On the importance of cAMP and Ca ÷÷ in mandibular condylar growth and adaptation Tuomo Kantomaa and Brian K. Hall** Oulu, Finland, attd Halifax, Nova Scotia, Canada

T h e role of the condylar cartilage in mandibular growth hag been an insurpassable problem in orthodontic research for, despite extensive investigations and even more discussion, there is no agreement about the.relationship between function and the condylar cartilage. Some researchers believe this cartilage plays a totally subordinate role, while others maintain that it plays a far more active one, and there has been some movement in opinion toward the view that condylar cartilage growth is not independent of environmental factors but can be affected by function. The purpose of this review is to discuss in the light of existing literature, and especially recent literature, the nature of the growth of the condylar cartilage and the effect of function on it. HISTOLOGY OF THE MANDIBULAR CONDYLE Proliferating cells

Secondary cartilages develop on membrane bones as chondrogenie evocations of periosteal cells in response to mechanical stress. They do not develop in the absence of such stress, as shown in paralyzed chicken embryos, for instance, x-' All secondary cartilages in birds develop from periosteal cells, whereas the mammalian condylar cartilage, which is a secondary cartilage, develops as a cellular blastema separate from the body of the mandible. 5s In contrast to avian secondary cartilages, the condylar cartilage develops independently of muscle function or movement and will develop in organ culture in the absence of any function. 9 The proliferating cells in the postnatal mandibular condyle t°12 are considered to be relatively undifferentiated mesenchymal cells that later differentiate, mature, and enlarge, becoming first chondroblasts and then hypertrophic chondrocytes.X3x7 It seems, however, that these proliferating mesenchymal cells are already committed to becoming chondroblasts and have some features of these cells--e.g., differentiation is initiated "Institute of Dentistry, University of Oulu, Finland. **Department of Biol.ogy, Dalhousie University. Halifax, Nova Scota. Canada. 811/19998

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during embryogenesis, when the cellular density of the condylar blastema increases. Petrovic ~s regards skeletoblasts as serving as a cell pool for the more actively dividing prechondroblasts. These cells would differentiate only into chrondroblasts. Skeletoblasts would differentiate spontaneously into preosteoblasts elsewhere. Although collagen type II has not been found in the proliferating cell layer, the intercellular matrix of these cells in the periochondrium of postnatal condyles already shows metachromasia, while that in the periosteum does not. x9 Metachromasia, after staining with toluidine blue dye, reveals the secretion of acid mucopolysacharides into the extracellular matrix and is a sign of chondroblast differentiation. :° Postnatal growth is thus a progressive expression of differentiation. The mesenchymal cells have been found to continue to mature into chondroblasts without the underlying hypertrophic cartilage and without articulating function, to the point that most of the tissue explant has hypertrophied and mineralized. 2''22 Kosher23 states that, after initial differentiation, extracellular matrix synthesis and deposition allow the cartilage to selfdifferentiate. Thus the permissive factor for chondrogenesis in proliferating cells would not be function, as such, but the extracellular matrix. It has been suggested that the proliferating cells should not be included as part of the condylar cartilage, '6 which would then comprise only hypertrophic cartilage. This concept does not seem logical in the light of the foregoing statements. After all, these proliferating cells serve to produce the condylar cartilage. The mandibular condylar cartilage differs in development from many other secondary cartilages in that its origin is not periosteal and it develops in the absence of function. The proliferating cells are prechondroblasts that already show features of chondroblasts. The cells continue chondrogenesis for a short time, even without any articulating function, under transplantation and organ-culture conditions.

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GROWTH OF THE CONDYLAR CARTILAGE AND ITS ARTICULATING FUNCTION

In general, the chemical and structural properties of cartilage may be said to be ideal to sustain loading. Collagen gives tensile strength, and the proteoglycans provide resilience. 24A dilemma nevertheless exists over the effect of function on the mandibular condylar cartilag.e. The generally accepted hypothesis that function is somehow needed for the continuation of postnatal growth in the mandibular condyle 17"25'z6can be regarded as a basis for discussion. To clarify further the role of function on condylar growth, we shall first look at the factors that may mediate the effects of function on cells. DIFFERENTIATION OF THE CELLS IN THE CONDYLAR CARTILAGE AND ARTICULATING FUNCTION The role of cAMP in differentiation of mesenchymal cells of the mandibular condyle

Proliferating cells in the mandibular condyle are relatively undifferentiated mesenchymal cells or prechondroblasts,which later mature and hypertrophy (see previous section). Function affects the maturing process and may be mediated by cAMP and Ca + +. Cyclic AMP, which is produced in the cell membrane by the action o~- the enzyme adenyl cyclase and is destroyed in the cytosol by phosphodiesterase, affects the activity of many enzymes that already exist in the cell. 27"2s The relationship between cAMP and Ca +÷ is a very complicated one. One possibility is that Ca ++ may inhibit adenyl cyclase, leading to reduced intracellular cAMP levels. On the other hand, cAMP causes a release of intracellular Ca + +,27-29 C a + + could thus act either directly or through regulation of the amount of cAMP. It has recently been suggested that cAMP may affect the phosphorylation of the non-histone protein designated PCP 35.5 (precartilage chromatin protein), since this phosphorylation increases 12- to 15-fold in the presence of cAMP. A loss of precartilage chromatin protein is thought to be involved in the reorganization of chromatin, which would further lead to changes in gene expression during chondrogenesis. 3° Because there is a lot to explain in the relationship between these two, they will be discussed separately. In other embryonic cartilages in which cAMP has been studied, its concentration has been shown to change during embryogenesis along with the differentiation of mesenchymal cells into precartilage and cartilage cells. 3~33 Hunter and Caplan ~ found that the cAMP level increased concomitantly with increasing cell density in the limb bud, followed by cartilage cell differentiation. Solursh et al: 33 observed similar alter-

41 9

ations in the wing mesenchyme simultaneously with cartilage expression. This did not happen in low-density cultures, but after the addition of cAMP the mesenchymal cells differentiated into chondrogenic cells. Solursh et al. a3 concluded that the rise in cAMP was a result of cell-to-cell interaction. The differentiation state of the cells and the length of exposure to elevated cAMP levels may also have an effect. Solursh et al. 3-" found that cells from stage 19 chick embryos did not react to butyrylated cAMP, whereas cells from stage 24 chick wings did, and they differentiated into chondroblasts. Also, the degradation of exogenous cAMP increases the intracellular adenosine level, which inhibits many cellular functions. Butyrylated cAMP derivatives do not have this effect. The only study dealing with the effect of cAMP on differentiationin the mandibular condyle is that in which Copray and Jansen 35 cultured mandibular condyles from 4-day-old rats and added cAMP to the culture medium. When the transition of young chondroblasts to a hypertrophic state was accelerated, the total length of the transplants, as compared with the controls, increased. In conclusion, a rise in cAMP seems "to accelerate the differentiation of mesenchymal cells and their maturation to hypertrophic ceils. It should be mentioned, however, that the role of the rise in cAMP level is not unique to chondrogenesis, for similar findings have been reported regarding the differentiaton of skeletal muscle, 36"37 mammalian secondary palatal epithelium, ~s'39heart, "° and pigment cells, 4~ for instance. The statement of Friedman 2s that cAMP hardly causes any differentiaton itself but, rather, enhances the expression of differentiation thus seems justified. Ca* + and differentiation

Ca ++ ions are another important factor in the differentiation of mesenchymal to chondrogenic cells. Chondrogenesis was enhanced when Ca + ÷ was present in the culture medium, 42 and it seemed to mediate the effect of high cell density and Was also able to initiate chondrogenesis in normally nonchondrogenic, low celldensity cultures. Bee and Jeffries 43 later reported a steady increase in the intracellular calcium level, claiming that this increase is an essential factor for chondrogenesis in limb bud mesenchyme. Petrovic ~sreports that intracellular Ca ++ levels increase when prechondroblasts of the mandibular condyle mature. It has also been shown that chondrocytes have higher intracellular Ca ++ concentrations than many other cell types, ~4 although unusually high levels achieved with retinoic acid inhibited chondrogenesis. 4~ Deshmukh et al. 4s nevertheless found that collagen type II was produced if the

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culture medium did not contain Ca + + but that the chondrocytes switched their synthesis to collagen I when Ca ++ was added. The same effect was achieved by increasing intracellular calcium two- to threefold with the Ca ionophore A23187. This result is in accord with the findings of San Antonio and Tuan 4"- and Bee and Jeffries, 43 provided that the two- to threefold increase in the calcium level is considered unusually high. To the surprise of researchers, calcium seemed to elevate cAMP levels in the cells. A further interesting point is the observation by Jacenko and Tuan 46 that a calcium deficiency induces the expression of a cartilage-like phenotype in chick embryonic calvaria. This seems not to agree with the above reports, which indicate that relatively high intracellular calcium is important for cartilage differentiation..Jacenko and Tuan's study does not contain any measurements of intracellular calcium, however, although cartilage expression was always observed in areas of poorly calcified bone. It may be concluded that Ca + + functions as a mediator in the initiation of chondrogenesis and that exogenous Ca + + is able to initiate chondrogenesis in normally nonchondrogenic cultures. What is the role of funcion in mandibular condyle differentiation? UrisP 7 claims that mechanical compression and avascularity are neither inductive or initiative for chondrogenesis. Instead, he emphasizes the importance of the extracellular matrix for differentiation of mesenchymal cells in general. 4s51 One is then led to ask what is the role of function, which has so convincingly been shown to be an essential factor in condylar growth, if it is really extracellular matrix that counts? In fact, extracellular matrix could link together function and the differentiaton of mesenchymal cells in the mandibular condyle. Proliferating cells in the mandibular condyle change their differentiation pathway from chondrogenic to osteogenic if environmental factors are altered. 2L5~~4The extracellular matrix is an immediate environment for these cells. First FelP 5 and then Fell and Landauer 56 found an association between the maturation of cartilage tissue and differentiation in the adjacent perichondrial mesenchymal cell population. If chondrocytes do not hypertrophy and mineralize, as the cartilages in the ear and trachea, for instance, subperiosteal ossification is not found, s7 Transplantation studies on hypertrophied and nonhypertrophied cartilages have confirmed that mature cartilage induces bone formation, whereas proliferative, nondifferentiating chondroblasts do n o t : 8-6-"

Am. J. Orthod. Dentofac. Orthop. May 1991

Findings supporting the assumption that the extracellular matrix also directs the differentiaton of condylar cartilage come from the organ-culture studies of Weiss et al., 2"- who found that the mesenchymal cells of the condylar cartilage continue differentiation to chondroblasts until the processes of hypertrophy and mineralization reach them, whereafter bone formation begins. Thus mature cartilage induces the adjacent prechondroblasts to differentiate to osteogenic instead of chondrogenic cells during normal growth. The progressive formation of a bony collar around the condylar cartilage 63 is the product of this differentiation. If maturation proceeds faster, it also hastens the formation of the bony collar and vice versa. This has been demonstrated in a mutant brachypod mouse, in which hypertrophy of the fibula is 2 weeks late as compared with the tibia or femur in the same animal or the fibula in the normal mouse. Subperiosteal osteogenesis does not appear until hypertrophy of the cartilage in the fibula starts, 2 weeks after birth. 57"6~'65 We can see that function comes into play by slowing down the maturation process in the mandibular condylar cartilage. The effect of articulating function on the condylar cartilage, and especially its maturation, has been studied recently in an in vitro experiment that monitored calcification. The mandible was articulated in different positions in a novel organ culture system that provided an articulating function for the temporomandibular joint. When the posterior part of the mandibular condyle was denied this function, maturation of the cartilage was accelerated at that point. 66 This finding agrees with the histochemical observation that metabolic activity in the posterior part of the condyle is enhanced after the mandible is forced in a distal direction. 67 The relationship between cAMP, pressure, and maturation seems to explain these findings well. The decrease in pressure leads to increased cAMP levels that enhance matu, ration. This assumption gains circumstantial support from the facts that thyroxin enhances the maturation of the condylar cartilage and that this effect is also mediated by an increased cAMP level. 68 Thus the effects of thyroxin and of reduced loading on the mandibular condyle cartilage would actually be parallel. The hypothesis that function slows down the maturation process in mandibular condylar cartilage assigns function a new role--that of keeping the cartilage tissue young and adaptive for the purpose of enabling chondrogenesis of prechondroblasts to continue. Otherwise, hypertrophy would progress too fast and would create a situation in which the extracellular matrix of the mature cartilage induced the differentiation of prechondroblasts to osteogenic rather than chondrogenic

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Fig. 1. A, Schematic presentation of growth events in the mandibular condyle in situ. Small cells in the perichondrium of the condyle enlarge and differentiate into chondroblasts and hypertrophy to become chondrocytes. New growth takes place in a posterosuperior direction. In the periphery of the condyle, where mesenchymal cells are seen in the vicinity of hypertrophied chondrocytes (darker enlarged cells), these mesenchymal cells are differentiating into osteoblasts, producing osteoid formations and a bony collar around the condylar process. B, A condylar process growing under nonfunctional conditions. Maturation and hypertrophy of the cartilage, when not slowed by articulating function, progress rapidly. Mature cartilage induces mesenchymal cells in the perichondrium to differentiate into osteoblasts instead of chondroblasts, a process that leads to a cessation of further growth in the cartilage. C, Schematic presentation of growth events in the mandibular condyle when the position of the mandible has rotated in a posterior direction--e.g., in association with mouth breathing. The anterior aspect of the condyle is now devoid of function. This development results in increased hypertrophy and maturation of cartilage there, and since a mature cartilage induces mesenchymal cells in the perichondrium to produce bone instead of cartilage, growth in the anterior aspect ceases. The increased fucntion in the posterior aspect retards maturation, however, which slows down the advancement of the bony collar. Thus the mesenchymal cells continue the productic~nof cartilage, and new growth takes place in a more posterior direction.

cells. ~ This is what happens in transplantation studies and in organ cultures without articulating function (Fig. I). 21'22.sz's4 This hypothesis also explains why the prenatal condylar cartilage is able to continue its growth for a longer period without function than is the postnatal condylffr cartilage. 69 The maturation front is farther behind the prechondroblast cell layer in prenatal cartilages than in

older cartilages, so it takes longer for the maturation process to reach the prechondroblast layer after the condyle assumes a nonfunctional state. During that time, the prechondroblasts continue their production of new cartilage. Furthermore, the hypothesis that function slows down the maturation process in mandibular condylar cartilage is in accord with the idea that when function

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is no longer present in the joint, the cartilage can be allowed to mature and be replaced by bone. A major advantage of having the switch in the differentiation pathway be transmitted only through the maturation process could nevertheless be to prevent the joint from reacting to every short-term lack of function by switching from chondrogenesis to osteogenesis. Instead, the production of chondroblasts would continue for a short time and would thus be ready to resume if function were restored. The hypothesis can also explain the adaptive mechanism in mandibualr condylar growth. 19.66 When the anterior part of the condyle (Fig. 1) is not used in articulation, as in mouthbreathing, maturation of cartilage proceeds fast there and results in a shift of the differentiation pathway from chondrogenic to osteogenie. Ho.wever, in the posterior aspect, maturation is slowed and proliferating cells are allowed to continue chondrogenesis. This reaction leads to an expansive growth in the posterior part of the condyle. We may conclude, therefore, that the low level of postnatal function in the mandibular condylar cartilage seem to favor its growth, but because the prechondroblasts of the condylar cartilage are multipotential, they switch their differentiation pathway toward the direction of osteoblasts in the absence of function, and the grow!h of cartilage ceases. This regulation of differentiation is mediated by maturation of the cartilage cells. If function is not present, maturation advances rapidly and the mature cartilage induces bone formation instead of cartilage. Cyclic AMP and Ca are important mediators in this process because they affect the advancement of maturation. PROLIFERATION OF THE CELLS IN THE CONDYLAR CARTILAGE AND ARTICULATING FUNCTION The role of cAMP in mediating the effect of function on proliferating cells

Pressure seems to increase the cellular cAMP concentration. Bourret and Rodan 7° found that a low pressure of 60 g m / c m 2 applied to a tibial epiphysis reduced the amount of cAMP from 4.08 to 3.21 pmol/10 6 cells in proliferative cells. They repeated the experiment with separated cells from these layers, with similar results. Generally, when the amount of intracellular cAMP decreases, mitotic activity increases. Deshmukh, Kline, and Sawyer ~5 found that lowering the cAMP level increased the proliferation of the cells in epiphyseal cartilage, and most other experiments seem to support this finding. -'sin'73 Opposing evidence has nevertheless been obtained-'8'74; the results of De Witt et a i . 75 a r e somewhat

Am. J. Orthod. Dentofac. Orthop. May 1991

difficult to interpret, as stretching of cells was considered to apply loading to the chondrocytes. It seems that cAMP could play a role in mediating the effect of pressure on the proliferating cells in the mandibular condyle, too. Petrovic tg regards the antimultiplicative effect of cAMP not as a direct one but as a result of the amplification of specific, growth selfregulation signals, cAMP has been found in the condylar process, although studies on its role there are few. Ehrlich et a l . 76 observed that its distribution was highly uniform in the intermediate cell layer from which it disappeared after the bite was raised with an occlusal splint fixed over the molars. If one assumes that cAMP affects the proliferation of mesenchymal cells in the mandibular condyle, this change should induce an inCrease in mitotic activity, as was indeed the case when thymidine incorporation was measured in a similar experiment. 77 However, the animals concerned were adult rather than young rats, as in the experiment of Ehrlich et al. 76 A more direct approach was that of Copray and Jansen,35 who cultured mandibular condyles in vitro and found that when cAMP was added to the culture medium, there was a decrease in the number of mitotic figures in the intermediate zone. Furthermore, the effect of a very small amount of direct pressure on the mandibular condyle, which had earlier been found to increase the mitotic activity of mesenchymai cells in vitro, was inhibited by the presence of cAMP in the medium. Copray and Jansen counted all the mitosis in the condyles and found that cAMP accelerated maturation of the chrondroblasts. Enhancement of transit of cells out of the proliferating pool and into the matur,'ttion process may also reduce the number of proliferating cells. Despite the seemingly controversial findings surrounding cAMP, it is apparent that it does play some role in mediating the effect of pressure on proliferating cells. Pressure would reduce the amount of cAMP, inducing an increase in proliferation. Effect of Ca* ÷ on cell proliferation

Ca ++ is another factor involved in both cell differentiation and proliferation in general. In addition to its above-mentioned effect of inhibiting adenyl cyclase in cell membranes and thereby decreasing intracellular c A M P , 57'7°'7s cAMP may also release intracellular Ca ++ , which would be the ultimate step in the numerous ones affecting cell function, z8 One of these steps would involve stimulating thymidylate synthesis. While thymidine is used in cell division, it also stimulates the cell division process. 2s'79 Ca + + influx into cells has been found to increase

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Fig. 2. A, Sagittal section of temporomandibular joint of 50-day-old control rabbit. B, Sagittal section of temporomandibular joint of 50-day-old experimental rabbit, in which the glenoid fossa has been shifted upward and posteriorly by means of artificial cranial synostosis. The cartilaginous layer is somewhat thicker and a concavity is seen in the erosion front.

from 0.81 to 2.07 nmol per 10 6 cells in epiphyseal proliferating chondroblasts exposed to a mild hydrostatic pressure of 60 g m / c m 2 concomitantly with an increase in cellular proliferation. The effect is thought to be mediated through the action of Ca ÷ + on cAMP. 66~s Although Ca ÷+ influx also increased from 0.75 nmol to 1.52 per 106 cells in hypertrophied chondrocytes when exposed to pressure, the cAMP level did not increase in these cells. This was attributed to the differentiating state of the cells. T° In contrast to mild

pressure (60 gm/cm2), which increases cellular proliferation in both long-bone growth plate and the mandibular condyle of the neonatal rat (forces of less than 0.5 gm), s° high forces reduce it in long-bone growth plate, s~ and forces greater than 0.5 gm suffice for this purpose in the mandibular condyle, s° No measurements of intracellular Ca + ÷ levels were made in the mandibular condyle. However, Maor and Silbermann 82 observed that when dexamethasone and the calcium ionophore A23187 elevated intracellular Ca +* in neo-

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natal condylar cartilage in vitro, they caused a dosedependent depression in cellular proliferation. Henning et al. 83 found that the effect of Ca + + was biphasic in epidermal cells (with low levels stimulating DNA synthesis and high levels inhibiting it). We do not know, however, whether this effect is also a factor in the mandibular condyle. Such a finding would be parallel to the observation of Bee and Jeffries 43 that Ca ++ enhances chondrogenesis in the limb bud mesenchyme but that an unusually high intracellular Ca ++ level, achieved with retinoic acid, inhibits it.

between the pressure changes and proliferation in the mandibular condyle. It could perhaps be concluded from these findings that a low level of function is necessary for mesenchymal cells to proceed to chondrogenesis. Any direct pressure of function on the cells, except for very small forces, will reduce mitosis. Despite the indications in the experiments of Copray s° that the level at which the effect of pressure changes from stimulating to inhibiting may be very low, the in vivo situation is still unknown.

Experiments in which condylar function is altered

The origin o f the mandibular condylar cartilage is not periosteal, like that of the other secondary cartilages; this cartilage originates in a cellular blastema of its own. Despite the fact that the development of secondary cartilages, in general, is dependent on mechanical irritation, that Of the condylar cartilage is not. The low level o f function experienced p.ostnatally seems to favor growth, but because the proliferation cells of the condylar cartilage are multipotential, they switch their differentiation pathway in the direction of osteoblasts in the absence of function, and growth of the cartilage ceases. This regulation of differentiation is mediated by maturation of the cartilage cells. If function is not present, maturation advances rapidly, and the mature cartilage induces bone formation instead of cartilage. Cyclic A M P and Ca are important mediators in this process, because they affect the advancement of maturation.

A uniform findiog has been the thickening of cartilage posteriorly in experiments in which the mandible has been forced forward, s~-ss This thickening is thought to be a result of increased mitotic activity and hypertrophy in these cartilage cells, but this reason need not be the only one. The findings on the relationships of cAMP to pressure, on one hand, and on its effect on the maturing process, on the other, could also provide an explanation. Pressure reduces the amount of cAMP, slowing down the transit o f cells from the dividing pool to the maturation process. 35 This slowing, which is reflected in a thickening of the mesenchymal cell layer, may also cause an increase in total mitotic figures. A decrease in the maturation process will result in reduced cartilage erosion, leading to thickening of the whole cartilage. The picture that emerges from numerous experiments, sSsT'sg9° of a concavity in the erosion, actually seems to give an impression that erosion has slowed down in the condyle (Fig. 2). In vivo experiments in which mitotic activity has been measured directly have shown convincingly that it changes after alterations in the functional pattern of the masticatory apparatus. Petrovic and his associates found that mitotic activity increased after the mandible was forced forward with a hyperpropulsor and decreased after a chincap had been used. 91 Folke and Stallard 92 neveretheless observed increased mitotic activity after forcing the mandible in a distal direction. This pair of experiments tells o f the difficulties in investigating single factors in in vivo experiments. Tonge et a l . 93 did not find any significant increase in proliferation of the cells in the mandibular condyle when the mandible was forced forward, but they did find an increase in the total amount of DNA. Although Tonge et al. 93 seem to exclude the possibility that function may have affected the maturation process, their finding could be explained by the assumption that function detracts from the maturation process. A number of experiments confirm the assumption that mitotic activity is affected by functional factors, but more controlled in vivo experiments are needed to determine the exact relationship

SUMMARY

REFERENCES 1. Murray PDF, Smiles M. Factors in the evocation of adventitious (secondary) cartilage in the chick embryo. Aust J Zool 1965; 13:351-81. 2. Hall BK. Differentiation and maintenance of articular (secondary) cartilage on avian membranebones. Conferenceon articular cartilage. Ann Rheum Dis [Suppl] 1975;34:145. 3. Hall BK. Selective proliferation and accumulation of chondroprogenitor cells as the mode of action of biomecbanical factors during secondary chondrogenesis. Teratology 1979;20:81-91. 4. Hall BK. The role of movement and tissue interactions in the development and growth of bone and secondary cartilage in the clavicle of the" embryonic chick. J Embryol Exp Morpbol 1986;93:133-52. 5. Moss ML. Embryology,growth and malformations of the temporomandibularjoint. In: SchwartzL, ed. Disordersof the TMJ, Philadelphia, WB Saunders, 1959. 6. Baume LJ. Ontogenesisof the human temporomandibularjoint. 1. Developmentof the condyles. J Dent Res 1962;41:1327-39. 7. Frommer J. Prenatal development of the mandibular joint in mice. Anat Rec 1964;150:449-61. 8. Duterloo HS, Jansen HWB. Chondrogenesisand osteogeuesis in the mandibular condylar blastema. Trans Eur Orthod Soc 1969:109-18. 9. Glasstone S. Differentiation of the mouse embryonic mandible and squamo-mandibularjoint in organ culture. Arch Oral Biol 1971;16:723-9.

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10. Blackwood HJJ. Growth of the mandibular condyle of the rat studied with tritiated thymidine. Arch Oral Biol 1966;11:493500. 11. Folke LEA, Stallard RE. Cellular kinetics within the mandibular joint. Acta Odontol Scand 1967;25:437-69. 12. Heeley JD, Dobeck JM, Derice RA. 3H-thymidine uptake in cells of rat condylar cartilage. Am J Anat 1983;167:451-62. 13. Rrnning O, Paunio K, Koski K. Observations on the histology, histochemistry and biochemistry of growth cartilages in young rats. Suom Hammasl~Sk Toim 1967;63:187-95. 14. Koski K. Cranial growth centers: facts or fallacies? AMJ ORTHOD 1968;54:566-8 i. 15. Koski K. Cartilage in the face. In: Birth defects: original article series. 1975;11:231-54. 16. Koski K. Reflexions on craniofacial growth research. Acta Morphol Need Scand 1985;23:357-68. 17. Meikle MC. The role of the co~ldyle in the postnatal growth of the mandible. Axi J ORTHOD 1973;64:50-62. 18. Petrovic AG. Postnatal growth of bone: a perspective of current trends, new approaches and innovations. In: Dixon AD, Sarnat, BG, eds. Factors and mechanisms influencing bone growth. New York: Alan R. Liss, 1982:297-331. 19. Kantomaa T. New aspects on the histology of the mandibular condyle in the rat. Acta Anat (Basel) 1986;126:218-22. 20. Hall BK. Histochemical aspects of the differentiation of adventitious cartilage on the membrane bones of the embryo chick. Histochemistry 1968;16:206-219. 21. Silbermann M, Lewinson D, Gonen H, Lizarre MA, yon der Mark K. In vitro transformation of chondroprogenitor cells into osteoblasts and the formation of new membrane bone. Anat Rec 1983;206:373-83. 22. Weiss A, yon der Mark K0 Silbermann MA. Tissue culture system supporting cell differentiation, extracellular mineralization, and subsequent bone formation, using mouse condylar progenitor cells. Cell Differ 1986;19:103-13. 23. Kosher RA. Inhibition of "spontaneous" notochord-induced, and collagen-induced in vitro somite chondrogenesis by the cyclic AMP derivatives and theophylline. Dev Biol 1976;53: 265-76. 24. Caplan A. Cartilage. Sci Am 1984;251:84-94. 25. Duterloo HS, Wolters JM. Experiments on the significance of articular function as a stimulating chondrogenie factor for the growth of secondary cartilages of the rat mandible. Trans Eur Orthod Soc 1971-1972;103-15. 26. Engelsma SO, Jansen HW, Duterloo HS. Growth of the mandibular condyle in a functional position: an in vivo transplantation study in the rat. Arch Oral Biol 1980;25:305-11. 27. Stockwell RA. Biology of cartilage cells. London: Cambridge University Press, 1979. 28. Friedman DL. Role of cyclic nucleotides in cell growth and differentiation. Physiol Rev 1976;56:651-708. 29. Rasmussen H. Cellcommunication, calcium ion and cyclic adenosine monophosphate. Science 1970;170:404-12. 30. Leonard CM, Newman SA. Nuclear events during early chon° drogenesis: phosphorylation of the precartilage 35.5 kDa domainspecific chromatin protein and its regulation by cyclic AMP. Dev Biol 1987;120:92-100. 31. Ahrens PB, Solursh M, Reiter RS. Stage related capacity for being chondrogenesis in cell culture. Dev Biol 1977;60:6982. 32. Solursh M, Reiter R, Ahrens PB, Pratt RM. Increase in levels of cyclic AMP during avian limb chondrogenesis in vitro. Differentiation 1979;15:183-6. 33. Solursh M, Reiter RS, Ahrens P~, Verter BM. Stage and position related changes in chondr~enic response of chick embryonic

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