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Hinton - 2014 - Histología y Genes Que Regulan El Crecimiento de La ATM
Hinton - 2014 - Histología y Genes Que Regulan El Crecimiento de La ATM
Hinton - 2014 - Histología y Genes Que Regulan El Crecimiento de La ATM
DOI: 10.1002/DVDY.24130
REVIEW
Robert J. Hinton*
Department of Biomedical Sciences, Texas A&M Baylor College of Dentistry, Dallas, Texas
Compared with the joints of the limbs, our understanding of the genes that regulate development and growth in the tempo-
romandibular joint (TMJ) is fairly limited. Because the morphogenesis of the secondary cartilage and other intra-articular struc-
tures in the TMJ occurs later and in a different manner than in the limbs, the genetic control of TMJ development might
reasonably be assumed to differ from that in the limbs. However, studies of the specific genes regulating TMJ morphogenesis
and growth have only begun to appear in the literature within the last decade. This review attempts to survey and interpret
the existing knowledge on this topic and to suggest fruitful avenues of investigation for the future. Studies to date using
knockout and over-expression of candidate genes suggest that a developmental hierarchy of joint structures exists, with
DEVELOPMENTAL DYNAMICS
condyle development primary. A hierarchy of gene expression also exists: Runx2 and Sox9 expression is critical for condylar
cartilage formation. Several of the other genes discussed in this report may regulate TMJ morphogenesis by affecting
Sox9 and Runx2 expression and control the ihh-PTHrP axis by means of these genes. Developmental Dynamics 00:000–000,
2014. VC 2014 Wiley Periodicals, Inc.
Key words: temporomandibular joint; development; gene expression; condylar cartilage; mandibular fossa; articular disc
Submitted 30 January 2014; First Decision 11 March 2014; Accepted 17 March 2014; Published online 00 Month 2014
Fig. 1. Continuity of perichondrium in mandibular condylar cartilage et al., 1980; Glineberg et al., 1982), reduced loading (Bouvier and
with periosteum of adjacent ramus in growing (postnatal) rat. Note how Hylander, 1984; Hinton, 1998), and placement in a nonfunctional
the fibrous layer of the periosteum (long arrows) on the condylar neck environment (Duterloo and Wolters, 1971; Petrovic et al., 1975;
is continuous with the articular layer of the condylar cartilage (long Englesma et al., 1980).
arrows). Similarly, note how the osteogenic layer of the periosteum
(short arrows) is continuous with the prechondroblastic layer of the
In light of this unusual manner of development and the dis-
condylar cartilage (short arrows). Alcian blue stain. tinctive characteristics of the dividing cells in the MCC, it would
not be surprising if the molecular determinants of development
relatively undifferentiated (prechondroblastic) (Fig. 2) secrete a and growth of the TMJ were somewhat different from those in
matrix rich in type I collagen rather than the type II collagen primary cartilaginous joints. However, studies of the specific
matrix secreted by chondrocytes (Silberman et al., 1987; Mizogu- genes regulating TMJ morphogenesis and growth have only
chi et al., 1990). It is these relatively undifferentiated cells of the begun to appear in the literature within the last decade, although
prechondroblastic zone of the perichondrium, not the chondro- many of these developmental and structural differences have
cytes in deeper layers, that proliferate and mature to effect been known for years. To a significant degree, this recognition
growth at the mandibular condylar cartilage (Petrovic et al., may reflect a belated examination of the TMJ in existing trans-
1975; Carlson et al., 1980). Unlike the proliferative chondrocytes genic and gene knockout models, prompted by a realization of
of primary cartilaginous joints (inset, Fig. 2), the prechondrocytes the peculiarities of this “dental” joint. The present study is an
in the condylar cartilage exhibit a dual potential, forming either attempt to synthesize what we have learned from these models
cartilage or bone, depending on the mechanical forces impinging and to reflect on what we still need to know.
on the tissue (Glineberg et al., 1982; Lydiatt and Davis, 1985).
This phenotypic lability is underscored by the expression of both Genes Affecting Morphogenesis of the TMJ
Sox9 and Runx2 RNA (markers for the chondrogenic and osteo-
genic pathways, respectively) in the mesenchymal cell condensa- The formation of the temporomandibular joint in the mouse (Fig.
tion and later in the prechondroblastic cells of the developing 3) largely resembles the sequence that occurs in humans: the
MCC (Shibata et al., 2006) and by the preferential localization of appearance of mesenchymal condensations that will become the
the cell fate mediators Notch and Twist to these cells (Serrano condyle, mandibular fossa, and articular disc (embryonic day [E]
et al., 2011). Because the localized transformation of a periosteum 13.5), followed by the differentiation of chondrocytes in the
to a perichondrium is thought to occur in regions subjected to deeper layers of the MCC (E15.0) and bone formation in the man-
biomechanical forces or low oxygen tension (Hall, 1972), second- dibular fossa. The process finishes with the formation of the artic-
ary cartilages can shrink or be replaced by bone if the evoking ular disc and the upper and lower joint cavities (E17.5) (Shibata
stimulus is reduced or eliminated. Numerous examples of this et al., 1996; Gu et al., 2008). The inactivation of several genes
lessening or loss of the cartilaginous phenotype have been docu- has been shown to result in the absence or major diminution of
mented for the MCC in response to lack of movement (Carlson structures at each of these developmental stages.
GENES AND TEMPOROMANDIBULAR JOINT 3
Mandibular Fossa
Only two studies have reported a malformed or absent mandibu-
lar fossa. One of these is the Sox9 knockout described above
(Wang et al., 2011). Taking advantage of the fact that the man-
dibular fossa is derived from cranial neural crest cells but does Fig. 3. A: Temporomandibular joint at blastematic stage showing con-
not express Sox9, Wang et al. were able to examine fossa devel- dylar (CO) and temporal (T) blastemas separated by less dense mesen-
chyme that will form the future disc. Mandibular bone, MB. Mouse,
opment in the absence of the mandibular condyle. Although the
embryonic day 15. Hematoxylin and eosin, sagittal section. B: Temporo-
mesenchymal condensation for the fossa formed normally at mandibular joint at cavitation stage illustrating chondro-differentiation of
E14.5, it experienced a delay in ossification (expression of condylar cartilage and formation of joint spaces in progress. Superior
Runx2) and began to gradually regress, so that only a small bit of joint space is evident (upper right), but inferior joint space is not yet
bone remained laterally at day E18.5 (Fig. 4J). Thus, the mandib- formed. CC, condylar cartilage; AD, articular disc; LPM, lateral pterygoid
muscle; TB, temporal bone. Mouse*, embryonic day 17. Hematoxylin
ular fossa was not congenitally absent but rather failed to sustain and eosin, sagittal section. *The superior joint space forms earlier in a
its development and actually regressed over time. The authors mouse, opposite the human condition. C: Temporomandibular joint at
were able to further test this relationship by using two mouse maturation stage. Both inferior and superior joint spaces are fully
models that were “natural experiments”: one in which the devel- formed, lateral pterygoid muscle is attached to condylar neck and articu-
oping condyle becomes dislocated from the developing mandibu- lar disc begins to resemble postnatal form. CC, condylar cartilage; AD,
articular disc; LPM, lateral pterygoid muscle; TB, temporal bone. Mouse,
lar fossa and one in which a greatly enlarged Meckel’s cartilage embryonic day 19. Hematoxylin and eosin, sagittal section.
displaces the condyle from its normal position relative to the
mandibular fossa. Dislocation of the mandibular condyle from
the mandibular fossa (mimicking the absence of the condyle) fossa permitted normal fossa development to continue. These
once again resulted in the arrested development of the fossa, experiments suggest that normal fossa development depends on
while the presence of Meckel’s cartilage in articulation with the normal condyle development.
4 HINTON
perichondrial cells of the TMJ. Examination of the gene expres- Frizzled 4 (8), are highly expressed in the perichondrium (Ser-
sion in the perichondrial (PC) and underlying cartilaginous (C) rano et al., in press).
portions of the MCC micro-dissected from 2-day-old mouse con- An additional indication that b-catenin signaling affects
dylar cartilages using a gene array permits the identification of cells similar to MCC prechondroblasts arises from its effect on
genes that are preferentially expressed in the perichondrium superficial zone (SFZ) cells in the articular cartilage. These cells
(Hinton et al., 2009). Use of an array profiling 84 genes related to have gene expression and phenotypic profiles distinct from
the Notch signaling pathway indicated that the perichondrium of those of the underlying articular chondrocytes and exhibit
the MCC was enriched in many Notch signaling pathway genes chondro-progenitor properties with a strong capacity for prolif-
(Serrano et al., in press). Genes with considerably higher expres- eration over time (Yasuhara et al., 2011). The activation of b-
sion in the PC sample compared with the C sample included catenin signaling caused a strong increase in proliferation and
Notch 3 and Notch 4 (5, 3.5), their ligands Jagged 1 and 2 lubrican expression in these cells, whereas the ablation of b-
(4, 5), and other regulators of Notch ligand specificity and catenin signaling produced the opposite effects. Although the
downstream signaling, such as MFNG (7), Deltex (13), and SFZ cells still retain the properties of articular chondrocytes, it
presenilin enhancer 2 (4). Another notch receptor, Notch1, has is interesting that they represent a chondro-progenitor cell pop-
been shown using immunohistochemistry to be localized in the ulation phenotypically labile in response to varying levels of b-
superficial layers of the MCC, most prominently in the prechon- catenin signaling. Moreover, these progenitor cells express the
droblastic layer (Serrano et al., 2011). Moreover, Notch1 expres- Notch1 receptor, which mediates their proliferation (Dow-
sion in the MCC explants from E17 mice was up-regulated by thwaite et al., 2004).
DEVELOPMENTAL DYNAMICS
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