Ultrastructure of the articular cartilage of the mandibular condyle: aging and degeneration

Ultrastructure of the articular cartilage of the mandibular condyle: Aging and degeneration Lumbert G. M. de Bont, D.D.S.,* Robert S. B. Liem,** and Geert Boering. D.D.S., Ph.D., *** Groningen, The Netherlands

OROFACIAL RESEARCH GROUP, UNIVERSITY OF GRONINGEN

To obtain more insight into the pathogenesis of osteoarthrosis of the temporomandibular joint, we examined the ultrastructure of articular cartilage of six healthy and sixteen osteoarthrotic human mandibular condyles. Ultrastructural changes due to aging and osteoarthrosis are described and compared with the findings of other ultrastructural studies of articular cartilage of synovial joints. Aging was accompanied by some slight degenerative signs. Osteoarthrotic hyaline cartilage and fibrocartilage showed a striking similarity. The only ultrastructural difference was the presence of elastic fibers in the latter. Therefore, both seem to have the same pathogenesis. Several current statements on the pathogenesis of osteoarthrosis are discussed. (ORAL SURC. ORAL MED. ORAL PATHOL. 60~631-641, 1985)

A lthough osteoarthrosis (degenerative joint disease, osteoarthritis, and arthrosis deformans) is an extremely common disease of synovial joints, the pathogenesis still remains obscure.‘-3 The articular cartilage of most synovial joints consists of hyaline cartilage. Only the temporomandibular joint (TMJ) and the sternoclavicular joint are covered with fibrocartilage.4 Except for this difference, one can expect that the TMJ, being a synovial joint, will show great morphologic resemblance to the joint components of other synovial joints in health as well as in disease. Age-related changes in human synovial joint morphology are well described, despite the scarcity of suitable juvenile material for ultrastructural studies.5S9 Age-related changes in human TMJ morphology are described only on a light microscopic leve1.10-‘4 Ultrastructural characteristics of TMJ articular cartilage due to aging are still not known.

The clinical features and gross radiographic changes in cases of osteoarthrosis of the TMJ have

*Department of Oral and Maxillofacial Surgery, University Hospital Groningen. **Research Associate, Department of Oral Biology, University of Groningen. ***Professor and Head, Department of Oral and Maxillofacial Surgery, University Hospital Groningen.

been well described.‘5-‘8 The histopathologic features of osteoarthrosis of the TMJ are also well known.3v lo, II, ‘9x 2o However, the sequence of events in the pathogenic pathway on a microscopic and a submicroscopic level in the development of degenerative changes of the TMJ has not been determined. It is reasonable that an understanding of the nature of histopathologic conditions can be greatly enhanced by electron microscopic studies.9, 21 Thus, in their ultrastructural study, Meachim and Roy’ described a surface disintegration too minute to be seen with the light microscope. In his electron microscopic studies of osteoarthrotic mandibular condylar cartilage, Tol- ler22*23 described profound ultrastructural changes that affect the joint’s sliding properties and its mechanical integrity under loading stress. The aim of the present study is (1) to describe the ultrastructure of articular cartilage from aged healthy and osteoarthrotic mandibular condyles, (2) to compare the ultrastructural characteristics of TMJ osteoarthrosis with those of other studies, and (3) to interpret the findings in order to obtain greater insight into the pathogenesis of osteoarthrosis.

MATERIALS AND METHODS

Twenty-two specimens of articular cartilage taken from mandibular condyles were examined. Six mandibular condyles not affected by degenerative joint

631

632 de Bont, Liem and Boering

Fig. 1. Chondrocyte from the fibrocartilaginous zone of Fig. 2. Articular zone of a healthy mandibular condyle a healthy mandibular condyle. N, Nucleus. CP, Cell (aged 53 yearsj. AS, Articular surface. The collagen fibrils processes. A well-developed rough endoplasmic reticulum are organized in layers nearly parallel to the articular is observable (arrows), indicating an active cell. The surface. The most superficial layer shows a looser texture. territorial matrix, consisting of proteoglycan particles and Fibril diameter is not uniform. Note the thin surface layer associated filaments, appears more electron-dense than the of electron-dense material (arrows). (TEM. Magnification, general matrix. (TEM. Magnification, ~9,184.) x12,160.)

disease were obtained from specimens obtained during hemimandibulectomies performed for oncologic reasons. The patients, ranging in age from 53 to 88 years (mean, 68 years), had different types of malig- nant lesions in the mandible beyond the TMJ region. The other sixteen condyles were obtained during TMJ surgery (high condylectomy) from twelve patients who for many years had suffered from severe TMJ pain as a result of degenerative joint disease. These twelve patients, ranging in age from 18 to 48 years (mean, 33 years), were all women.

After dissection, the mandibular condyles were immediately transferred to a fixative containing 0.5% glutaraldehyde and 2% paraformaldehyde in 0.1 M sodium cacodylate buffer, pH 7.4. After a fixation period of several weeks, all specimens were divided into 2 mm thick slices by cutting the condyle in the sagittal plane with a 0.15 mm thick water- cooled diamond blade. Each slice consisted of full- thickness articular cartilage with the underlying subchondral bone. Two adjacent slices, from the

midsagittal to the lateral part of the condyle, were submitted for light microscopy (LM) and transmis- sion electron microscopy (TEM), respectively. In order to select areas of interest for TEM, the LM samples were decalcified in a solution of 25% formic acid containing 10% sodium citrate, pH 7.0, dehydrated in a graded series of ethanol and embedded in Paraplast. Serial sections, 7 microns thick, were prepared and stained with hematoxylin and eosin and by the Van Gieson method. After LM examination, the TEM slices were dissected into smaller samples measuring 2 x 2 x 2 mm, each consisting of full- thickness articular cartilage and subchondral bone. Thereafter, these samples were washed in several changes of 0.1 M sodium cacodylate buffer and postfixed in a solution of 1% osmium tetroxide in 0.1 M sodium cacodylate buffer, pH 7.4, for 2 to 4 hours. The samples were rinsed and stored in the buffer solution for one night. Then the samples were dehydrated in a graded series of ethanol and propy- lene oxide and embedded in Polybed 8 12. Semithin

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Yltrastructure of articular cartilage of condyle 633

Fig. 3. Fibrocartilaginous zone of a healthy mandibular condyle (aged 63 years), showing a tight network of collagen fiber bundles. Note the variations in fibril diameter. (TEM. Magnification, X7,886.)

(1 pm) sections were cut with a Reichert OMU4 ultramicrotome, stained with toluidine blue, and examined with a light microscope to select areas of interest for electron microscopy. Ultrathin sections, approximately 60 nm thick, were prepared with a diamond knife, mounted on 200-mesh naked or formvar-coated one-hole grids, and stained with uranyl acetate and lead citrate. The sections were examined and photographed with a Philips transmis- sion electron microscope EM-201 or EM-300.

RESULTS Healthy condyles of aged persons

Cells. Chondrocytes and fibrocytes were found distributed throughout the articular cartilage. Blast- like or immature cells and necrotic cells were seen frequently. The chondrocytes were rounded, sometimes irregularly polygonal in shape. They contained a well-developed rough endoplasmic reticulum and were well endowed with Golgi apparatus and mitochondria, indicating cell activity (Fig. 1). The fibrocytes showed a flattened configuration with their long axes predominantly parallel to the articular surface.

Fig. 4. Interface between subchondral bone (SB) and articular cartilage of a healthy mandibular condyle. It is an exception that mineral nodules are absent as shown in this section. Note the alignment of some collagen fibrils running perpendicular to the subchondral bone. (TEM. Mag- nification, X 12,564.)

The fibrocytes predominated in the articular zone, the fibroblasts and chondroblasts in the proliferative zone, and the chondrocytes in the deeper zones. Identification of the proliferative zone was possible only on rare occasions.

Matrix. The articular cartilage matrix consists of collagen fibrils and interfibrillar ground substance, the proteoglycans. As described earlier, the collagen fibrils create a network with a special system in every zone.24 In the articular zone the collagen fibrils were predominantly arranged in layers of interlacing fibrils running nearly parallel to the surface. The main alignment of the fibrils differed in every layer, while the surface layer showed a looser texture. All collagen fibrils were characteristically banded. The fibril diameter varied remarkably. Proteoglycan particles were scarcely detectable. Occasionally, electron-dense material was seen as a thin surface covering and focally just underneath the articular surface (Fig. 2).

In the fibrocartilaginous zone the collagen fibrils were organized in randomly oriented bundles, creat-

634 de Bont, Liem and Boering Oral Surg. December. 19x5

Fig. 5. Collagen fiber bundles (CFB) in the fibrocartilaginous zone of a healthy mandibular condyle (aged 53 years). Note the presence of transversely cut elastic fibers (arrows). F. Fibrocytes. (TEM. Magnification, X4,636.)

ing a tight, three-dimensional network (Fig. 3). Matrix vesicles derived from necrotic chondrocytes were scarcely found.

In the calcified cartilage zone randomly oriented dense collagen fiber bundles were found with mineral nodules near the subchondral bone. Areas without calcifications were occasionally found (Fig. 4). Elas- tic fibers were observed among the collagen fibrils in some sections. The elastic fibers were sometimes organized in layers, separating the collagen network (Fig. 5).

Osteoarthrotic condyles

Cells. Chondrocytes and fibrocytes were found throughout the tissue. The chondrocytes were frequently arranged in small groups or clusters. Many degenerated and necrotic chondrocytes were observed as evidence of increased cell death and destruction, especially in the deeper zones, while other cells appeared anatomically functional. The most prominent pathologic features observed in the degenerated chondrocytes were a prominent nuclear fibrous lamina and an accumulation of intracytoplas-

Fig. 6. Chondrocyte from the articular zone of an osteoarthrotic mandibular condyle. Note the abundant intracytoplasmic filaments (IF) and a nuclear fibrous lamina (arrows) of nearly 43 nm thickness. (TEM. Magnifica- tion, X46,284.)

mic filaments (Fig. 6). They also contained a dilated or vesiculated rough endoplasmic reticulum, lysosome-like bodies, swollen mitochondria with dis- torted cristae, a few vacuoles and vesicles, and sometimes a well-developed Golgi apparatus. Degen- erated fibrocytes with vacuolated cytoplasmic inclu- sions were also found.

Matrix. A zonal classification of the matrix was difficult. The proliferative zone, the interface between the articular zone and the fibrocartilaginous zone, was never detectable.

In the superficial layers, particularly immediately beneath the articular surface, the density of the collagen fibrils was diminished. The collagen fibrils showed a loose and very disordered arrangement. The individual fibrih were reduced in diameter and showed signs of degeneration, Disintegration of fibrils into filamentous and fine granular material was noted; this electron-dense material accumulated at the articular surface (Figs. 7 and 8). Wavy surface layers resulting in articular undulations or shallow clefts were also noted (Fig. 8).

In the deeper layers, the collagen fiber bundles

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Uhrastructure of articular cartilage of condyle 636

Fig. 7. Surface area of the articular zone of osteoarthrotic articular cartilage. The collagen fibrils disintegrate into fine granular structures which create a layer of amorphous electron-dense material at the articular surface (AS). Note the wide separation of collagen fibrils. (TEM. Magnification, ~36,480.)

showed a looser texture, and numerous elastic fibers were found. A disruption of the general matrix and a reduction of normal collagen content were noted (Figs. 9 and 10). Collections of giant collagen fibrils varying from 180 to 200 nm in diameter were found. Occasionally, solitary giant collagen fibrils were seen (Figs. 11 and 12).

Numerous matrix vesicles (Fig. 13) and lipid globules (Fig. 14) derived from necrotic chondrocytes were found throughout the matrix. Needle- shaped calcium apatite crystals were often seen inside these vesicles and globules representing the so-called mineral-containing matrix vesicles and mineral nodules. Both structures were more frequently found in the region adjoining the calcified cartilage, whereas the collagen density was diminished (Fig. 15).

In the calcified cartilage zone, an increased amount of mineral nodules was found (Fig. 16).

DISCUSSION

Aged articular cartilage of the TMJ scarcely shows ultrastructural degenerative changes. The

Fig. 8. Undulation of an osteoarthrotie articular surface. The collagen fibrils follow the surface contour. Electron-dense as well as fine fibrillar material is situated at the articular surface (AS) and accumulated between the collagen fibrils (arrows). (TEM. Magnification, x21,920.)

fibrous component of the matrix consists of a well- organized collagen network, occasionally dispersed with elastic fibers. The presence of elastic fibers may correlate with the age-related loss of tensile fatigue strength in the fiber network of the articular cartilage matrix, as described by Weightman and Kemp- son.25 We agree that such a loss of fatigue strength with age indicates a change in the matrix components and their interrelationships.8 However, the total amount of collagen in the articular cartilage of synovial joints normally does not decrease during aging; maybe the amount of cross links and the binding quality of the proteoglycans do.26 The proteoglycan content decreases and its composition changes with age. The proportion of keratan sulfate increases and chondroitin sulfate concentration decreases. Finally, the cellularity decreases during aging.32 Such age-related changes in the articular cartilage affect the mechanical properties of the articular cartilage, which may facilitate the pathogenesis of osteoarthrosis. g.27 It seems clear that our knowledge of age-related TMJ changes will increase substantially if further studies are made by compar-

636 de Bont, Liem and Boering Oral Yurg. Lkcember, 19X'

Fig. 9. Loss of collagen content in the deeper layers of osteoarthrotic articular cartilage. Cross-sectioned elastic fibers (arrows) are distributed throughout the disrupted general matrix between the collagen fibrils. (TEM. Mag- nification, X3,904.)

ing the data obtained from younger and older TMJ specimens.

Osteoarthrotic articular cartilage shows several ultrastructural changes in the cells and matrix as summarized in Table I. Comparing our results with those of Ghadially’s extended ultrastructural studies on osteoarthrotic cartilage of synovial joints,9 it can be concluded that osteoarthrosis of fibrocartilage shows generally the same ultrastructural changes that osteoarthrosis of hyaline cartilage does. There- fore, we may conclude that osteoarthrosis is a disease of synovial joints without differentiation between fibrocartilage and hyaline cartilage.

Comparing our results with Toller’s,**~ 23 we found a greater number of ultrastructural changes. Toller’s conclusion that the ultrastructural appearances of articular cartilage from frank degenerative joint disease of the mandibular condyle are indistinguish- able from material obtained from patients with pain-dysfunction syndrome confirms our clinical impression that the pain-dysfunction syndrome, arthropathy, and osteoarthrosis of the TMJ are synonyms of the same degenerative joint disease,

Fig. 10. Detail of a longitudinally cut elastic fiber (Et;]. CF, Collagen fibrils. (TEM. Magnification, Xl 1.200.)

with its characteristic signs and symptoms.15, 18, 20, 22. 23. 3o Generally speaking, osteoarthrosis begins focally in the articular cartilage without clinical symptoms. In later stages clinical signs and symptoms become evident, and in the final stages degenerative radiographic signs appear.3’-33 As pointed out by Boering” in his extended clinical study on osteoarthrosis of the TMJ, radiographic changes often occur after a certain period of severe pain and dysfunction.16, 3o, 34 Conversely, the confusing absence of correlation between joint symptoms and the extent or degree of pathologic or roentgenologic changes has been described several times.35 This phenomenon can be clarified by the structural relationship between osteoarthrosis and aging. Several age-relat- cd changes, such as fibrillation and lipping, are also histopathologic characteristics of osteoarthrosis and structurally not distinguishable from each other.7-9* 331 36 Remodeling, a physiologic mechanism in bone and cartilage, results in reshaping of form and size of the joint components, whereas the mechanical integrity of the articular surfaces remains intact. Conversely, reshaping of joint components can also be a sign of osteoarthrosis3’ As reviewed by Howell,2 there are currently three major types of osteoarthrosis relative to etiology and patho-

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Ultrastructure of articular cartilage of condyle 637

Fig. 11. Collection of giant collagen fibrils (diameter 18.J200nm) in osteoarthrotic articular cartilage. (TEM. Magnification, ~39,672.)

genesis. The first is based on the major role of physical.forces and biomaterial failure of the articular cartilage. The second attributes a major part of the disease to failing articular chondrocyte responses involving both degradation and repair. The third considers extracartilaginous factors, such as bone remodeling, synovial responses, microfractures, and vascular changes, as primary problems.2 The results of the present study support mainly the first type but also support the second type. However, to understand the nature of the condition, more insight into the sequence of events in the development of degenerative changes is needed.38 The dilemma of which came first has not been resolved by our ultrastructural results at present. The most striking degenerative change ,in our study was the disintegration of the collagen network with fragmentation of the collagen fibrils into filamentous and granular material that accumulated in the surface layers. Collagen network disintegration permitted the proteoglycans to imbibe more water. As a result of this imbibition, the cartilage swelled, the collagen fibrils became more separated, and the proteoglycans leaked from the matrix. This proteoglycan depletion accompanied by collagen network disintegration dramatically im-

Fig. 12. Detail of a giant collagen fibril. Major and minor bands are evident. The perk&city of the banding is 59 nm. Compare the diameter of the giant collagen fibril with the diameter of surrounding normal collagen fibrils. (TEM. Magnification, x42,864.)

paired the mechanical capacity of the articular cartilage. The cartilage matrix developed structural failure from repeated application of cyclic loading at stresses and frequencies that it was able to withstand without damage at first. 2* 8, 3o In such a weakened joint, normal loading can injure the articular tissues, as a repetitive overload might do in a healthy joint.

We agree with Ghadially9 and Weiss and Mirow2* that articular cartilage is not an indolent tissue but one that reacts to degenerative changes leading to a loss of cells, collagen, and proteoglycans by producing each of these elements in an abortive attempt at repair and regeneration. The proliferative zone of the articular cartilage of the mandibular condyle should have such a reparative capacity.12 It is evident also from the present study that an attempt to compen- sate for loss of cells and matrix occurs in osteoarthrotic cartilage. The formation of chondrocyte clusters and the presence of many active cells, well endowed with a rough endoplasmic reticulum and Golgi apparatus, which represent active processing of proteoglycans and collagen, can be considered as a reparative response. Collagen synthesis in osteoar-

636 de Bont, Liem and Boering Oral Surg. December, 1985

Fig. 13. Numerous electron-dense matrix vesicles scattered throughout the general matrix. The chondrocytes show signs of degeneration such as vacuohzation in the cytoplasm. (TEM. Magnification, ~5,505.)

throsis should be substantially greater than in healthy joints. 39 However, the rate of collagen loss as well as proteoglycan loss in osteoarthrosis is greater than the rate of its synthesis.28~40 The presence of a prominent nuclear fibrous lamina in a cartilage cell and an accumulation of intracytoplasmic filaments represent a pathologic state.41 The presence of electron-dense lysosome-like bodies indicates an increased amount of several lysosomal enzymes. Not only the lysosomal enzymes, such as cathepsins D, B, and F, and cysteine proteinases which are proteoglycan- and collagen-degrading proteinases, but also several other enzymes such as collagenase (a metal- loproteinase), collagenase inhibitors (a tissue inhibi- tor of metalloproteinases), hyaluronidase, and acid and alkaline phosphatase, might be involved in osteoarthrotic cartilage breakdown.g.26*42-46 The increased amount of necrotic chondrocytes causes an increase in matrix vesicles and lipid globules derived from them. These structures are scattered within the collagen fibrils, seem to serve as initial sites for calcium deposition, and are known to play an impor- tant role in cartilage calcification.26* 29* 4’* 47 However, as seen frequently in the present study, the increased amount of mineral-containing matrix vesicles is

Fig. 14. Detail of matrix vesicles (arrows). lipid globules (Lj, mineral-containing matrix vesicles (arrow heads), and mineral nodules (MNj. Note the lipid globules with a corona of needle-shaped crystals (star). (TEM. Magnificd- tion, ~32,832.)

accompanied by a focal decrease in collagen content and a disintegration of the matrix. We therefore presume that both phenomena impair cartilage integrity under stress in the deeper layers of the osteoarthrotic articular cartilage. In this view, the horizontal splitting, as revealed by histopathologic examination, could be caused by these phenomena 3,48 Obviously, an abnormal mineralization pro- ce.& in the articular cartilage changes the local concentration of calcium. This could alter the vari- ous physicochemical properties of the tissue and thus may cause a stiffening of the deeper layers of the articular cartilage.29,49

The increased amount of elastic fibers in osteoarthrotic articular cartilage of the mandibular condyle, as found by Tollerz2, 23 and in the present study, may contribute to the mechanical failure of the articular cartilage. We agree with Toller that this phenomenon may be a form of stress elastosis, but it might be also an age-related change. However, so far as we know, elastic fibers were found only in the osteoarthrotic fibrocartilage and not in the osteoarthrotic hyaline cartilage. Pre-elastic filaments or oxytalan filaments were noted by Silva50 in the TMJ of the guinea pig as a collection of electron-dense filaments.

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Fig. 15. Detail of the area adjoining the calcified cartilage. Note the absence of collagen fibrils. MN, Mineral nodules. MV; Matrix vesicles. Arrows, Mineral-containing matrix vesicles. (TEM. Magnification, X44,688.)

Fig. 16. Calcified cartilage zone (CCZ). Note the numerous mineral nodules (MN). (TEM. Magnification, x16,000.)

Table I. Summary of the ultrastructural changes in human osteoarthrotic articular cartilage

Mandibular Mandibular Ariicular condyle condyle cartilage Articular Knees Knees

(de Bont et al., (Toller/Wileox, (Ghadially. cartilage ( Weiss/Mirow, (Meachim/Roy, Specimen 1985) 1977, 197PlrJ 19839) (Ali 198P”) I 972z8) 1968, I969*, ‘)

Chondrocytes Clusters of chondrocytes + - + + + Prominent nuclear fibrous lamina k - + Dilated rough endoplasmic + -c + CL +

reticulum Accumulation of intracytoplasmic + - + t +

filaments Electron-dense lysosome-like bodies t - + + + Increased cell death and cell + - + + +

destruction Matrix Increased amount of matrix vesicles ++ - ++ ++ + + Mineral-containing matrix vesicles ++ - * ++ Degeneration/disintegration of + + iT + +

collagen Giant collagen fibrils + - + - Elastic fibers ++ ++ - Electron-dense material at surface + + t + + Infoldings of articular surface + + f + +

++ = Abundant. ‘- + = Present. r = Scarce. - = Absent.

640 de Bont, Liem and Boering orat Surg. December. I985

This observation was not confirmed in the present study.

The presence of giant collagen fibrils must be considered as a degenerative as well as an age-related change in articular cartilage. A collection of giant collagen fibrils creates a microscar, termed amianthoid degeneration.5’ The significance of this change, as of several other ultrastructural changes in osteoarthrotic articular cartilage, is still not clear.4’ We agree with Ghadially9 that ultrastructural studies contribute to the understanding of the changes that occur. However, as mentioned by Weiss and Mirow,28 conventional electron microscopy does not permit assessment of osteoarthrotic changes in a truly quantitative fashion. Degradation of the matrix due to osteoarthrosis, even when dispersed in the tissue, characteristically is focal and varies from area to area in the same joint. ” Therefore, by examination of multiple ultrathin sections, which are extremely small samples, the method can serve only by producing a qualitative statement.28

On the basis of this study, ultrastructural characteristics of TMJ osteoarthrotic articular cartilage differ from those of other synovial joints only with regard to the presence of elastic fibers. However, the onset of TMJ osteoarthrosis seems to differ from other joints in that its clinical symptoms start mainly in the third decade and sometimes in early childhood as juvenile osteoarthrosis.15, 52 Therefore, some support can be found in this study for special pathogenic TMJ environmental factors, such as increased stress on the joint surfaces and neuromuscular imbalance during early life.53However, as pointed out by Ali, even excessive use of joints does not necessarily lead to osteoarthrosis. No support was found for purely dental factors in the pathogenesis of osteoarthrosis of the TMJ.16 Therefore, because of insufficient knowledge of a definitive cause of osteoarthrosis, we consider osteoarthrosis of the TMJ a primary or idiopathic osteoarthrosis. The present study supports the theory that osteoarthrosis is a multifactorial disease of synovial joints; it is the final result of an imbalance between the stress applied to the joint and its ability to tolerate that stress, perhaps influenced by degradative enzymes from the synovial mem- brane.49, 54

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Reprint requests to: Lambert G.M. de Bont Department of Oral and Maxillofacial Surgery University Hospital Ant. Deusinglaan 1 97 I3 AV Groningen, The Netherlands

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Ultrastructure of the articular cartilage of the mandibular condyle: aging and degeneration