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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;
Correspondence: * corresponding author, gshe6437{at}mail.usyd.edu.au
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ABSTRACT
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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
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INTRODUCTION
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Mandibular 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.
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THE DISTINCTIVE ASPECTS OF CONDYLAR CARTILAGE OVER EPIPHYSEAL AND OTHER ARTICULAR CARTILAGES
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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. 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 ).
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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 µm).
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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 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 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 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).
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CHONDROGENESIS—THE INITIAL STAGE OF CONDYLAR REMODELING
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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 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 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 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 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).
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OSTEOGENESIS—THE TERMINAL STAGE OF CONDYLAR REMODELING
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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 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.
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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 µm).
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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 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 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).
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SUMMARY
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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.
Received for publication October 5, 2004.
Accepted for publication February 17, 2005.
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Journal of Dental Research, Vol. 84, No. 8,
691-699 (2005)
DOI: 10.1177/154405910508400802
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ABSTRACT
INTRODUCTION