotype is more pronounced
in mice than in humans. Sox9 +/- mice die perinatally with cleft palate, hypoplasia and bend-
ing of many long bones. Other abnormalities, such as expanded hypertrophic chondrocyte
zone and premature mineralization of many bones also exist in these mutant animals.
10
These
data suggest that Sox9, in addition to controlling the mesenchymal condensation of cartilage
primordia, may also prevent chondrocytic hypertrophy. The latter action of Sox9 may be me-
diated by a PTHrP signaling pathway.
11
Two other HMG-containing proteins, L-Sox5 and Sox6, are found to be coexpressed with
Sox9 in all precartilaginous condensations and continue to be expressed in hypertrophic
chondrocytes of mouse embryos.
12
In vitro, they bind the chondrocyte-specific enhancer of
a1(II) collagen and induce its expression in non-chondrocytic cells.
12,13
Together with Sox9,
they induce endogenous expression of chondrocyte differentiation marker genes, such as
α
1(II)
collagen, and aggrecan in vivo. L-Sox5 and Sox6 that have no activation domain, have a high
degree of sequence identity to each other but have no similarity to Sox9 except for the HMG-box.
Consistent with their identical pattern of expression, Sox5 and Sox6 have redundant function
in vivo, since single null mutant mice are virtually normal. However, targeted deletion of both
Sox5 and Sox6 leads to embryonic lethality due to a generalized chondrodysplasia,
14
demon-
strating their essential role in control of chondrocyte differentiation. Sox5 and Sox6 are possi-
bly genetically downstream of Sox9 since the chondrogenesis is not completely blocked in the
double mutant animals.
14
The intramembranous bone collars develop normally in double mu-
tant animals
14
ruling out the involvement of these Sox proteins in the control of intramembra-
nous ossification.
A group of nuclear factor of activated T cells (NFATs) are transcription factors that regulate
the expression of many cytokines in lymphocytes
15
and also cardiac valve formation.
16,17
One
of these proteins, NFAT1, whose activity is essential for cardiac valve morphogenesis also modu-
lates chondrogenesis in adult animals. Indeed NFAT1 acts as a repressor of chondrocyte differ-
entiation since its overexpression in chondrocytic cell lines suppresses the expression of mo-
lecular markers of chondrocyte and NFAT1-deficient mice develop fixed joints due to
spontaneous ectopic formation of cartilage after 6 months. The newly formed cartilage con-
tains ordered and columnar chondrocytes with distinct morphologies and is eventually re-
placed by bone, recapitulating the process of endochondral ossification.
18
Curiously NFAT1
mutation affects female more severe than males. These NFAT1-deficient mice provide a good
animal model for studies of age-related skeletal diseases.
Chondrocytic hypertrophy is a mandatory step for endochondral bone development to
occur and core binding factor
α
1 (Cbfa1), or Runx2, is the only transcription factor that has
been demonstrated so far to induce chondrocyte hypertrophy in vivo.
19,20
In cartilage Cbfa1
expression is restricted to prehypertrophic chondrocytes.
20,21
Cbfa1-deficient mice have a de-
layed chondrocyte hypertrophy in many long bones.
22,23
Continuous expression of Cbfa1 in
hypertrophic chondrocytes induced
α
1(X) collagen expression and chondrocytic hypertrophy
in transgenic mice. Moreoever, expression of Cbfa1 in non-hypertrophic chondrocytes in
Cbfa1-deficient genetic background corrected the lack of hypertrophic chondrocytes of these
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