Journal of Dental Research

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The Adaptive Remodeling of Condylar Cartilage−− A Transition from Chondrogenesis to Osteogenesis

G. Shen and M. Ali Darendeliler
J DENT RES 2005 84: 691
DOI: 10.1177/154405910508400802

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International and American Associations for Dental Research

 CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE
The Adaptive Remodeling of Condylar Cartilage—
A Transition from Chondrogenesis to Osteogenesis
G. Shen* and M. Ali Darendeliler
Discipline of Orthodontics, Faculty of Dentistry, Sydney Dental
Hospital, The University of Sydney, 2 Chalmers Street, Surry Hills,
NSW 2010, Australia; *corresponding author,
gshe6437@mail.usyd.edu.au
J Dent Res 84(8):691-699, 2005
ABSTRACT
Mandibular condylar cartilage is categorized as articular
cartilage but markedly distinguishes itself in many
biological aspects, such as its embryonic origin,
ontogenetic development, post-natal growth mode, and
histological structures. The most marked uniqueness of
condylar cartilage lies in its capability of adaptive
remodeling in response to external stimuli during or after
natural growth. The adaptation of condylar cartilage to
mandibular forward positioning constitutes the
fundamental rationale for orthodontic functional therapy,
which partially contributes to the correction of jaw
discrepancies by achieving mandibular growth
modification. The adaptive remodeling of condylar
cartilage proceeds with the biomolecular pathway
initiating from chondrogenesis and finalizing with
osteogenesis. During condylar adaptation, chondrogenesis
is activated when the external stimuli, e.g., condylar
repositioning, generate the differentiation of mesenchymal
cells in the articular layer of cartilage into chondrocytes,
which proliferate and then progressively mature into
hypertrophic cells. The expression of regulatory growth
factors, which govern and control phenotypic conversions
of chondrocytes during chondrogenesis, increases during
adaptive remodeling to enhance the transition from
chondrogenesis into osteogenesis, a process in which
hypertrophic chondrocytes and matrices degrade and are
replaced by bone. The transition is also sustained by
increased neovascularization, which brings in osteoblasts
that finally result in new bone formation beneath the
degraded cartilage.
KEY WORDS: condylar cartilage, endochondral
ossification, growth factor, chondrocyte phenotype.
Received October 5, 2004; Accepted February 17, 2005
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International and American Associations for Dental Research
INTRODUCTION
M andibular condylar cartilage has been of much interest in many
studies, due to its integral role in mandibular growth, and,
more importantly, to its involvement in condylar remodeling in
adaptation to orthodontic bite-jumping therapy. Conflicting views
remain, however, as to the biomolecular mechanism through which
condylar cartilage is replaced by bone tissue in the process of
natural growth or growth modification. Based on an extensive
review of the literature and an analysis of the synthesized data, this
review is dedicated to clarifying the distinctive biological aspects of
the condylar cartilage compared with other synovial cartilages, and
to exploring its adaptive remodeling pathway by identifying the
phenotypic response during the transition from chondrogenesis to
osteogenesis.
THE DISTINCTIVE ASPECTS OF CONDYLAR CARTILAGE
OVER EPIPHYSEAL AND OTHER ARTICULAR CARTILAGES
The biological characteristics of articular chondrocytes differ
markedly from those of epiphyseal chondrocytes of the long-bone
growth plate. Articular chondrocytes are present throughout post-
natal life and remain unchanged in their morphological and
biosynthetic features (Roberts and Hartsfield, 2004). In contrast, the
epiphyseal chondrocytes persist only through growth in puberty,
and undergo profound phenotypic changes as they participate in the
process of endochondral ossification (Fawcett, 1997). Condylar
cartilage, which belongs to articular cartilage but exhibits many
distinguishing biological features, is present throughout post-natal
life but, unlike other articular cartilages, undergoes adaptive
changes in response to external stimuli (Garant, 2003). The
mechanisms that regulate these diverse developmental programs in
articular and growth-plate chondrocytes remain to be elucidated.
Some investigators, however, have attempted to determine whether
the phenotypic changes occurring during endochondral ossification
are genetically pre-determined or are under micro-environmental
control (Castagnola et al., 1987; Fuentes et al., 2003; Akiyama et
al., 2004). It has been claimed that chondrocytes possess the
intrinsic potential to express traits associated with endochondral
ossification, and that the active expression of these traits is
controlled by micro-environmental cues (Bruckner et al., 1989;
Inoue et al., 2002). Articular cartilage other than condylar cartilage
is present throughout post-natal life and does not undergo
endochondral ossification, indicating that its intrinsic potential for
endochondral ossification is restrained.
Condylar cartilage distinguishes itself from both epiphyseal and
articular cartilage in the following respects:
Histological Structures
The gene expression patterns of chondrocytes during condylar
growth have been categorized into two phases: maturation and
mineralization (Inoue et al., 1995). The chondrocyte maturation is
initiated with mesenchyme differentiation into pre-chondroblasts
and terminated with highly matured hypertrophic chondrocytes.
691
692
Figure 1. Cellular response of condylar cartilage during natural growth
(Sprague-Dawley rats at 56 days of age). The progression of cellular
response generated by natural growth is well-reflected by the zone-like
packing of chondrocytes, from the superficial layer downward,
consecutively being (A) the articular zone, (R) the resting zone, (P) the
proliferative zone, (H) the hypertrophic zone, and (E) the erosive zone.
The thickness of cartilage is of substantial proportion to that of the bony
tissue underneath, indicating the dominance of chondrogenesis with
moderate transition into osteogenesis (H&E, Bar = 10 ␮m).
This process is well-manifested by cellular and phenotypic
responses of chondrocytes, resulting in a unique zone-like
packing of condylar cartilage (Shen, 2000) (Fig. 1).
Articular Zone
The most superficial part covering the articular surface is the
articular fibrous layer, in which there are densely packed
collagenous fibers with fibroblasts. The dense fibrous tissue is
continuous with the periosteum of the condylar neck. The
fibroblasts are arranged mostly parallel to the surface of the
condylar head. Deep to the layer of fibrous tissue is the layer of
mesenchymal cells (Bergman et al., 1996).
Resting Zone
Beneath the articular zone is the condylar cartilage. The most
superficial layer of the cartilage is a zone of reserve cartilage
cells. The cartilage cells in this zone are small, and the amount
of chondroid matrix is less, relative to the deeper layer. The
high nuclei-to-cytoplasm ratio reflects the high mitotic
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Shen & Ali Darendeliler J Dent Res 84(8) 2005
potential of the cells in this layer (Shen et al., 2000).
Proliferative Zone
This deeper layer consists of mature cartilage with abundant
intercellular cartilaginous matrix. The individual cartilage cells
are relatively larger than in the overlying layer. Cartilage cells
are enclosed in lacunae, with a clear zone sandwiched in
between. Unlike in epiphyseal cartilage, there is no orderly
formation or column-like arrangement of cartilage cells
(Cheung, 1992; Zhao et al., 1999).
Hypertrophic Zone
The chondrocytes in this zone become highly mature. It should
be noted that hypertrophic chondrocytes do not lose
proliferative activity, at least during the embryonic period
(Suda et al., 1999). The first sign of calcification of the
cartilage is present in this layer. Unlike the more superficial
layer, this zone has a high density of collagen fibers in the
intercellular matrix. The collagenous matrix is continuous with
the osteoid matrix underneath, and they merge at the junction.
The sizes of lacunae increase, and some cartilage cells start to
degenerate and have a pyknotic appearance (Garant, 2003).
Erosive Zone
This is the zone where chondrogenesis ends and osteogenesis
begins. The cartilage here is in direct contact with the
connective tissue of the marrow cavity. Cell death and cartilage
breakdown occur, forming cartilaginous spicules that undergo
provisional calcification with hydroxyapatite crystals. Blood
vessels invade the degenerating cartilage. Further down, bone
and marrow spaces are present. The bony trabeculae are not
arranged perpendicularly to the articulating surface, but instead
are arranged randomly (Shen et al., 2000; Meikle, 2002).
Secondary Cartilage
There are some important reasons to define condylar cartilage
as secondary cartilage:
(1) In pre-natal development, most other synovial joints
have already been formed before the temporomandibular joint
(Suda et al., 1999; Meikle, 2002). The delayed occurrence of
condylar cartilage was confirmed by immunolocalization of
types II and X collagen in the fetal mouse mandible, where the
immunoreactions were not positive until day 15 of pregnancy
(Shibata et al., 1997). The new articulation between the
temporal bone and the mandible is therefore indicated as
secondary, in contrast to primary joints formed earlier.
(2) Subsequent to all other true primary cartilages that form
within the mesenchymal blastema of what will be the future
mandible, new cartilage formation begins as a secondary event
in 4 regions: the condylar process, the coronoid process, the
symphysis, and the gonial area. The latter 3 will have
disappeared around birth. Condylar secondary cartilage,
however, remains for the rest of our lives. Probably due to
articular functioning, cartilage is induced and maintained
within the membranous components of the condylar process of
the mandible (Dibbets, 1990).
(3) Being late in ontogenetic development, the new
cartilage develops within a mesenchymal blastema. Primary
cartilages are covered by a thin perichondrium. Secondary
cartilage, in contrast, is covered by a fully developed
mesenchymal tissue layer. The mesenchymal covering of the
condyle is responsible for a fundamental characteristic of the
condylar cartilage. There are mesenchymal cells first, and these
J Dent Res 84(8) 2005 Adaptive Remodeling of Condylar Cartilage
cells differentiate into cartilage only as a secondary event
(Enlow, 1992; Delatte et al., 2004).
(4) The term 'secondary cartilage' may also apply to the
characteristic response of the condyle during growth. Primary
epiphyseal cartilage reacts during development, primarily to
systemic growth stimuli such as hormones. In contrast,
condylar cartilage only secondarily follows these overall
stimuli after additional modulation by local growth factors
(Enlow, 1992; Sperber, 2001).
Mode of Growth
Primary cartilage growth starts with the cartilage cells within
the central layer of an epiphyseal plate. It then reaches the
subsequent developmental condition—normal mitosis. As a
result of mitosis, 2 daughter cells will originate, together
containing the total amount of organic substance from the
original progenitor cell. Each will inherit half of the duplicated
maternal chromosomes, and each cell will be smaller than the
original (Ross et al., 1995). The next phase during epiphyseal
growth is enlargement of the 2 daughters, each to the full size
of their progenitor. At this stage, both mature cells produce and
secrete extracellular matrix, which will make them drift apart.
One may remain within the germinative layer and probably be
a new progenitor; the other may drift away and subsequently be
eroded and replaced by bone (Dibbets, 1990). This highlights
one of the essential elements of primary cartilage growth:
cleavage of previously differentiated mature cartilage cells.
Apparently, cell divisions take place in the middle part of an
epiphyseal plate of the long bone. The type of growth in which
new material is formed within existing tissue is interstitial
growth (Garant, 2003).
Secondary condylar cartilage growth starts with the
mesenchymal tissue covering the pre-natal or post-natal
condyle. It consists of a thin layer of undifferentiated cells
directly overlying the cartilage of the condyle. Under the
developmental conditions, the mesenchymal cells split
themselves into even smaller new cells. Shortly thereafter,
these new cells will attain full size, resulting in the migration of
some of them out of the covering membrane in the direction of
the interior of the condyle (Grant, 2003; Kajikawa et al., 2003).
When the mesenchymal cells migrate into the cartilage,
differentiation takes place, during which the mesenchymal cell
becomes an immature cartilage cell. The new members of the
cartilage family have therefore been added without the mitosis
of existing cartilage progenitor cells, but through mitosis of
undifferentiated mesenchymal cells. The mode of growth in
which new cells are added from the exterior is appositional
growth (Dibbets, 1990; Luder, 1994).
Adaptive Remodeling
Both condylar cartilage and other articular cartilages are
present throughout post-natal life. Articular cartilage is a
permanent tissue whose cells do not take part in endochondral
ossification. This points to the fact that articular cartilage is not
adaptive to the changes or stimuli exerted on it. Condylar
cartilage, in contrast, has a special multidirectional capacity for
growth and remodeling, and therefore is adaptive to the
mechanical or positional changes by altering or regenerating
chondrogenesis and subsequently by endochondral ossification
(Sakamoto and Takano, 2002). It is agreed that the most
intriguing biological aspect of condylar cartilage that differs
from other synovial or epiphyseal cartilage lies in its ability to
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International and American Associations for Dental Research
693
remodel in response to the changes in condylar repositioning,
articular functioning, and mechanical loading (Kantomaa and
Ronning, 1997; Nakano et al., 2003; Shen et al., 2003).
Condylar remodeling has also been considered to be an
important factor influencing mandibular morphology during or
after natural growth. Numerous studies have revealed that
mandibular advancement with the use of bite-jumping
orthodontic functional appliances enhances condylar growth,
indicating an important role of condylar adaptation in reshaping
the morphology of the mandible, even beyond natural growth
(for review, see Rabie et al., 2003a).
Condylar remodeling is observed in the post-natal growth
period as well as after growth has ceased. Experiments on
growing rats have revealed that maturation of chondrocytes is
accelerated and that endochondral ossification is subsequently
enhanced when the condyle is positioned forward (Rabie et al.,
2003b). The repositioning of the mandibular condyle in adult
rats, in contrast, led to a reactivation of chondrogenesis in
condylar cartilage which otherwise is at resting status, and
finally results in increased bone formation (Chayanupatkul et
al., 2003; Rabie et al., 2004a).
CHONDROGENESIS—THE INITIAL STAGE
OF CONDYLAR REMODELING
The Regulatory Growth Factors Controlling
the Pathway of Chondrogenesis
Chondrogenesis is a biological and biomolecular process in
which chondrocytes undergo phenotypic as well as
morphologic changes featured by progressive maturation.
Chondrogenesis and the consequent endochondral bone
formation observed at the mandibular condyle are regulated by
various growth factors (Itoh et al., 2003). It is well-established
that extracellular growth factors—such as insulin-like growth
factors (IGF), transforming growth factors (TGF), fibroblast
growth factors (FGF), bone morphogenetic proteins (BMP),
parathyroid-hormone-related peptide (PTHrP), and members of
the hedgehog (Ihh) and Wnt gene families—provide important
signals for the regulation of cell proliferation, differentiation,
and maturation during chondrogenesis. Transduction of these
signals within the developing mesenchymal cells and
chondrocytes results in changes in gene expression, mediated
by transcription factors including Sox family and core-binding
factor alpha (Cbfa) (Shum and Nuckolls, 2002).
Factors Regulating Mesenchyme
Chondrogenic Differentiation
The transcription factors L-Sox5, Sox6, and Sox9 belong to
the Sry-related family of HMG box DNA-binding proteins,
which include many members implicated in cell fate
determination in various lineages. They are also master
transcription factors that control the genetic program of
differentiation of mesenchymal cells into chondrocytes
(Lefebvre et al., 2001). It has been reported that when the
Sox9 gene is inactivated after mesenchymal condensations,
most cells are arrested as condensed mesenchymal cells and
will not undergo overt differentiation into chondrocytes (de
Crombrugghe et al., 2000). Except for the HMG-box, L-Sox5
and Sox6 have no similarity to Sox9 and, hence, are likely to
have a function complementary to that of Sox9. The
hypothesized transcriptional mechanism is that Sox9 utilizes a
cAMP-response element-binding protein (CREB)-binding
694
protein (CBP)/p300 to exert its effects. CBP and p300 function
as co-activators of Sox9 for cartilage tissue-specific gene
expression and chondrocyte differentiation (Tsuda et al.,
2003).
Factors Regulating Mesenchyme
and Chondrocyte Proliferation
FGF
Pre-chondrogenic mesenchymal cells are likely the targets of
FGF-2, which probably promotes the formation of cartilage by
stimulating an expansion of the chondroprogenitor population
(Hiraki et al., 2001). Local administration of this protein in
articular cartilage with full-thickness defects caused
regeneration of chondrogenesis resulting from an increased
proliferative capacity of the undifferentiated mesenchymal cells
(Hiraki et al., 2001). bFGF (basic fibroblast growth factor), in
constrast, has the ability for inhibitory regulation of condylar
growth, via the inhibition of proliferation of chondrocytes
(Ogawa et al., 2003). It is suggested that this inhibitory
regulation is related to the down-regulation of the growth
factors and transcription factors, such as PTHrP and Cbfa1
(Ogawa et al., 2003).
TGF and IGF
Local applications of IGF-I and TGF-beta1 during the early
phase of fracture healing displayed an earlier appearance of
cartilage, and this was accompanied by an onset of cell
proliferation in chondrocytes, as revealed by the cell
proliferation marker bromodeoxyuridine (BrdU) (Wildemann et
al., 2003). Local administration of IGF-I to the bilateral
mandibular articular cavities in rats has also been reported to
cause an increase in the thickness of the condylar cartilage,
resulting from enhanced proliferation of chondrocytes (Itoh et
al., 2003). Intracellular signaling cascades, particularly those
involving the mitogen-activated protein (MAP) kinases, have
been shown to be activated by TGF-betas in promoting
cartilage-specific gene expression (Tuli et al., 2003).
PCNA
PCNA (proliferating cell nuclear antigen) functions as a DNA
sliding clamp for DNA polymerase delta and is an essential
component for eukaryotic chromosomal DNA replication.
PCNA has therefore been used as a marker for cell proliferation
(Tsurimoto, 1999). PCNA localizes in the nuclei of
chondroblasts of the reserve cell layer and the upper
hypertrophic layer. In condylar cartilage, the percentage of
PCNA-positive cells is significantly higher when there is an
increase in chondrocyte mitosis (Sharawy et al., 2002). Recent
studies revealed that PCNA is able to interact with multiple
partners involved in DNA repair, DNA methylation, and
chromatin assembly, and that proteins involved in cell-cycle
regulation may also exhibit PCNA-binding activity (Tsurimoto,
1999).
D-type Cyclins
Cell-cycle activation is coordinated by D-type cyclins which
are rate-limiting and essential for progression through the G1
phase of the cell cycle. As a member of the retinoblastoma
family, D-type cyclins exhibit complementary expression
patterns that correlate with the distinct proliferation and
differentiation states of chondrocytes (Yang et al., 2003). D-
type cyclins bind to and activate the cyclin-dependent kinases
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Shen & Ali Darendeliler J Dent Res 84(8) 2005
Cdk4 and Cdk6, which subsequently activate the expression of
S-phase genes, thereby inducing cell-cycle progression
(Coqueret, 2002).
Wnt
The complementary roles of Wnt in stem cell proliferation are
evident (Otto and Rao, 2004). Wnt5a and Wnt5b appear to
coordinate chondrocyte proliferation and differentiation by
differentially regulating cyclin D1 and p130 expression, as well
as chondrocyte-specific Col2a1 expression (Yang et al., 2003).
Rudnicki and Brown (1997) infected micromass cultures of
pre-chondrogenic mesenchyme in vitro and found that
expression of Wnt-1 caused a severe block in chondrogenesis.
Further analysis of this phenomenon showed that Wnt-1 and
Wnt-7a had mitogenic effects in early pre-chondrogenic
mesenchyme, followed by a block to differentiation at the late-
blastema stage.
BMP
Both BMP-2 and -4 appear to play regulatory roles in the
process of endochondral ossification, due to their involvement
in cellular proliferation (Ueno et al., 2003). It has been recently
shown that the chondrogenic activity of BMP-2 in vitro
involves the action of the cell-cell adhesion protein, N-
cadherin, which functionally complexes with beta-catenin
(Fischer et al., 2002). BMP-2-induced chondrogenesis, in
contrast, is significantly inhibited by Wnt signaling, indicating
an antagonism between Wnts and BMP-2 during mesenchymal
condensation.
Factors Regulating Chondrocyte Maturation
and Differentiation
PTHrP/Ihh
A signaling cascade involving Ihh and PTHrP has been
reported in which hypertrophic differentiation is limited as
chondrocytes become committed to hypertrophy. In this
negative-feedback loop, Ihh inhibits hypertrophic
differentiation by regulating the expression of PTHrP, which in
turn acts directly on chondrocytes in the growth plate that
expresses the PTH/PTHrP receptor (Alvarez et al., 2002). The
hypothesis that PTHrP regulates chondrocyte maturation in
condylar cartilage was supported by the study where mice with
a targeted deletion of PTHrP developed a form of
dyschondroplasia, resulting from premature maturation of
chondrocytes (Amizuka et al., 2000). The mechanism has been
proposed that TGFbeta-2 acts as a signal relay between Ihh and
PTHrP in the regulation of cartilage hypertrophic
differentiation (Alvarez et al., 2002).
Cbfa/Runx2
Apart from its role in osteoblast differentiation, Cbfa is also
expressed in chondrocytes, and its expression increases with
increasing chondrocyte maturation (Inada et al., 1999). Cbfa1
regulates the post-natal growth of the mandibular condyle by
coupling the processes of chondrocyte maturation and
degradation during endochondral bone formation (Rabie et al.,
2004b). Runx2 (runt-related transcription factor 2) is another
important transcription factor required for chondrocyte
maturation. Depletion of Runx2 resulted in the loss of the
differentiated phenotype in chondrocytes in vitro, where
chondrocyte hypertrophy is severely impaired (Enomoto et al.,
2004; Wang et al., 2004). The protein that may modulate the
J Dent Res 84(8) 2005 Adaptive Remodeling of Condylar Cartilage
activity of Runx2 is Grg5, a groucho homologue. The
shortening of the proliferative and hypertrophic zones in the
growth plates of Runx2(+/-) Grg5(-/-) mice is associated with
reduced Ihh signaling (Wang et al., 2004).
Wnt
Recently, members of the Wnt family of secreted signaling
molecules have been implicated in regulating chondrocyte
differentiation (Hartmann and Tabin, 2000). In vitro studies
showed that Wnt-1 and Wnt-7a caused a severe block in
chondrogenesis, and that the block to differentiation was at the
late-blastema/early-chondroblast stage (Rudnicki and Brown,
1997). Wnt4 blocks the initiation of chondrogenesis and
accelerates terminal chondrocyte differentiation in vitro
(Church et al., 2002). Wnt-7a induces dedifferentiation of
articular chondrocytes by stimulating transcriptional activity of
beta-catenin (Hwang et al., 2004).
The Expression of Growth Factors during Adaptive
Remodeling of Mandibular Condylar Cartilage
There is considerable evidence that proliferation and growth in
the mandibular condylar cartilage might be altered after a
change in the postural position of the mandible (Fuentes et al.,
2003). It has been reported that mandibular advancement
solicits a cascade of molecular responses in condylar cartilage
induced by enhanced signaling of growth factors (Rabie et al.,
2003c).
IGF and FGF
The expression of IGF-1, FGF-2, and their receptors (IGF-1r,
FGFr1, 2, 3) was monitored after the placement of intra-oral
appliances in the mouths of rats to produce a lateral functional
shift of the mandible. Gene expression for 5 of the 6 genes
studied was significantly higher (P < 0.05) in the protruded side
than in the non-protruded side (Fuentes et al., 2003). In another
rat model, where the mandible was repositioned by means of a
propulsive appliance, expression of IGF-1 and IGF-2 increased
significantly, in parallel with increased PCNA expression
(Hajjar et al., 2003). It is suggested that the enhanced
expression of these peptides might partly underlie changes in
proliferative activity of condylar cartilage after alteration in
mandibular posture (Fuentes et al., 2003).
VEGF
Forward mandibular positioning was found to solicit a
sequence of cellular events leading to increased
vascularization, indicated by increased expression of VEGF
(Vascular Endothelial Growth Factor). It was also found that
the highest acceleration of vascularization preceded that of
new bone formation (Rabie et al., 2002). In a study where the
alteration of mandibular positioning was created by stepwise
mandibular advancement, it was found that the second
advancement resulted in a significant increase in VEGF
expression when compared with the one-step group and the
natural growth control group, indicating that the changes in
the amplitude of mechanical loading have a significant effect
on the production of VEGF by chondrocytes (Leung et al.,
2004).
PTHrP
The pattern of expression of PTHrP was evaluated and
correlated to cellular dynamics of chondrocytes in condylar
cartilage during mandibular advancement, and it was found that
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695
the higher levels of PTHrP expression coincided with the
slowing of chondrocyte hypertrophy (Rabie et al., 2003c). It
was therefore suggested that mandibular advancement
promoted mesenchymal cell differentiation and triggered
PTHrP expression, which retarded their further maturation to
allow for more growth (Rabie et al., 2003c).
Sox9
Quantitative assessment revealed a substantial increase in Sox9
expression during mandibular protrusion, which correlated to
an increase in the amount of newly formed bone (Rabie et al.,
2003a). It was therefore concluded that functional appliance
therapy accelerates and enhances condylar growth by
accelerating the differentiation of mesenchymal cells into
chondrocytes, leading to an earlier formation and increase in
amount of cartilage matrix (Rabie et al., 2003a).
Type X Collagen
As a member of the family of short-chain collagens, type X
collagen is specifically expressed in hypertrophic cartilage,
indicating its role in the terminal stage of chondrocyte
maturation (Fukada et al., 1999). A significantly increased
expression of this protein was observed when the mandible was
set forward (Rabie and Hägg, 2002), and an important temporal
correlation between synthesis of this protein and the amount of
endochondral ossification was confirmed (Rabie et al., 2000).
The proposed mechanisms of type X collagen include
providing an easily resorbed fabric for the deposition of bone
matrix and regulating the calcification process during
endochondral ossification (Bonen and Schmid, 1991).
OSTEOGENESIS—THE TERMINAL STAGE
OF CONDYLAR REMODELING
Transition from Chondrogenesis to Osteogenesis
The histological reactions and cellular responses to the
transition from chondrogenesis into osteogenesis occurring
during post-natal growth in epiphyseal cartilage of long bone
have been well-documented (for review, see Meikle, 2002).
Limited studies, however, have focused on this specific area in
condylar cartilage, especially the transition during condylar
remodeling. It is reported that, in the erosive zone of
hypertrophic cartilage, where transition takes place,
hypertrophic chondrocytes begin to synthesize alkaline
phosphatase, and, concomitantly, the cartilage matrix
undergoes calcification (Luder et al., 1988; Meikle, 2002).
The matrix, when calcified, inhibits diffusion of nutrients,
ultimately causing the death of the chondrocytes. With the
death of the chondrocytes, much of the matrix breaks down,
and neighboring lacunae become confluent, producing an
increasingly large cavity. Empty lacunar spaces and
discontinuity of the mineralized intercellular partitions create
spaces for vascular invasion. The invading capillaries bring
osteogenic progenitor and bone marrow stem cells that
differentiate into osteoblasts (Cancedda et al., 2000; Garant,
2003). The osteoblasts assume their positions on the spicules
and remnants of lacunar cartilage and begin to lay down
osseous tissue, or osteoid, which will subsequently become
calcified, resulting in formation of new bone (Gartner and
Hiatt, 1997). Bone forms over the naked ends of the
mineralized cartilage strands, thereby fusing the condylar
cartilage to the osseous mass of the ramus (Garant, 2003). The
696
Figure 2. Cellular response of condylar cartilage during adaptive
remodeling triggered by mandibular protrusion (Sprague-Dawley rats at
56 days of age, with 21 days of mandibular advancement). The
enhanced chondrogenesis results in increased thickness of the
proliferative zone (P). The accelerated transition from chondrogenesis to
osteogenesis is taking place in the erosive zone (E), where hypertrophic
chondrocytes and surrounding matrices are degenerated and are
replaced by the advent of endochondral bone formation (H&E, Bar = 10
␮m).
typical cellular advances and histological structures of
condylar cartilage undergoing adaptive remodeling are shown
in Fig. 2, where chondrogenesis is enhanced, as indicated by
the thicker zone of proliferative chondrocytes, and the
transition from chondrogenesis to osteogenesis is stimulated,
as demonstrated by decreased thickness of hypertrophic and
erosive zones, which are being replaced by new bone
underneath.
It is reasonable to contend that the invasion of capillary
endothelium is critical to sustain the transition from
hypertrophic cartilage into the progression of endochondral
ossification (Carlevaro et al., 2000). In an attempt to verify the
linkage between penetration of vasculature and the emergence
of osteogenesis, investigators generated adaptive
chondrogenesis of condylar cartilage by repositioning the
mandible in rats (Shen et al., 2003). They conducted
immunolocalization of capillary endothelium to identify
neovascularization in condylar cartilage. Strong
immunoreactivity was observed, specifically in the erosive
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Shen & Ali Darendeliler J Dent Res 84(8) 2005
zone (the boundary area between cartilage and bone), and in
the bony tissue underneath, where osteogenesis took place
(Shen et al., 2003). Neovascularization of the erosive zone has
also been demonstrated and is further correlated to the
formation of new bone, as shown by quantitative imaging
analysis in other studies (Rabie et al., 2002; Leung et al.,
2004).
Endochondral Ossification
in Relation to Condylar Repositioning
The causes that lead to adaptive remodeling of condylar
cartilage are still under investigation. Many studies agree,
however, that the change of condyle position relative to the
glenoid fossa constitutes an important trigger for this
adaptation (e.g., Rabie et al., 2003a). The deviation of the
condyle from the glenoid fossa by mandibular forward
translation is the basis for orthodontic functional therapy,
which aims to enhance condylar growth and therefore to
eliminate the discrepancy between upper and lower jaws. Many
studies have attempted to elucidate the mechanisms that link
mandibular forward positioning and condylar growth
modification. Recent experimental studies in rats have attracted
much attention by identifying the cellular response of condylar
cartilage during mandibular advancement in rats (Rabie et al.,
2003a,b,c). With mandibular advancement, the mesenchymal
cells in the articular zone were found to be stretched and
oriented toward the direction of the pull (Rabie et al., 2001;
Shen et al., 2003). The directional orientation and physical
stretching of the cells evoked an increase in the mesenchyme
population and stimulated their differentiation into
chondrocytes (Rabie et al., 2001). This assertion has been
further echoed by a recent experiment where Ihh, a critical
mediator transducing mechanical signals to stimulate
chondrocyte proliferation, was examined in condylar cartilage
when the mandible was forward-positioned (Tang et al., 2004).
It was observed that the high level of Ihh expression coincides
with an increase in the population and a shortening in the
turnover time of the replicating mesenchymal cells, suggesting
that Ihh acts as a mediator of mechanotransduction that
conveys mechanical signals resulting from condylar
repositioning to the mesenchymal cells, which, in turn, initiate
a chain reaction toward eventual endochondral ossification
(Tang et al., 2004).
The influences of mandibular repositiong or mechanical
loading on adaptation of condylar cartilage have also been the
goals of many studies. It has been found that a decrease in
compressive loading enhances condylar growth, whereas an
increase in loading inhibits growth (Rabie et al., 2001; Sinsel et
al., 2002), indicating that articulating function, i.e., the condyle
coming into contact with the fossa, could slow the maturation
process and consequently defer endochondral ossification in
condylar cartilage. The effect of articulating function on the
condylar cartilage, especially its maturation, has been studied
in in vitro and in vivo experiments that have monitored matrix
calcification and bone formation. When the posterior part of the
condyle deviates from the fossa, maturation of the cartilage is
accelerated at that point (Kantomaa and Hall, 1988; Nakano et
al., 2003). As mentioned earlier, cartilaginous maturation,
which is characterized by chondrocyte hypertrophy, leads to the
transition of chondrogenesis into osteogenesis (endochondral
ossification). It is therefore safe to contend that condylar
unloading stimulates condylar growth, while articulating
J Dent Res 84(8) 2005 Adaptive Remodeling of Condylar Cartilage
function, in contrast, slows condylar growth. This contention is
in agreement with the statement that when articulating function
is not present in the mandibular jaw joint, the cartilage matures
and is replaced by bone (Kantomaa and Hall, 1991; Takahashi
et al., 1998).
The mechanism behind the phenotypic shifting of
chondrocytes, as a result of the status of condylar positioning,
is that, because the pre-chondroblasts in condylar cartilage are
multipotential, they switch their biomolecular pathway toward
the direction of osteoblasts in the absence of articulating
function, and the growth increases. This regulation of the
chondrocyte pathway is mediated by maturation of the cartilage
cells. If the condylar-articulating function is not present,
maturation advances rapidly, and the highly mature cartilage is
destined to induce bone formation (Kantomaa and Hall, 1991;
Takahashi et al., 1995).
This hypothesis assigns the articulating function of the
condyle a new role: It keeps the cartilage tissue young and
adaptive for the purpose of enabling chondrogenesis to
continue. Otherwise, hypertrophy would progress too fast and
would create a situation in which the extracellular matrix of
the mature cartilage induces the conversion of hypertrophic
chondrocytes to osteogenic rather than chondrogenic cells
(Weiss et al., 1986; Kantomaa and Hall, 1988; Garant, 2003).
This hypothesis also explains why the pre-natal condylar
cartilage is able to continue its growth without articulating
function for a longer period than is the post-natal condylar
cartilage (Koski, 1981; Merida-Velasco et al., 1999). The
maturation front is farther behind the pre-chondroblast cell
layer in pre-natal cartilage than in older cartilage, so it takes
longer for the maturation process to reach the pre-chondroblast
layer after the condyle assumes a non-functional state. During
that time, the pre-chondroblasts continue their production of
new cartilage (Kantomaa and Hall, 1988). This hypothesis can
also explain the condylar morphology which is influenced by
natural growth. When the anterior part of the condyle is not
used in articulation, maturation of cartilage proceeds fast at
that side and results in a shift of the differentiation pathway
from chondrogenic to osteogenic. However, in the posterior
part, maturation is slowed, and proliferating cells are allowed
to continue chondrogenesis. This reaction leads to an
expansive growth in the anterior part of the condyle
(Kantomaa and Ronning, 1997; Voudouris and Kuftinec,
2000).
SUMMARY
Adaptive remodeling in response to alterations in the micro-
environment constitutes one of the most marked biological
features of mandibular condylar cartilage. Condylar adaptation
triggered by mandibular repositioning, e.g., mandibular
forward advancement, solicits a cascade of molecular responses
that alters the chondrogenic pathway by stimulating
mesenchymal chondrogenic differentiation, accelerating
chondrocyte proliferation and maturation, and increasing
neovascularization. Compared with those in condylar natural
growth, the regulatory growth factors and transcription factors
found to increase during condylar adaptive remodeling
transduce signals for up-regulation of chondrogenesis and its
transition into osteogenesis, resulting in enhanced
endochondral bone formation.
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International and American Associations for Dental Research
697
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