Regulation of Growth in

Mandibular Condylar Cartilage

Robert J. Hinton* and David S. Carlson*,
The mandibular condylar cartilage (MCC) has a distinctly different developmental and
phylogenetic history from cartilages of the limbs and cranial base. Because the cells that
divide to effect growth and adaptation in the MCC are of perichondrial/periosteal rather
than chondrogenic origin, the cellular and molecular mechanisms that regulate MCC
growth are only beginning to be understood. This article summarizes information regarding
receptors and their ligands that are potential growth regulators at the MCC, and examines
how growth regulation at the MCC may differ from the mechanisms that take place in
growth plate. Finally, emerging evidence bearing on the possibilities for altering MCC
growth rate or direction for therapeutic purposes will be discussed.
Semin Orthod 11:209 218 2005 Elsevier Inc. All rights reserved.

nterest in the development and growth of the mandibular condylar cartilage (MCC) has been prominent
within the orthodontic community for many years, due in
large part to the contribution made by the MCC to growth
in length and height of the mandible. Although initially
considered a growth center with an intrinsic capacity for
growth,1,2 it is currently understood that MCC growth is
highly adaptive, and responsive to growth in adjacent regions of the head, particularly the maxilla.3 Clinical interest was heightened during the 1960s and 1970s as research emerged suggesting that it might be possible to take
advantage of this adaptability to alter the rate and/or direction of MCC growth. This report will review the unique
structural features and growth plasticity of the MCC as
well as our emerging understanding of the cellular and
molecular mechanisms that may regulate MCC growth. It
will conclude by examining how these regulatory mechanisms might someday be exploited to alter the kinetics of
MCC growth for therapeutic purposes.

*Department of Biomedical Sciences, Baylor College of Dentistry, Texas

A&M University System Health Science Center, Dallas
Research and Graduate Studies, Texas A&M University System Health
Science Center, College Station, TX.
Supported in part by a grant from the American Association of Orthodontists
Foundation (to RJH).
Address correspondence to Dr. Robert J. Hinton, Texas A&M University
System Health Science Center, Baylor College of Dentistry, Department of Biomedical Sciences, 3302 Gaston Avenue, Dallas, TX
75246; Phone: (214) 828-8272; Fax: (214) 828-8951. E-mail:
bhinton@bcd.tamhsc.edu

1073-8746/05/$-see front matter 2005 Elsevier Inc. All rights reserved.

doi:10.1053/j.sodo.2005.07.005

Structural and
Functional Characteristics of
Mandibular Condylar Cartilage
MCC as Secondary Cartilage
Unlike cartilages in the limbs and cranial base, the MCC is
derived from cells of periosteal origin4-6; it develops adjacent
to the intramembranous bone of the mandible, distinct from
Meckels cartilage.7 Because its morphogenesis occurs late in
prenatal development, the MCC has been designated as a
secondary cartilage in contradistinction to primary cartilages
of the limbs and cranial base.8 Secondary cartilages are structurally distinct from both limb growth plate and articular
cartilage. They are found, transiently in some instances, at
many locations in the developing craniofacial complex,7 and
persist postnatally in regions such as the mandibular condyle, angular process of the mandible, and intermaxillary
suture.9,10 A secondary cartilage such as the MCC differs primarily in its superficial layers, which comprise a perichondrium in which undifferentiated (prechondroblastic) cells
(Fig 1) secrete a matrix rich in type I collagen rather than the
type II collagen matrix secreted by chondrocytes.11,12 It is
these undifferentiated cells that proliferate and mature to
effect growth at the MCC, not the chondrocytes in deeper
layers.13,14 The perichondrium that caps the cartilage of the
MCC is continuous with the periosteum covering the bone of
the mandibular ramus: thus, the most superficial (articular)
layer of the MCC has direct continuity with the fibrous layer
of the periosteum, while the prechondroblastic (proliferative) layer of the MCC has direct continuity with the osteogenic layer of the periosteum (Fig 2).
209

R.J. Hinton and D.S. Carlson

210

Figure 1 Histological structure of the growing (subadult) mandibular condylar cartilage of a rat showing its constituent
layers. Attwoods stain. (Color version of figure is available online.)

The histomorphology of the MCC derives from its developmental and evolutionary origin and, as a result, undoubtedly has important implications for concepts about the regulation of MCC growth. Unfortunately, however, a number
of schemes, each with somewhat distinct terms, have been
proposed to describe the histomorphology of the mandibular
condyle.15,16 This fact alone has led to some degree of confusion about the nature of the MCC and of the factors that may
affect its development and growth. Table 1 provides a summary comparison of the terminology that has been used to
describe the growing MCC.

Evolution and Development of the MCC

Evolutionary studies suggest that the temporomandibular
joint evolved in mammals as a new joint by the juxtaposition of two intramembranous bones, the quadrate and articular, that had not heretofore been in articulation in reptiles.17
Viewed in this context, the development of the condylar cartilage from a perichondrium that is transformed from a periosteum in a localized region of articulation accounts nicely
for the different structural organization of the MCC. This

phylogenetic process is mirrored during development as

shown elegantly by Hall, who documented the formation of
adventitious (secondary) cartilage at sites of articulation on
intramembranous bones in the chick embryo.18 Hall further
showed that paralysis of the embryo by injection of a toxin
resulted in regression and eventual loss of the cartilage, suggesting that some aspect of movement or articulation is critical to the
initiation and maintenance of secondary cartilage.19
A similar phenotypic lability has been noted in the MCC.
Severe restriction of jaw movements by intermaxillary fixation (Fig 3) results in progressive loss of chondrocyte hypertrophy, reduced proteoglycan content of the matrix, significant reduction of cartilage thickness, and some
transformation of cartilage into bone in the MCC.14,20,21
These changes are reversible by mobilization of the mandible. Similarly, removal of the MCC from its functional milieu
by transplantation to a nonarticular location22,23 or by placement in explant culture13 has been found to elicit a transformation of the MCC to bone within days. Moreover, proliferation of MCC explants is reduced much more than in primary
cartilage explants (eg, growth plate, synchondrosis) cultured

Mandibular condylar cartilage

211

Figure 2 Coronal section of mandibular condyle in a

growing rat. Note how the fibrous layer of the periosteum (long arrows) on the condylar neck is continuous with the articular layer of the condylar cartilage (long arrows). Similarly, note how the
osteogenic layer of the periosteum (short arrows) is
continuous with the prechondroblastic layer of the
condylar cartilage (short arrows). Alcian blue stain.
(Color version of figure is available online.)

under identical conditions.13 Thus, unlike the proliferative

chondrocytes of primary cartilage, the dividing cells of the MCC
exhibit a dual potential for a chondrogenic or an osteogenic
phenotype, with the phenotypic expression dependent on illdefined aspects of the functional environment of the joint.

Summary
In summary, the MCC is a secondary cartilage that in
subadult individuals serves both as a site of growth and as a
place of articulation. As such, it displays some functional
characteristics of both a growth plate as well as an articular
cartilage, but it differs from both in fundamental aspects of its
development and structure throughout ontogeny.16,24 Its
most superficial layers are not cartilaginous in phenotype,
but rather perichondrial/periosteal. Importantly, the chondrocytes of the MCC are derived via mitosis in cells that are
themselves not chondrocytes, similar to embryonic cartilage
but not to the growth plate in which the cells that proliferate
are chondrocytes.25 Finally, the prechondrogenic phenotype
of these dividing cells in the MCC can be readily modulated
to a preosteogenic phenotype by changes in the periarticular

environment. Taken together, these features define a tissue

with structural and growth characteristics that set it apart
from other cartilaginous growth sites.

Cell/Molecular Biology
of the Condylar Cartilage
Characteristics of the
Dividing Cell Population
Most of the information on the cellular and molecular characteristics of the MCC has been obtained within the last 10 to
15 years, and especially within only the last 5 years. As a
result, the cellular and molecular mechanisms that regulate
the growth of the MCC or its modulation to an osteogenic
phenotype are not well understood, and the nature of the
prechondroblastic cell population and the factors that regulate their rate of proliferation and differentiation are only
beginning to be explored.
Stutzmann and Petrovic contended that the mitotic layer
of the MCC is comprised of two cell types.26 The first of these

R.J. Hinton and D.S. Carlson

212

Table 1 Comparison of Terminology Used to Describe the Histomorphology of the Condylar Cartilage. (Adapted from Beresford8
and Luder et al.15)
Blackwood71
Articular zone

Intermediate
zone

berg
et al.73

Durkin
et al.25

Wright &
Moffett4

Petrovic
et al.13

Thilander
et al.72

Carlson
et al.5

Luder
et al.15

Connective
tissue lining
(articular
layer)
Proliferative
layer
(undifferentiated
mesenchyme)
Transitional
zone
Cartilage

Resting
surface
articular
layer
Transitional
or
proliferative
layer

Articular layer

Fibrous capsule

Surface
articular
layer

Fibrous
articular
tissue

Perichondrium
Articular layer

Proliferative
layer

Prechondroblastic layer

Proliferative
layer

Prechondroblastic
(proliferative)
zone

Polymorphic
cell layer
Flattened cell
layer (1&2)

Zone of
matrix
production

Zone of
maturation
Functional
chondroblasts
Hypertrophic
chondroblasts

Hypertrophic
zone (nonmineralized)

Chondroblastic
zone
(maturation
and
hypertrophy)

Hyaline
cartilage
Flattened cell
layer (3)
Upper
hypertrophic
cell layer
Lower
hypertrophic
cell layer

Hypertrophic
cartilage

Spongy bone

Hypertrophic
cartilage

Zone of cell
hypertrophy

Erosion zone

Zone of
calcification
and
resorption

Subchondral
bone

is the so-called skeletoblast, a fibroblast-like pluripotent cell

thought to originate from embryonic mesenchymal cells; the
second cell type is a so-called prechondroblast, a rounded cell
thought to be derived from the skeletoblast. They postulated
that skeletoblasts, characterized by a relatively long intermitotic interval and a relatively large number of cell divisions,
normally differentiate into preosteoblasts and then into osteoblasts, but that they differentiate into prechondroblasts
under rapid growth conditions created by factors such as
mandibular position and muscle activity, the effects of which
may be amplified by hormonal factors. Prechondroblasts, by
contrast, exhibit a relatively short intermitotic interval and, as
a differentiated cell type, have a much more limited potential
number of cell divisions than skeletoblasts. Although Stutzmann and Petrovic designated the skeletoblast a pluripotential stem cell, the validity of this description, as well as their
characterizations of the two cell types present in the mitotic
layer of the MCC, have not been verified (Guan and coworkers, this issue).
Beginning with pioneering efforts by Silberman and colleagues, the last decade has seen a significant expansion of
knowledge concerning the receptors present on MCC cells
and the responsiveness of the MCC to stimulation by their
ligands.27-29 It has been shown that the potent mitogen fibroblast growth factor 2 (FGF-2) is present in the matrix of the
MCC,30,31 and that cells of the MCC express cell surface receptors for FGF-2 receptor subtypes. In young rats, the subtype 2 receptor (FGFR2) was most prominent in the prechondroblastic or mitotic layer and the type 1 and 3 receptors
subtypes (FGFR1, FGFR3) were localized (Fig 4) to the
deeper chondroblastic and hypertrophic layers,32 whereas
the distribution of FGFRs was somewhat different in cultured

Hypertrophic
zone
(mineralized)

Zone of erosion
Degenerating
chondroblasts
Zone of
endochondral
ossification

Zone of bone
deposition

neonatal MCC.33,34 Insulin-like growth factor 1 (IGF-I), an

anabolic factor for matrix synthesis in limb cartilage, has also
been reported present in the MCC35-37 and its type 1 receptor
(IGF-1R) has been localized to the chondroprogenitor (prechondroblastic) zone of MCC explants from perinatal mice38
and to the upper chondroblastic layer32,39 in postnatal rats. It
is intriguing in limb cartilage that IGF-1R and FGFR3 are
most strongly immunoreactive in the proliferative (ie, mitotic) zone in growth plate,40,41 while they are most strongly
reactive in MCC in the chondroblastic zone, where there is
essentially no mitotic activity. However, in both zones the
cells are chondrocytes. In the MCC, the strongest immunoreactivity in the mitotic (prechondroblastic) zone is for FGFR2, suggesting a potentially fundamental difference in the
receptor subtypes expressed on dividing cells between primary and secondary cartilage. Stimulation of MCC explants
in vitro with FGF-2 or IGF-I has been shown to alter MCC
proliferative activity.32,38,42 Since the abundance of IGF-I and
FGF-2 mRNA in the MCC has been demonstrated to change
considerably with the initiation of mastication and with puberty,32,43 it is likely that activation of receptors for either or
both of these growth factors is important in growth of the
MCC. Less is known of the presence or importance of other
growth factors, such as TGF- or transforming growth factor-beta,36 PDGF or platelet-derived growth factor,34 or EGF
or epidermal growth factor.44
Knowledge of hormonal receptors in the MCC and its responsiveness to hormones is even more rudimentary. Initial
research by Silberman and colleagues showed that matrix
synthesis and proliferation in the MCC could be affected by
thyroxine and glucocorticoids.45,46 Somewhat more information, some of it conflicting, is available for growth hormone

Mandibular condylar cartilage

213

Figure 3 Representative sagittal sections of mandibular condylar cartilage in growing Macaca mulatta
with no fixation (upper) and after 3 weeks of maxillomandibular fixation (lower). Note the extreme
reduction in thickness of the MCC, especially in the
chondroblastic layer, and the loss of chondrocyte
hypertrophy following fixation. Hematoxylin and
eosin stain. (Color version of figure is available online.)

(GH). Injection of GH, or supplementation of GH-deficient

dwarf rats with GH, has been shown to increase mitotic activity in MCC13,47 and to promote a thicker cartilage.48,49 In
addition, Maor and coworkers demonstrated that chondroprogenitor and chondroblastic zones of neonatal mouse condylar cartilage became thickened in response to in vitro administration of GH.28 There is also some evidence that GH
may stimulate proliferation in MCC of old (20 month old)
mice.50 By contrast, Copray and associates found no mitotic
stimulatory effect for GH in 4-day-old rat condylar cartilage
explants, although mitotic stimulation was present in costal
cartilage.51 However, Visnapuu and colleagues demonstrated
that receptors for GH were present in the MCC of growing
rats.37
Although systematic comparisons between primary and
secondary cartilages have yet to be performed for receptor
localization and response to stimulus by various ligands, several lines of evidence suggest that other comparisons may
also be fruitful. Rather, it is possible that the chondroprogenitor cells of the mandibular condylar cartilage and the osteoprogenitor cells of cranial sutures (SUT) share regulatory ex-

tracellular matrix molecules and cell-surface receptors,

distinct from the chondrocytes in primary cartilage or in the
MCC, that regulate their rates of growth. It has been shown
that the prechondroblastic (chondroprogenitor) cells of the
MCC, similar to the preosteogenic (osteoprogenitor) cells of
developing sutures,52 express cell surface FGFR2 receptors.32,33 FGFR2 expression and mitotic activity are present in
the same cell layer (proliferating osteoprogenitor cells) of
developing sutures, with FGFR1 expressed as these cells differentiate into osteoblasts.52 These findings parallel the observed distribution in the MCC of FGFR2 and mitotic activity
in prechondroblasts (chondroprogenitor cells) and FGFR1 in
chondroblasts, the differentiated phenotype.32 FGF-2,
known to be present in MCC (see earlier discussion), is also
found in the midsutural mesenchyme and calvarial bones of
developing sutures.53 These similarities between MCC and
SUT are not surprising in view of the periosteal origin of both
tissues. Given that the phenotype of the dividing cell population in the MCC differs fundamentally from that in the
growth plate but resembles that in cranial sutures, it is plausible that the mechanisms governing the growth of the MCC

214

Figure 4 Schematic drawing of distribution of immunoreactivity for

IGF-1R and FGFR1, FGFR2, and FGFR3 in mandibular condylar
cartilage. Drawing adapted from Enlow DH: Handbook of Facial
Growth. Philadelphia, Saunders, 1975. Data from Fuentes and colleagues.66

may have as much in common with those regulating cranial

sutures as those regulating the growth plate.

New Knowledge from the Growth Plate:

Can It Be Applied to the Condylar Cartilage?
In the last few years, a number of studies have established the
importance of signals from the periosteum/perichondrium
for the regulation of proliferation and differentiation of
growth plate chondrocytes (see Kronenberg54 for a review).
Several reports have suggested that Indian hedgehog (ihh) is
central to a negative feedback loop that regulates the rate of
hypertrophic differentiation.55-57 They have proposed that
ihh, secreted by prehypertrophic postmitotic chondrocytes,
signals via its receptors in the perichondrium, which indirectly induces the expression of parathyroid hormone-related protein (PTHrP). Binding of PTHrP to its receptor on
prehypertrophic chondrocytes attenuates further hypertrophy. Growth factors such as TGF- and FGF-2 have been
shown to act outside this loop to directly alter PTHrP in the
perichondrium,41,58 thereby affecting differentiation. In addition, it has been recently demonstrated that removal of the
periosteum/perichondrium (PO/PC) from metatarsal explants before culture increases longitudinal growth of the
explants, suggesting that the PO/PC exerts a negative regulation of growth.59,60 Taken together, these studies suggest that
substances secreted by postmitotic chondrocytes may indirectly regulate proliferation and differentiation of proliferating chondrocytes via signals from the perichondrium/periosteum. It remains to be seen whether this regulation differs in
a tissue such as the MCC in which the dividing and differentiating cells are themselves of periosteal/perichondrial origin.
Of interest in this regard is an experiment performed by
Stutzmann and Petrovic, who showed that proliferation in
the MCC in organ culture varies as a function of the tissue
composition of the explants.61 They placed proliferative layer

R.J. Hinton and D.S. Carlson

(perichondrium) explants dissected from the MCC of intact
rats in close association in organ culture with the chondroblastic layers from other MCC or cranial base cartilages. In
the explants containing only perichondrium, cell division
was elevated by almost a factor of 10 over that in perichondrial explants cultured with the cartilaginous portion of the
MCC or cranial base. They interpreted their results as evidence of an inhibitory effect of the cartilaginous portion of
the MCC on proliferation, a concept that prefigured the work
in growth plate by 15 years.
A recent study involving secondary cartilage on the membrane bones of the developing chick provides the first solid
evidence as to how growth might be regulated in a secondary
cartilage.62 As previously documented by Murray63 and
Hall,18 secondary cartilage forms in response to movement
on certain membranous bones of the developing chick between embryonic days 11 and 14. The source of the secondary chondrocytes is a germinal region of cells expressing
genes that are characteristic of preosteoblasts but which can
be diverted into chondrogenesis (in remarkable similarity to
Petrovics skeletoblasts). As noted above for the MCC, Buxton and colleagues remarked that in the chick secondary
cartilage the periosteum (germinal region) is the source of
the chondrocytes as well as the responding tissue (p.
4737).62 However, unlike growth plate chondrocytes, Buxton and colleagues found that the secondary chondrocytes
hypertrophy very rapidly, thereby exiting the cell cycle.62
They showed that if the explants are not mechanically stimulated in vitro, commitment of the germinal zone cells to the
chondrocytic lineage ceases, which supports the known phenotypic lability of MCC explants or immobilized joints in
vivo. As they differentiate and leave the cell cycle, secondary
chondrocytes, like those in the growth plate, secrete ihh,
which stimulates proliferation in germinal zone; blocking of
ihh production eliminates this stimulation. These findings,
derived using explants containing secondary cartilage from
the chick quadrate-quadratojugal joint rather than the temporomandibular joint, shed considerable light on the ways in
which growth regulation at secondary cartilages, presumably
including the MCC, resembles that in the growth plate and
the ways in which it does not.

Can Condylar
Growth Be Regulated
for Therapeutic Purposes?
Buxton and colleagues noted that a characteristic feature
of secondary chondrogenesis appears to be the lack of a
self-renewing chondrocyte-committed precursor pool
such as exists in the growth plate.62 This trait may account
for its perceived role as an adaptive, rather than an intrinsic, site of growth that is dependent on mandibular postural position and function. Accordingly, the germinal
zone (prechondroblastic layer in the MCC) expands only
as much as its external stimulus (typically movement or
articulation) dictates. A logical correlate of this is that an
increase in the external stimulus could conceivably in-

Mandibular condylar cartilage

215

Figure 5 Representative sagittal sections of temporomandibular joint in normally growing Macaca

mulatta (upper) and 2 weeks following placement
of appliance that forces protrusion on closure
(lower). Note the pronounced hyperplasia of the
MCC, especially in the posterior region, and evidence of new bone formation on the posterior neck
of the condyle and the anterior aspect of the postglenoid spine. Hematoxylin and eosin. (Color version of figure is available online.)

crease the pool of cells that commit to the chondrocytic

phenotype, thereby ultimately increasing growth rate.
Moreover, since it is known that the action of growth
factors and hormones can be superimposed on the feedback loop that is thought to regulate proliferation and
differentiation of growth plate chondrocytes, it may be
possible for the pool to be further enlarged in the MCC by
this means. The implications for an increase in proliferation that could, in theory, produce a clinically significant
increase in mandibular length are obvious.
Following anterior postural change of the mandible elicited by an incisor-borne appliance in rats, Petrovic and associates found a significant increase in the number of dividing
cells in the MCC after 4 weeks and an increase in the overall
length of the mandible.13,64 Similarly, in growing monkeys,
McNamara and Carlson found that the MCC became thickened and hyperplastic within two weeks of placement of an
appliance that prompted protrusion on closing (Fig 5).65
They also noted that this was a transient response that
reached a maximum at 6 weeks and returned to baseline
levels by 12 weeks. In both the rat and monkey models,

appliances that caused retrusive postures had opposite effects

on the MCC, that is, thinner cartilage and decreased cell
proliferation. These experimental findings were the basis for
a cybernetic model of mandibular growth regulation13 proposed well before the molecular underpinnings that we are
now beginning to acquire.
Until the last few years, essentially nothing was known of the
cellular or molecular changes that might underlie the structural
and growth changes observed in the MCC following a change in
mandibular postural position. However, several recent studies
have begun to explore this question utilizing appliances that
replicate the effects (increased mitotic activity, cartilage thickness) found by investigators in the 1960s and 1970s. Fuentes
and coworkers used an incisor-borne appliance that prompted a
crossbite in growing rats and produced a differential change in
proliferation and cartilage thickness between the crossbite and
noncrossbite sides.66 In animals wearing the appliance, gene
expression for IGF-I and FGF-2 and their receptors in MCC was
altered from that in control rats. The changes in gene expression,
which typically preceded the changes in mitotic activity and
cartilage thickness, were in most instances opposite in direction

R.J. Hinton and D.S. Carlson

216

Figure 6 Gene expression for FGF-2 and its receptors in experimental condyles as a percentage of expression in condyles
from animals with no appliance. Experimental group animals were fitted with an appliance that prompted a unilateral
crossbite, resulting in one condyle being protruded and the other with no translation or some retrusion (inset).
Reprinted from Am J Orthod Dentofac Orthop 123:160-166, 2003, with permission from the American Association of
Orthodontists.

between the crossbite and noncrossbite sides (Fig 6). The altered
gene expression, most prominent at 3 and 7 days following
appliance placement, was mostly attenuated by 14 days. Using a
similar design, Hajjar and associates found that rats fitted with
an incisor-borne appliance that prompted anterior displacement of the mandible exhibited increased expression of both
IGF-I and IGF-II mRNA and protein in the MCC as assessed by
in situ hybridization and immunohistochemistry, respectively.67 These changes, which occurred in parallel with increased mitotic activity, progressively increased in intensity over
a 2-week period.
In a series of studies utilizing a similar incisor-borne appliance, Rabie and colleagues demonstrated that the immunohistochemical expression of Sox9 and type II collagen, both markers for chondrocyte differentiation, was increased in the MCC
and glenoid fossa of rats wearing the appliance for 1 to 2
weeks68,69; this change was more pronounced in the posterior
region of the MCC. In a subsequent study, the percentage of
cells demonstrating immunoreactivity for Indian hedgehog

(ihh) increased by 60% to 70% over controls 3 to 7 days following appliance placement. This higher level of ihh expression
coincided with the increase of mitotic activity and reduced turnover time in the cells of the prechondroblastic layer,70 a finding
consistent with the work of Buxton and colleagues in chick
secondary cartilage.62

Conclusions: Are We Ready

(and Able) to Grow Mandibles?
This review has briefly summarized the evidence underlying
the view that the developmental history and structure of the
MCC differs considerably from that of primary cartilages in
the limbs and cranial base. In addition, it should be apparent
that our knowledge of the growth factors and other agents
that may regulate aspects of MCC proliferation and differentiation has increased considerably in the last decade, and that
we are beginning to extrapolate models of growth regulation

Mandibular condylar cartilage

derived from the growth plate to secondary cartilage. Several
studies have shown that ihh and growth factors, agents
known to regulate growth in both limb primary cartilage and
secondary cartilage, are upregulated in the MCC in conjunction with the increased proliferation that accompanies an
anterior postural position of the mandible. Once we understand more fully the characteristics of the germinal cells or
prechondroblasts or skeletoblasts that proliferate in the
MCC, it may be possible to effect a profound increase in their
mitotic capabilities. The explosion in knowledge of stem
cells of all types may provide scientists interested in craniofacial tissues with novel modalities for altering the phenotypic characteristics of multipotent cells. While these developments may seem far from ready for application to clinical
treatment, the increased knowledge of growth regulation in
the MCC gained in just the last 5 years is encouragingand
exciting.71,72

References
1. Weinmann JP, Sicher H: Bone and Bones. Fundamentals of Bone Biology. St Louis, CV Mosby, 1947
2. Scott JH: The growth of the human face. Proc R Soc Med 47:91-100,
1954
3. Carlson DS: Biological rationale for early treatment of dentofacial deformities. Am J Orthod Dentofac Orthop 121:554-558, 2002
4. Wright DM, Moffett B: The postnatal development of the human temporomandibular joint. Am J Anat 141:235-249, 1974
5. Carlson DS, McNamara JA Jr, Jaul DH: Histological analysis of the
growth of the mandibular condyle in the rhesus monkey (Macaca mulatta). Am J Anat 151:103-118, 1978
6. Shibata S, Fukada K, Suzuki S, et al: Immunohistochemistry of collagen
types II and X, and enzyme-histochemistry of alkaline phosphatase in
the developing condylar cartilage of the fetal mouse mandible. J Anat
191:561-570, 1997
7. Vinkka H: Secondary cartilages in the facial skeleton of the rat. Proc
Finn Dent Soc 78:1-137, 1982
8. Beresford WA: Chondroid Bone, Secondary Cartilage, and Metaplasia.
Baltimore, Urban and Schwartzenberg, 1981
9. Hinton RJ: Response of the intermaxillary suture cartilage to alterations
in masticatory function. Anat Rec 220:376-387, 1988
10. Petrovic A: Mechanisms and regulation of mandibular condylar
growth. Acta Morphol Neerl Scand 10:25-34, 1972
11. Mizoguchi I, Nakamura M, Takahashi I, et al: An immunohistochemical study of localization of type I and type II collagens in mandibular
condylar cartilage compared with tibial growth plate. Histochemistry
93:593-599, 1990
12. Silbermann M, Reddi AH, Hand AR, et al: Further characterization of
the extracellular matrix in the mandibular condyle in neonatal mice. J
Anat 151:169-188, 1987
13. Petrovic AG, Stutzmann JJ, Oudet CL: Control processes in the postnatal growth of the condylar cartilage of the mandible, in McNamara JA
Jr (ed): Determinants of Mandibular Form and Growth. Ann Arbor, MI,
Center for Human Growth and Development, University of Michigan,
1975, pp 101-154
14. Carlson DS, McNamara JA Jr, Graber LW, et al: Experimental studies of
growth and adaptation of TMJ, in Irby WB (ed): Current Advances in
Oral Surgery. St Louis, Mosby, 1980, pp 28-77
15. Luder HU, Leblond CP, von der Mark K: Cellular stages in cartilage
formation as revealed by morphometry, radioautography and type II
collagen immunostaining of the mandibular condyle from weanling
rats. Am J Anat 182:197-214, 1988
16. Carlson DS: Growth of the temporomandibular joint, in Zarb GA,
Carlsson GE, Sessle BJ, et al (eds): Temporomandibular Joint and Masticatory Muscle Disorders. Copenhagen, Munksgaard, 1994, pp 128155

217
17. Crompton AW: Development and adaptation of the temporomandibular joint, in Carlson DS, McNamara JA Jr, Ribbens KA (eds): Developmental Aspects of Temporomandibular Joint Disorders. Ann Arbor, MI,
Center for Human Growth and Development, University of Michigan,
1985, pp 1-18
18. Hall BK: The fate of adventitious and embryonic articular cartilage in
the skull of the common fowl, Gallus Domesticus (Aves: Phasianidae).
Aust J Zool 16:795-805, 1968
19. Hall BK: Immobilization and cartilage transformation into bone in the
embryonic chick. Anat Rec 173:391-404, 1972
20. Glineberg RW, Laskin DM, Blaustein DI: The effects of immobilization
on the primate temporomandibular joint. A histologic and histochemical study. J Oral Maxillofac Surg 40:3-8, 1982
21. Lydiatt DD, Davis LF: The effects of immobilization on the rabbit temporomandibular joint. J Oral Maxillofac Surg 43:188-193, 1985
22. Duterloo HS, Wolters JM: Experiments on the significance of articular
function as a stimulating chondrogenic factor for the growth of secondary cartilages of the rat mandible. Trans Eur Orthod Soc 103-115, 1971
23. Engelsma SO, Jansen HWB, Duterloo HS: An in vivo transplantation
study of growth of the mandibular condyle in a functional position in
the rat. Archs Oral Biol 25:305-311, 1980
24. Copray JCVM, Dibbets JMH, Kantomaa T: The role of condylar cartilage in the development of the temporomandibular joint. Angle Orthod
58:369-380, 1988
25. Durkin J, Heeley J, Irving JT: The cartilage of the mandibular condyle.
Oral Sci Rev 2:29-99, 1973
26. Petrovic AG, Stutzmann JJ, Oudet CL: Defects in mandibular growth
resulting from condylectomy and resection of the pterygoid and masseter muscles, in McNamara JA Jr, Carlson DS, Ribbens KA (eds): The
Effect of Surgical Intervention on Craniofacial Growth, Monograph
Number 12, Craniofacial Growth Series. Ann Arbor, MI, Center for
Human Growth and Development, University of Michigan, 1982, pp
251-272
27. Silbermann M, Weiss A, Toister Z, et al: Studies on hormonal regulation
of the growth of the craniofacial skeleton: I. Effects of a glucocorticoid
hormone on cartilage calcification. J Craniofac Genet Dev Biol 1:285298, 1981
28. Maor G, Hochberg Z, Silbermann M: Growth hormone stimulates the
growth of mouse neonatal condylar cartilage in vitro. Acta Endocrinol
120:526-532, 1989
29. Silbermann M, Shurtz-Swirski R, Lewinson D, et al: In vitro response of
neonatal condylar cartilage to simultaneous exposure to the parathyroid hormone fragments 1-34,28-48, and 53-84 hPTH. Calcif Tissue
Int 48:260-266, 1991
30. Tajima Y, Kawasaki M, Kurihara K, et al: Immunohistochemical profile
of basic fibroblast growth factor and heparan sulfate in adult rat mandibular condylar cartilage. Arch Oral Biol 43:873-877, 1998
31. Ogawa T, Shimozuma K, Fukada K, et al: Localization and inhibitory
effect of basic fibroblast growth factor on chondrogenesis in cultured
mouse mandibular condyle. J Bone Miner Metab 21:145-153, 2003
32. Fuentes MA, Opperman LA, Bellinger LL, et al: IGF-1 and FGF-2 regulate cell proliferation of rat mandibular condylar cartilage in explant
culture. Arch Oral Biol 47:643-654, 2002
33. Molteni A, Modrowski D, Hott M, et al: Differential expression of fibroblast growth factor receptor-1, -2, and -3 and syndecan-1, -2, and -4 in
neonatal rat mandibular condyle and calvaria during osteogenic differentiation in vitro. Bone 24:337-347, 1999
34. Visnapuu V, Peltomaki T, Ronning O, et al: Distribution of fibroblast
growth factors (FGFR-1 and -3) and platelet-derived growth factor
receptors (PDGFR) in the rat mandibular condyle during growth.
Orthod Craniofac Res 5:147-153, 2002
35. Maor G, Laron Z, Eshet R, et al: The early postnatal development of the
murine mandibular condyle is regulated by endogenous insulin-like
growth factor- I. J Endocrinol 137:21-26, 1993
36. Xiao-Bing LI, Zhou Z, Luo S-J. Expressions of IGF-1 and TGF-1 in the
condylar cartilages of rapidly growing rats. Chin J Dent Res 2:52-56,
1998
37. Visnapuu V, Peltomaki T, Ronning O, et al: Growth hormone and

R.J. Hinton and D.S. Carlson

218

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

insulin-like growth factor-I receptors in the temporomandibular joint

of the rat. J Dent Res 80:1903-1907, 2001
Maor G, Hochberg Z, Silbermann M. Insulin-like growth factor I accelerates proliferation and differentiation of cartilage progenitor cells in
cultures of neonatal mandibular condyles. Acta Endocrinol 128:56-64,
1993
Livne E, Laufer D, Blumenfeld I. Differential response of articular cartilage from young growing and mature old mice to IL-1 and TGF-beta.
Arch Gerontol Geriatr 24:211-221, 1997
Oberbauer AM, Peng R. Fractionation of growth plate chondrocytes:
Differential expression of IGF-I and growth hormone and IGF-I receptor mRNA in purified populations. Connect Tissue Res 31:179-187,
1995
Deng C, Wynshaw-Boris A, Zhou F, et al: Fibroblast growth factor
receptor 3 is a negative regulator of bone growth. Cell 84:911-921,
1996
Molteni A, Modrowski D, Hott M, et al: Alterations of matrix- and
cell-associated proteoglycans inhibit osteogenesis and growth response
to fibroblast growth factor-2 in cultured rat mandibular condyle and
calvaria. Cell Tissue Res 295:523-536, 1999
Watahiki J, Yamaguchi T, Irie T, et al: Gene expression profiling of
mouse condylar cartilage during mastication by means of laser microdissection and cDNA array. J Dent Res 83:245-249, 2004
Kronmiller JE, Upholt WB, Kollar EJ: Expression of epidermal growth
factor mRNA in the developing mouse mandibular process. Arch Oral
Biol 36:405-410, 1991
Silbermann M, Weiss A, Raz E: Retardative effects of a corticosteroid
hormone upon chondrocyte growth in the mandibular condyle of neonatal mice. J Craniofac Genet Dev Biol 1:109-122, 1981
Lewinson D, Bialik GM, Hochberg Z: Differential effects of hypothyroidism on the cartilage and the osteogenic process in the mandibular
condyle: recovery by growth hormone and thyroxine. Endocrinology
135:1504-1510, 1994
Ramirez-Yanez GO, Young WG, Daley TJ, et al: Influence of growth
hormone on the mandibular condylar cartilage of rats. Archs Oral Biol
49:585-590, 2004
Collins DA, Becks H, Simpson ME, et al: Growth and transformation of
the mandibular joint in the rat: I. Normal female rats. J Orthod Oral
Surg 32:431-442, 1946
Hoskins WE, Asling CW: Influence of growth hormone and thyroxine
on endochondral osteogenesis in the mandibular condyle and proximal
tibial epiphysis. J Dent Res 56:509-517, 1977
Livne E, Laufer D, Blumenfeld I: Comparison of in vitro response to
growth hormone by chondrocytes from mandibular condyle cartilage
of young and old mice. Calcif Tissue Int 61:62-67, 1997
Copray JCVM, Brower N, Prins APA: Effects of polypeptide growth
factors on mandibular condylar cartialge of the rat in vitro. J Biol Buccale 16:109-117, 1988
Iseki S, Wilkie AOM, MorrissKay GM: Fgfr1 and Fgfr2 have distinct
differentiation- and proliferation-related roles in the developing mouse
skull vault. Development 126:5611-5620, 1999
Rice DPC, Aberg T, Chan Y-S, et al: Integration of FGF and Twist in
calvarial bone and suture development. Development 127:1845-1865,
2000

54. Kronenberg HM: Developmental regulation of the growth plate. Nature

423:332-336, 2003
55. Karaplis AC: PTHrP: novel roles in skeletal biology. Curr Pharm Des
7:655-670, 2001
56. Lanske B, Karaplis AC, Lee K, et al: PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273:
663-666, 1996
57. Vortkamp A, Lee K, Lanske B, et al: Regulation of rate of cartilage
differentiation by Indian Hedgehog and PTH-related protein. Science
273:613-622, 1996
58. Alvarez J, Horton J, Sohn P, et al: The perichondrium plays an important role in mediating the effects of TGF-beta on endochondral bone
formation. Dev Dyn 221:311-321, 2001
59. Long F, Linsenmayer TF: Regulation of growth region cartilage proliferation and differentiation by perichondrium. Development 125:10671073, 1998
60. DiNino DL, Long F, Linsenmayer TF: Regulation of endochondral cartilage growth in the developing avian limb: cooperative involvement of
perichondrium and periosteum. Dev Biol 240:433-442, 2001
61. Stutzmann J, Petrovic A: Intrinsic regulation of the condylar cartilage
growth rate. Eur J Orthod 1:41-54, 1979
62. Buxton PG, Hall B, Archer CW, et al: Secondary chondrocyte-derived
Ihh stimulates proliferation of periosteal cells during chick development. Development 130:4729-4739, 2003
63. Murray PDF: Adventitious secondary cartilage in the chick embryo and
the development of certain bones and articulations in the chick skull.
Aust J Zool 368:368-430, 1963
64. Charlier J-P, Petrovic A, Herrmann J: Determinisme de la croissance
mandibulaire: effets de lhyperpropulsion et de lhormone somatotrope
sur la croissance condylienne de jeunes rats. Orthod Fr 39:567-579,
1968
65. McNamara JA, Carlson DS: Quantitative analysis of temporomandibular joint adaptations to protrusive function. Am J Orthod 76:593-611,
1979
66. Fuentes MA, Opperman LA, Buschang P, et al: Lateral functional shift
of the mandible: part II. Effects on gene expression in condylar cartilage. Am J Orthod Dentofac Orthop 123:160-166, 2003
67. Hajjar D, Santos MF, Kimura ET: Propulsive appliance stimulates
the synthesis of insulin-like growth factors I and II in the mandibular condylar cartilage of young rats. Arch Oral Biol 48:635-642,
2003
68. Rabie ABM, Hagg U: Factors regulating mandibular condylar growth.
Am J Orthod Dentofac Orthop 122:401-409, 2002
69. Rabie ABM, She TT, Hagg U: Functional appliance therapy accelerates
and enhances condylar growth. Am J Orthod Dentofac Orthop 123:4048, 2003
70. Tang GH, Rabie ABM, Hagg U: Indian hedgehog: a mechanotransduction mediator in condylar cartilage. J Dent Res 83:434-438, 2004
71. Blackwood HJJ: Cellular remodeling in articular tissue. J Dent Res
45(Suppl 3):480-489, 1966
72. Thilander B, Carlsson GE, Ingervall B: Postnatal development of the
human temporomandibular joint. I. A histological study. Acta Odontol
Scand 34:117-126, 1976
73. berg T, Fajers CM, Lohmander F, et al: Autoradiographic studies with
3
H-thymidine on cell proliferation and differentiation in the mandibular joint of young guinea pigs. Odontol Rev 18:327-344, 1967