You are on page 1of 8

INVESTIGATIVE RADIOLOGY

Volume 35, Number 10, 573–580


©2000, Lippincott Williams & Wilkins, Inc.

Anatomy, Biochemistry, and Physiology of Articular Cartilage

MONIKA HUBER, MD,* SIEGFRIED TRATTNIG, MD,† AND FELIX LINTNER, MD*

Huber M, Trattnig S, Lintner F. Anatomy, biochemistry, and depending on the layer of the cartilage plate,3 and are
physiology of articular cartilage. Invest Radiol 2000;35:573– responsible for the production, organization, and mainte-
580.
nance of the extracellular matrix.4 The specific structural
ABSTRACT. Articular cartilage serves as a load-bearing elas- organization of articular cartilage matrix endows this tissue
tic material that is responsible for the frictionless movement of
the surfaces of articulating joints. Its ability to undergo revers-
with special mechanical properties such as tensile strength
ible deformation depends on its structural organization, in- and elasticity, which enable it to absorb and distribute loads.
cluding the specific arrangement of the matrix macromolecules Chondrocytes can “sense” changes in the composition of the
and the chondrocytes. Interactions between the matrix and extracellular matrix and respond by effecting a balance
chondrocytes are responsible for the biological and mechanical between anabolism and catabolism and continual internal
properties of articular cartilage and enable it to respond by
effecting a balance between anabolism and catabolism as well
remodeling as the cells replace matrix macromolecules lost
as continual internal remodeling. Age-related changes in the through degradation. The biological and mechanical prop-
function of chondrocytes may contribute to the initiation and erties of articular cartilage depend on the interaction be-
progression of osteoarthritis. tween the chondrocytes and the matrix.
KEY WORDS. Articular cartilage; chondrocytes; extracellular
matrix; biochemistry; osteoarthritis. Structure of Articular Cartilage
Articular cartilage produced during limb development
RTICULATING ENDS OF diarthrodial joints are covered progressively differentiates until closure of the growth plate
A by hyaline cartilage. Articular cartilage is hypocel-
lular, aneural, alymphatic, and avascular. This unique
and also serves as a temporary template for skeletal struc-
tures. Cell density and the metabolic activity of cells are
connective tissue serves as a load-bearing elastic material highest during skeletal growth. The chondrocytes divide
that is responsible for resistance to compressive forces, and synthesize in the peripheral zone’s new enlarging ma-
distribution of load, and, together with the synovial fluid, trix; the central zone serves as the center of enchondral
frictionless movement of the surfaces of articulating joint ossification of the epiphysis. In mature cartilage, metabolic
components.1,2 activity is low and cell division declines,2 but the cells
Articular cartilage contains a small number of specific continue to produce collagens, proteoglycans, and noncol-
cells, the chondrocytes, which are located in an extracellular lagenous proteins.
matrix primarily composed of water and macromolecules, Articular cartilage consists of four horizontal layers: the
including collagens, proteoglycans, and noncollagenous superficial, transitional, deep, and calcified cartilage zones
proteins. Chondrocytes vary in number, size, and shape, (Fig. 1) The zonal organization is of functional importance,
and the size of the zones varies among joints and between
various species. Cells in various layers differ in size, shape,
and metabolic activity.3,5 In adult humans, cell density is
From the *Institute of Pathology and Bacteriology, Baumgartner Höhe,
Vienna, and †MR Institute, Department of Radiology, University of Vi- highest at the articular surface and decreases with increasing
enna, Vienna, Austria. distance from the surface, as well as with advancing age in
Reprint requests: Monika Huber, MD, Institute of Pathology and Bacteriology, every zone of the tissue.6 – 8
Baumgartner Höhe 1, 1145 Vienna, Austria; e-mail: hum@pkb.magwien.gv.at
Received February 15, 2000, and accepted for publication, after revision, The superficial zone (tangential zone) is the thinnest zone
June 8, 2000. of articular cartilage. Composed of flattened chondrocytes,

573
574 INVESTIGATIVE RADIOLOGY October 2000 Vol. 35

analysis of articular cartilage14 showed that, compared with


the international standards for surface preparations used by
machinists for metal surfaces, the articular cartilage surface
could be described as being smooth.
The transitional zone (intermediate or middle zone) is
composed of rounded chondrocytes surrounded by extracel-
lular matrix. The collagen fibers are arranged randomly, and
the proteoglycan content is increased.
In the deep zone (radial or radiate zone), the chondro-
cytes are mainly grouped in columns, and the cell volume
is at its lowest. This part of the matrix is most remote
from the chondrocytes. The proteoglycan content is high
and the concentration of water lowest. The collagen
fibers in the middle and deep zones are generally oriented
toward the articular surface in large bundles approxi-
mately 55 ␮m across10 and are randomly arranged.
A wavy, irregular line known as the tide mark separates
the deep zone from the calcified zone. Ultrastructurally, it
represent a band of fibrils that may serve as a tethering
mechanism for the collagen fibrils in the noncalcified zone
to prevent them from being sheared of anchorage to the
calcified zone. Small gaps in the tide mark may provide
channels for the passage of nutrients.15 The tide mark con-
tour is highly variable. Irregularities are related to the extent
of degenerative lesions and are most prominent in periph-
eral non–weight-bearing areas of joints (see Fig. 1).
The calcified zone is characterized by rounded chondro-
Figure 1. Articular cartilage with signs of mild degeneration from
cytes located in uncalcified lacunae and by the absence of
the medial femoral condyle of a 60-year-old female patient who
received a total knee endoprosthesis because of advanced gonar- proteoglycans. The collagen fibers are arranged perpendic-
throsis. In the peripheral non–weight-bearing area, the double, ir- ular to the articular surface11 and are anchored in a calcified
regular tide mark contour (black arrows at bottom right) and the four matrix. Electron microscopy scans have revealed small fiber
zones of cartilage are clearly visible: (S) superficial, (T) transitional, bundles that became grouped into larger bundles at the
(D) deep, and (C) calcified zone. (Four-micron-thick section of de-
calcified/uncalcified interface. The fibers in the deep and the
calcified and paraffin-embedded tissue. Azan staining ⫻40.)
calcified zones are of largest diameter. The calcified zone
contacts the underlying cortical bone, which is known as the
it has the highest concentration of water, a low proteoglycan articular end plate (see Fig. 1). Subchondral bone is very
content, and densely packed layers of uniform collagen thin in most areas16 and appears to run parallel to the joint.
fibers that are thin in diameter.9 This zone consists of two From the cartilage, dynamic forces are transmitted to the
collagen layers. The first layer, known as the lamina splen- subchondral cortex, which is thinner than cortical bone and,
dens, is composed of fine fibrils covering the articular to a certain extent, deformable.17 The organization of the
surface in the form of thickly packed bundles of collagen subchondral bone is characteristic for any joint and contains
fibers arranged parallel to each other to give the tissue its variable numbers of blood vessels.2
mechanical properties.10,11 The second layer consists of
collagen fibers arranged perpendicular to the articular sur- Chondrocytes
face. The specific organization of the superficial zone de- The specialized and highly differentiated cells of car-
termines the mechanical properties of the tissue and also tilage are mesenchymal cells, which in adult humans
may act as a barrier to the passage of large molecules such account for approximately 1% of the tissue volume.6
as antibodies from synovial fluid to cartilage. There is Chondrocytes are nonuniform and vary in number and
controversy as to whether the surface of articular cartilage is shape in different zones of the cartilage. They produce
smooth or rough. Investigators using the scanning electron the extracellular matrix and organize the collagens, pro-
microscope observed surface irregularities with various teoglycans, and noncollagenous proteins into a highly
numbers of undulations and depressions.12 Other investiga- ordered structure. Their metabolic activity differs in var-
tions showed that the observed rough articular cartilage was ious layers of the cartilage plate. For example, cells in the
due to processing artifact.13 Three-dimensional surface superficial zone synthesize different relative amounts of
No. 10 CHARACTERIZATION OF ARTICULAR CARTILAGE 䡠 Huber et al 575

aggrecan and nonaggregating proteoglycans than do Type IX collagen accounts for approximately 1% of total
chondrocytes in the deeper layer.5 Chondrocytes receive collagen, and its molecules are covalently linked to the
mechanical, electrical, and physicochemical signals surface of type II collagen fibrils. It is suspected to mediate
transmitted by the extracellular matrix and respond by fibril-fibril and fibril-proteoglycan interactions. Type IX
regulating their metabolic activity. collagen is concentrated pericellularly, with smaller quan-
tities in the territorial matrix and no interterritorial reactiv-
Extracellular Matrix ity.29 Type X collagen is present around hypertrophic chon-
The extracellular matrix is primarily composed of tissue drocytes of the growth plate and also in the underlying
fluid and macromolecules, including collagens, proteogly- calcified zone of articular cartilage.30 Microfibrillar type VI
cans, and noncollagenous proteins, with differences in con- collagen27 is located in the pericellular matrix and has
tent and distribution depending on the joint, the site in the uniform levels in the territorial and interterritorial regions.31
joint, and increasing age.18,19 The tissue fluid consists of This type may help the chondrocytes attach to the macro-
water with dissolved electrolytes, gases, small proteins, and molecular framework of the matrix. Type III collagen is
metabolites. Interactions between the fluid and the matrix located in a diffuse area around the chondrocytes pericellu-
macromolecules provide the stiffness of tissue and its resil- larly.32 Types II, IX, and XI are cartilage-specific and are
ience to mechanical forces. cross-linked together in a network that forms the extracel-
The matrix has been subdivided into the pericellular, lular framework, which gives the tissue its form and con-
territorial, and interterritorial regions around each chondro- tributes to its tensile stiffness and strength.33
cyte. These distinct regions are defined by structural differ-
Proteoglycans. Proteoglycans are molecules consisting of
ences and a specific distribution of proteoglycans, link pro-
glycosaminoglycan chains bound to a protein core. Large
tein, and hyaluronic acid (hyaluronan).20 They function
synergistically to produce an integrated, hydroelastic sus- aggregating proteoglycans (aggrecans) constitute 90% of
pension system capable of resisting compression.21 the total cartilage proteoglycan mass. Aggrecans are elastic
Each chondrocyte is surrounded by a thin, pericellular macromolecules that expand in solution and give the tissue
matrix that provides hydrodynamic protection for the chon- its ability to resist compression; they also contribute to its
drocyte during physiological loading and that plays a met- durability. Aggrecans bind to hyaluronan and link protein34
abolic role in pericellular retention. The chondrocyte and its and consist of a protein core as well as keratan sulfate and
pericellular microenvironment together represent the chon- chondroitin sulfate glycosaminoglycan chains. These chains
dron.22 Each chondron is composed of a single chondrocyte consist of numerous carboxyl and sulfate groups that, when
linked to a high pericellular concentration of sulfated pro- in contact with the interstitial fluid, become negatively
teoglycans, as well as hyaluronan, biglycans,23 and a range charged to attract cations. The composition depends on age
of matrix glycoproteins. This transparent pericellular glyco- and site.35 For instance, low-weight– bearing shoulder joints
calyx is enclosed by a fibrillar pericellular capsule.22 have a lower chondroitin sulfate content, and proteoglycan
The territorial region is well defined in the superficial, monomers from knee joint cartilage have the lowest intra-
transitional, and deep zones and is distinct from the peri- individual chondroitin 4-sulfate content.19 Link protein sta-
cellular and interterritorial regions. The collagen fibers are bilizes the aggregate by binding simultaneously to hyaluro-
of larger diameter and arranged in radial bundles.24 The nate and to aggrecan core protein.36,37 Collagen fibrils
concentration of proteoglycans rich in chondroitin sulfate is interact with the keratan sulfate–rich regions of several
higher in this region.25 aggrecan monomers aligned in a proteoglycan aggregate.38
The interterritorial region is clearly demarcated from the Large nonaggregating proteoglycans may represent de-
territorial region21 and has a higher concentration of pro- graded aggrecans (contribute up to 10%).
teoglycans rich in keratan sulfate.25 The collagen fibers of Hyaluronic acid (hyaluronan) binds to the collagen fibril-
largest diameter, previously named collagen arcades by lar network and determines the retention of aggrecan in the
Benninghof,26 predominate in this region. extracellular matrix.20 Hyaluronan is abundantly synthe-
sized in and secreted from the chondrocytes, particularly in
Macromolecules the transitional zone, whereas it is largely masked by pro-
Collagen. The collagen network resembles the endoskele- teoglycan constituents in the extracellular matrix.39 A part
ton of cartilage. Type II collagen forms, together with a of cartilage hyaluronan is free from endogenous binding
smaller amount of other (minor) collagens, the fibrous net- proteins, such as aggrecans and link proteins.40 Hyaluronate
work of the tissue. Type II collagen (80%–90% of total binding capacity was not found to be dependent on joint
collagen) consists of three identical ␣-1 chains in a helical location.19
form and provides the basic architecture of cartilage.27 Type Small proteoglycans (decorin, biglycan, and fibromodu-
XI collagen is found within type II collagen28 and is prob- lin) make up approximately 3% of the total proteoglycan
ably copolymerized with type II collagen in the matrix. mass. They bind to matrix macromolecules and help stabi-
576 INVESTIGATIVE RADIOLOGY October 2000 Vol. 35

lize the matrix. Biglycan and decorin are two forms of


dermatan sulfate proteoglycans41 often codistributed in ex-
tracellular matrix throughout all layers of adult cartilage.
They are most concentrated in the surface layer and least
concentrated in deep zones; in newborns this distribution is
reversed.20
Noncollagenous Proteins
Anchorin CII, a noncollagenous protein, appears to help
anchor chondrocytes to the collagen fibrils.42 Other noncol-
lagenous proteins, including tenascin and fibronectin, influ-
ence interactions between the chondrocytes and the matrix.
They may play roles in response to arthritis and osteoarthri-
tis.43,44 Cartilage matrix protein binds to chondrocytes and
is seen to increase in osteoarthritis. Chondrocytes may ex-
press the cartilage matrix protein in response to arthritic
stimuli.45,46 Intermediate-layer protein deposited in the in-
terterritorial matrix is seen to increase with age.47
Figure 2. Response of articular cartilage to mechanical loading.
Nutrition of Articular Cartilage
The nutrition of articular cartilage, which lacks blood chanical properties of the cartilage are influenced by the
vessels, lymph vessels, and nerves, is derived predomi- interaction of the water with the large, aggregating proteo-
nantly from the synovial fluid, which also serves to lubricate glycans.57,58 Proteoglycans are responsible for negative
the joint. Synovial fluid is a plasma ultrafiltrate produced charges that attract cations. Negatively charged sites in the
from synovium and consists of water and nutrients such as articular cartilage are derived mostly from chondroitin sul-
electrolytes, small molecules, and glucose as well as meta- fate, whose proteoglycans firmly bind to collagen fibrils. A
bolic wastes of the matrix turnover, such as oxygen and high concentration of cations dissolved in tissue fluid bal-
carbon dioxide. Synoviocytes can synthesize hyaluronate, ance the negatively charged proteoglycans.59
proteases, and mediators of inflammation that can affect the The deformation of the matrix causes different biophys-
cartilage, as in arthritis.2 To reach the chondrocytes, nutri- ical effects, such as increased pericellular concentrations of
ents of the synovial fluid must pass through a double dif- proteoglycans, changes in ion concentrations and pH, and
fusion system (first through the synovial membrane and deformation of chondrocytes.60,61 The deformation of chon-
then through the cartilage matrix).48,49 drocytes and the mechanical environment of the chondro-
Response of Articular Cartilage to cytes are nonuniform and depend on the viscoelastic prop-
Mechanical Loading erties of the pericellular matrix.62 Signals resulting from
mechanical loading of the articular surface are transmitted
Cartilage is regarded as a permeable, viscoelastic material to the chondrocytes by the matrix. Mechanical, electrical,
consisting of three principal phases: a solid phase, which is and physicochemical signals influence the response of chon-
predominately composed of a dense, collagen fibrillar net- drocytes, which causes flow of the tissue fluid and the
work and a high concentration of proteoglycan aggregates; production of a streaming potential by alteration of the
a fluid phase of water; and an ion phase with ionic species charge density around cells. Resulting intercharge repulsive
of dissolved electrolytes for neutralization of the charges forces and osmotic pressure effects provide a swelling pres-
fixed to the solid matrix.50 –52 The function of articular sure that influences the hydration state of the tissue and the
cartilage as a weight-bearing tissue and its ability to un- mechanical response to pressure and deformation (Fig. 2).50
dergo reversible deformation depend on the specific ar-
rangement of macromolecules in the extracellular matrix, Synthesis and Degradation (Internal Remodeling) of
especially the organization of collagen fibers into a three- the Extracellular Matrix
dimensional arranged collagen network that can balance the Use of the joint stimulates the synthetic activity of chon-
swelling pressure of the proteoglycan-water gel.53,54 Under drocytes and internal tissue remodeling; conversely, immo-
physiological conditions, the extension of the proteoglycan- bilization leads to a reduction of proteoglycan synthesis and
water gel is limited by the stiff collagen framework.55 The loss of cartilage.63 Chondrocytes undergo constant changes
water of articular cartilage is freely exchangeable with in their mechanical and physicochemical environment, and
synovial fluid, and its water content ranges up to 80%.56 The this influences their synthetic and degradative activity.
volume and concentration of the water as well as the me- Loading of the tissue causes changes in the intracellular
No. 10 CHARACTERIZATION OF ARTICULAR CARTILAGE 䡠 Huber et al 577

composition of chondrocytes, such as cell volume, pH, and


ionic content,64 and creates mechanical, electrical, and
physicochemical signals that help regulate the turnover of
the matrix macromolecules by continual replacement of
degraded matrix components.65
Cell metabolism is mainly directed by cytokines, includ-
ing interleukins, interferons, tumor necrosis factors, and
growth factors, which are synthesized and released into the
matrix by chondrocytes as a result of a variety of stimuli.
Cytokines may bind to cell surface receptors and stimulate
the catabolic and anabolic effects.66,67 They can enhance or
retard chondrocyte division and matrix synthesis and deg-
radation and can inhibit or promote their mutual effects.
Figure 3. Internal remodeling of the extracellular matrix. IL indi-
They may act synergistically or additively.24 cates interleukin; TNF: tumor necrosis factor; and TIMP, tissue
Cytokines induce degradation of the matrix molecules by inhibitor of metalloproteases.
the production and activation of proteolytic enzymes, such
as collagenase and proteoglycanase. For example, interleu-
kin-1 released by chondrocytes (autocrine regulation) or Degradation of matrix molecules is a feature of remod-
other cells such as synoviocytes or leukocytes (paracrine eling in growing cartilage as well as in matrix turnover of
regulation, as in rheumatoid arthritis) induces the expres- the mature cartilage. It is controlled by cytokines, which
sion of matrix proteinases such as stromylesin (matrix met- regulate the activation or inhibition of proteinases. In adult
alloproteinase), which degrades aggrecan and type IX col- cartilage, an imbalance in the regulation of promotor and
lagen.27,68,69 Collagen type VI is catabolized by serine inhibitor leads to cartilage damage, as in arthritis (Fig. 3).
proteinases (eg, cathepsin G, plasmin, elastase) typically
associated with inflammatory lesions.70 Stromelysin, for Aging of Articular Cartilage and Osteoarthritis
instance, can cleave native type IX collagen molecules from The tensile strength of weight-bearing articular cartilage
the surface of type II collagen and can also act as a telopep- decreases after the third decade of life.76 Aging leads to
tidase on native type II collagen. This scenario resembles a alterations in the composition of the matrix and the activity
mechanism by which coating type IX molecules can be of the chondrocytes. The ability of human chondrocytes to
removed from the surfaces of type II fibrils, which then can respond to a variety of stimuli, such as growth factors,
increase in diameter by the accretion of additional type II decreases,77 as does the sensitivity and response to anabolic
molecules. Therefore, the fibrillar framework can remodel and catabolic regulative cytokines, such as interleukin-1 and
without being removed.27,71 Tumor necrosis factor-␣ and tumor necrosis factor-␣.78 These alterations and age-related
␥-interferon also inhibit the synthesis and stimulate the changes in the function of chondrocytes may contribute to
resorption of proteoglycans and collagens,66 but they are the initiation and progression of osteoarthritis.77
less potent than interleukins.27 Besides proteases, reactive The pericellular matrix plays a functional biomechanical
oxygen metabolites (released by chondrocytes and phago- role in articular cartilage, and alterations affect the biophys-
cytic leukocytes, for instance in arthritis) may also stimulate ical environment of the chondrocytes.61 Changes in the
degradation of matrix macromolecules.72 environment of the chondrocyte, such as ionic concentra-
Inhibitors of proteinases include tissue inhibitor of met- tions, pH, and osmotic pressure, influence the rate and type
alloproteases, plasminogen activator inhibitor, kallikrein, of proteoglycans synthesized. The size of aggrecan is pro-
and others. The production of tissue inhibitor of metallo- gressively reduced in aging cartilage. Intact molecules are
proteases, for instance, is induced by interleukins and re- less common, and the number of smaller, keratan sulfate–
sembles the tight balance between proteinase activity and rich molecules increases.79 Increased matrix turnover and
inhibition.73 degradation of proteoglycans results in matrix depletion by
Anabolic effects are produced by other cytokines, such as proteoglycan loss and tissue weakness.78,80 Type II collagen
growth factors (platelet-derived growth factor, fibroblast damage, resulting in the unwinding of the triple helix,81
growth factor, insulin growth factor, transforming growth occurs, and subsequently type II collagen content decreas-
factor-␤), which are powerful stimulants for DNA, protein es.82,83 The damaged collagen network cannot withstand the
synthesis, or both and oppose the catabolic activities.74,75 osmotic swelling pressure of hydrophilic proteoglycans, and
Also, several hormones, such as growth hormone, insulin, localized swelling occurs. This causes softening of the tis-
calcitonin, and androgens, stimulate chondrocyte prolifera- sue, and because of chronic mechanical forces the degen-
tion and the synthesis of matrix macromolecules; in con- erative process accelerates, resulting in cartilage destruc-
trast, glucocorticoids depress it.72 tion. Surface fibrillations of cartilage accompanied by
578 INVESTIGATIVE RADIOLOGY October 2000 Vol. 35

Figure 4. Area of articular cartilage from the lateral femoral con- Figure 5. Area of articular cartilage close to the denuded bone-
dyle with advanced degenerative lesions: vertical and tangential plate region of the lateral femoral condyle: thickening of the sub-
cleft formations and clusters of proliferating chondrocytes (arrows). chondral bone, crack of the double-contoured tide mark (arrows),
(Azan staining ⫻40.) and vascular ingrowth with surrounding fibrovascular tissue (arrow-
heads). (Azan staining ⫻60.)

further loss of proteoglycans can be shown as an early


change in osteoarthritis. These changes can be visualized by there is evidence that changes in the metabolism of sub-
magnetic resonance imaging with the delayed contrast-en- chondral bone may precede and determine the loss of car-
hanced technique.84 – 86 As a result of proteoglycan and tilage.90 –92 Cartilage and subchondral bone are regarded as
collagen loss, the pericellular microenvironment expands, a functional unit; therefore, changes in the dynamic inter-
and to occupy the depleted pericellular regions, the matrix play between subchondral bone and cartilage may deter-
repair precipitates clonal chondrocyte proliferation and an mine the development of osteoarthritis.
increase in matrix synthesis (intrinsic repair). However, Degeneration is the breakdown of load-bearing cartilage and
degradative enzymes overwhelm the synthetic capability, not simply the result of aging and mechanical wear resulting
and the repair fails. As the result of cell division and from excessive repetitive loading of the cartilage. Pathological
proliferation, the chondrocytes remain in clumps bound changes in osteoarthritis also involve the periarticular tissue
together by sheets of type VI collagen. The pericellular and are likely to be the result of multiple factors affecting
distribution of type VI collagen increases during osteoar- cartilage or subchondral bone directly or indirectly, such as
thritis, in contrast to the loss of type IX. The chondrocyte trauma, joint laxity, crystal deposition, bone microfractures,
expansion represents one of the earliest matrix changes immunological factors, or immobilization.
associated with cartilage catabolism.22,87
Histomorphologically, the effects of cartilage degenera- References
tion are visible in the tangential cleft formation at the 1. Brower TD, Hsu WY. Normal articular cartilage. Clin Orthop 1969;
cartilaginous surface, followed by vertical clefts that extend 64:9 –17.
to the calcified zone. Subsequently, the number of prolifer- 2. Mankin HJ, Radin EL. Structure and function of joints. In: McCarty
ating chondrocytes that lie in clumps and clones increases DJ, Koopman WJ, eds. Arthritis and allied conditions, 12th ed.
Philadelphia, PA: Lea & Febiger; 1993:181–197.
(Fig. 4). Finally, the end stage of cartilaginous degeneration 3. Aydelotte MB, Kuettner KE. Differences between sub-populations of
is characterized by eroded cartilaginous tissue with denuded cultured bovine articular chondrocytes, I: Morphology and cartilage
bone-plate regions, cracks in the subchondral plate, and matrix production. Connect Tissue Res 1988;18:205–222.
4. Muir H. The chondrocyte, architect of cartilage: Biomechanics, struc-
formations of subchondral bone cysts as a result of focal ture, function and molecular biology of cartilage matrix macromol-
resorption.88 ecules. Bioessays 1995;17:1039 –1048.
The vascular supply of the bone marrow allows an “ex- 5. Aydelotte MB, Greenhill RR, Kuettner KE. Differences between sub-
trinsic” repair. The newly formed tissue covering the bone- populations of cultured bovine articular chondrocytes, II: Proteo-
glycan metabolism. Connect Tissue Res 1988;18:223–234.
plate is mechanically suboptimal fibrocartilage. If the tide 6. Stockwell RA. The cell density of human articular and costal cartilage.
mark cracks, vascular ingrowth may occur, causing the J Anat 1967;101:753–763.
formation of fibrovascular tissue plugs in areas of damaged 7. Stockwell R. The interrelationship of cell density and cartilage thick-
ness in mammalian articular cartilage. J Anat 1971;109:411– 421.
cartilage (Fig. 5). These changes are accompanied by scle-
8. Mitrovic D, Quintero M, Stankovic A, Ryckewaert A. Cell density of
rosis of the subchondral bone and the development of os- adult human femoral condylar articular cartilage: Joints with nor-
teophytes as a response to new stress patterns.89 However, mal and fibrillated surfaces. Lab Invest 1983;49:309 –316.
No. 10 CHARACTERIZATION OF ARTICULAR CARTILAGE 䡠 Huber et al 579

9. Weiss C, Rosenberg L, Helfet AJ. An ultrastructural study of normal 33. Van der Rest M, Mayne R. Type IX collagen proteoglycan from
young adult human articular cartilage. J Bone Joint Surg [Am] cartilage is covalently cross-linked to type II collagen. J Biol Chem
1968;50:663– 674. 1988;263:1615–1618.
10. Minns RJ, Steven FS. The collagen fibril organization in human 34. Hardingham TE, Muir H. Hyaluronic acid in cartilage and proteogly-
articular cartilage. J Anat 1977;123:437– 457. can aggregation. J Biochem 1974;139:565–581.
11. Lane JM, Weiss C. Current comment: Review of articular cartilage 35. Bayliss MT, Venn M, Maroudas A, Ali SY. Structure of proteoglycans
collagen research. Arthritis Rheum 1975;18:553–562. from different layers of human articular cartilage. J Biochem 1983;
12. Ghadially FN, Moshurchak EM, Ghadially JA. A maturation change in 209:387– 400.
the surface of cat articular cartilage detected by the scanning 36. Hardingham TE. The role of link protein in the structure of cartilage
electron microscope. J Anat 1978;125:349 –360. proteoglycan aggregates. Biochem J 1979;177:237–247.
13. Ghadially FN, Yong NK, Lalonde JM. A transmission electron micro- 37. Buckwalter JA, Rosenberg L, Tang LH. The effect of link protein on
scopic comparison of the articular surface of cartilage processed at- proteoglycan aggregate structure: An electron microscopic study of
tached to bone and detached from bone. J Anat 1982;135:685–706. the molecular architecture and dimensions of proteoglycan aggre-
gates reassembled from the proteoglycan monomers and link pro-
14. Bloebaum RD, Radley KM. Three-dimensional surface analysis of
teins of bovine fetal epiphyseal cartilage. J Biol Chem 1984;259:
young adult human articular cartilage. J Anat 1995;187:293–301.
5361–5363.
15. Redler I, Mow VC, Zimny ML, Mansell J. The ultrastructure and 38. Hedlund H, Hedbom E, Heinegard D, et al. Association of the aggre-
biomechanical significance of the tidemark of articular cartilage. can keratan sulfate-rich region with collagen in bovine articular
Clin Orthop 1975;112:357–362. cartilage. J Biol Chem 1999;26:274:5777–5781.
16. Clark JM, Huber JD. The structure of the human subchondral plate. 39. Asari A, Miyauchi S, Kuriyama S, et al. Localization of hyaluronic
J Bone Joint Surg [Br] 1990;27:866 – 873. acid in human articular cartilage. J Histochem Cytochem 1994;42:
17. Radin EL, Paul IL, Lowy M. A comparison of the dynamic force 513–522.
transmitting properties of subchondral bone and articular cartilage. 40. Parkkinen JJ, Hakkinen TP, Savolainen S, et al. Distribution of
J Bone Joint Surg [Am] 1970;52:444 – 456. hyaluronan in articular cartilage as probed by a biotinylated
18. Meachim G. Effect of age on the thickness of adult articular cartilage binding region of aggrecan. Histochem Cell Biol 1996;105:187–
at the shoulder joint. Ann Rheum Dis 1971;30:43– 46. 194.
19. Gurr E, Mohr W, Pallasch G. Proteoglycans from human articular 41. Rosenberg LC, Choi HU, Tang LH, et al. Isolation of dermatan sulfate
cartilage: The effect of joint location on the structure. J Clin Chem proteoglycans from mature bovine articular cartilages. J Biol Chem
Clin Biochem 1985;23:811– 819. 1985;260:6304 – 6313.
20. Poole AR, Pidoux I, Reiner A, Rosenberg L. An immunelectron 42. Mollenhauer J, Bee JA, Lizarbe MA, von der Mark K. Role of
microscope study of the organization of proteoglycan monomer, anchorin CII, a 31,000-mol-wt membrane protein, in the interaction
link protein and collagen in the matrix of articular cartilage. J Cell of chondrocytes with type II collagen. J Cell Biol 1984;98:1572–
Biol 1982;93:921–937. 1579.
21. Poole CA, Flint MH, Beaumont BW. Morphological and functional 43. Saltner DM. Tenascin is increased in cartilage and synovium from
interrelationships of articular cartilage matrices. J Anat 1984;138: arthritic knees. Br J Rheumatol 1993;32:780 –786.
113–138. 44. Nishida K, Inoue H, Murakami T. Immunohistochemical demonstra-
22. Poole CA. Articular cartilage chondrons: Form, function and failure: A tion of fibronectin in the most superficial layer of normal rabbit
review. J Anat 1997;1991:1–13. articular cartilage. Ann Rheum Dis 1995;54:995–998.
23. Miosge N, Flachsbart K, Goetz W, et al. Light and electron micro- 45. Saxne T, Heinegard D. Cartilage oligomeric matrix protein: A novel
scopical immunohistochemical localization of the small proteogly- marker of cartilage turnover detectable in synovial fluid and blood.
can core proteins decorin and biglycan in human knee joint carti- Br J Rheumatol 1992;31:583–591.
lage. Histochem J 1994;26:939 –945. 46. Okimura A, Okada Y, Makihira S, et al. Enhancement of cartilage
matrix protein synthesis in arthritic cartilage. Arthritis Rheum
24. Poole AR. Cartilage in health and disease. In: McCarty DJ, Koopman
1997;40:1029 –1036.
WJ, eds. Arthritis and allied conditions, 12th ed. Philadelphia, PA:
Lea & Febiger; 1993:279 –333. 47. Lorenzo P, Bayliss MT, Heinegard D. A novel cartilage protein (CILP)
present in the mid-zone of human articular cartilage increases with
25. Meachim G, Stockwell RA. The matrix. In: Freeman MAR, ed. Adult
age. J Biol Chem 1998;273:23463–23468.
articular cartilage, 2nd ed. Turnbridge Wells, England: Pitman
48. Brower TD, Akahoski Y, Orlic PL. Diffusion of dyes through articular
Medical; 1979:1– 67.
cartilage in vivo. J Bone Joint Surg [Am] 1962;44:456 – 463.
26. Benninghoff A. Form und Bau der Gelenkknorpel in ihren Beziehun- 49. Kuettner KE. Biochemistry of articular cartilage in health and disease.
gen zur Funktion. Zweiter Teil: Der Aufbau des Gelenkknorpels in Clin Biochem 1992;25:155–163.
seinen Beziehungen zur Funktion. Z Zellforschung 1925;2:783–
50. Mow VC, Wang CC, Hung CT. The extracellular matrix, interstitial
862.
fluid and ions as a mechanical signal transducer in articular carti-
27. Eyre DR, Wu JJ, Woods PE. The cartilage collagens: Structural and lage. Osteoarthritis Cartilage 1999;7:41–58.
metabolic studies. J Rheumatol 1991;(suppl 27)18:49 –51. 51. Lai WM, Hou JS, Mow VC. A triphasic theory for the swelling and
28. Mendler M, Eich-Bender SV, Vaughan L, Winterhalter KM, Bruckner deformational behaviors of articular cartilage. J Biomech Eng 1991;
P. Cartilage contains mixed fibrils of collagen types II, IX, and XI. 113:245–258.
J Cell Biol 1989;108:191–197. 52. Gu WY, Lai WM, Mow VC. A mixture theory for charged-hydrated
29. Poole CA, Gilbert RT, Herbage D, Hartmann DJ. Immunolocalization soft tissues containing multi-electrolytes: Passive transport and
of type IX collagen in normal and osteoarthritic canine tibial swelling behaviors. J Biomech Eng 1998;120:169 –180.
cartilage and isolated chondrons. Osteoarthritis Cartilage 1997;5: 53. de Bont LG, Liem RS, Havinga P, Boering G, van der Korst J.
191–204. Collagenous network in cartilage of human femoral condyles: A
30. Schmid TM, Linsenmayer F. Immunohistochemical localization of light microscopic and scanning electron microscopic study. Acta
short chain cartilage (type X) in avian tissue. J Cell Biol 1985;100: Anat 1986;126:41– 47.
598 – 605. 54. Jeffery AK, Blunn GW, Archer CW, Bentley G. Three-dimensional
31. Poole CA, Ayad S, Schofiel JR. Chondrons from articular cartilage (I): collagen architecture in bovine articular cartilage. J Bone Joint Surg
Immunolocalization of type VI collagen in the pericellular capsule [Br] 1991;37:795– 801.
of isolated canine chondrons. J Cell Sci 1988;90:635– 645. 55. Maroudas A. Balance between swelling pressure and collagen tension
32. Wotton SF, Duance VC. Type III collagen in normal human articular in normal and degenerate cartilage. Nature 1976;260:808 – 809.
cartilage. Histochem J 1994;26:412– 416. 56. Mankin HJ, Thrasher AZ. Water content and binding in normal and
580 INVESTIGATIVE RADIOLOGY October 2000 Vol. 35

osteoarthritic human cartilage. J Bone Joint Surg [Am] 1975;57: 75. Osborne KD, Trippel SB, Mankin HJ. Growth factor stimulation of
76 – 80. adult articular cartilage. J Orthop Res 1989;7:35– 42.
57. Linn FC, Sokoloff L. Movement and composition of interstitial fluid of 76. Kempson GE. Relationship between the tensile properties of articular
cartilage. Arthritis Rheum 1965;8:481– 494. cartilage from the human knee and age. Ann Rheum Dis 1982;41:
58. Lai WM, Mow VC, Roth V. Effects of nonlinear strain-dependent 508 –511.
permeability and rate of compression on the stress behavior of 77. Buckwalter JA, Mankin HJ. Articular cartilage: Degeneration and
articular cartilage. J Biomech Eng 1981;103:61– 66. osteoarthritis, repair, regeneration, and transplantation. Instr Course
59. Yoshikawa T, Nishida K, Doi T, et al. Negative charges bound to Lect 1998;47:487–504.
collagen fibrils in the rabbit articular cartilage: A light and electron 78. Hardingham T, Bayliss M. Proteoglycans of articular cartilage:
microscopic study using cationic colloidal iron. Arch Histol Cytol Changes in aging and in joint disease. Semin Arthritis Rheum
1997;60:435– 443. 1990;20(suppl 1)3:12–33.
60. Gray ML, Pizzanelli AM, Grodzinsky AJ, Lee RC. Mechanical and 79. Webber C, Glant TT, Roughley PJ, Poole AR. The identification and
physicochemical determinants of the chondrocyte biosynthetic re- characterization of two populations of aggregating proteoglycans of
sponse. J Orthop Res 1988;6:777–792. high buoyant density isolated from postnatal human articular car-
61. Gu WY, Lai WM, Mow VC. Transport of fluid and ions through a tilages of different ages. Biochem J 1987;248:735–740.
porous-permeable charged-hydrated tissue, and streaming potential 80. Mlynarik V, Trattnig S. Physicochemical properties of normal articular
data on normal bovine articular cartilage. J Biomech 1993;26:709 – cartilage and its MR appearance. Invest Radiol 2000; 35:589 –594.
723. 81. Dodge GR, Poole AR. Immunohistochemical detection and immuno-
62. Guilak F, Jones WR, Ting-Beall HP, Lee GM. The deformation chemical analysis of type II collagen degradation in human normal,
behavior and mechanical properties of chondrocytes in articular rheumatoid and osteoarthritic articular cartilage and in explants of
cartilage. Osteoarthritis Cartilage 1999;7:59 –70. bovine articular cartilage cultured with interleukin-1. J Clin Invest
63. Palmoski MJ, Perricone E, Brandt KD. Development and reversal of a 1989;83:647– 661.
proteoglycan aggregation defect in normal canine knee cartilage 82. Pullig O, Kladny B, Weseloh G, Swoboda B. Metabolic activation of
after immobilization. Arthritis Rheum 1979;22:508 –517. chondrocytes in human osteoarthritis: Expression of type II colla-
64. Hall AC, Horwith ER, Wilkins RJ. The cellular physiology of articular gen. Z Orthop Ihre Grenzgeb 1999;137:67–75.
cartilage. Exp Physiol 1996;81:535–545.
83. Burstein D, Bashir A, Gray ML. MRI techniques in early stages of
65. Buckwalter JA, Mankin HJ. Articular cartilage: Tissue design and chon-
cartilage disease. Invest Radiol 2000;35:622– 638.
drocyte-matrix interactions. Instr Course Lect 1998;47:477– 486.
84. Trattnig S, Mlynárik V, Breitenseher M, et al. MRI visualization of
66. Saklatvala J. Tumor necrosis factor-␣ stimulates resorption and inhibits
proteoglycan depletion in articular cartilage via intravenous admin-
synthesis of proteoglycan in cartilage. Nature 1986;322:547–549.
istration of Gd-DTPA. Magn Reson Imaging 1999;17:577–583.
67. Lotz M, Blanco FJ, von Kempis J, et al Cytokine regulation of
chondrocyte functions. J Rheumatol 1995;43(suppl):104 –108. 85. Trattnig S, Mlynarik V, Huber H, Ba-Ssalamah A, Puig S, Imhof H.
68. McGuire-Goldring MB, Meats JE, Wood DD, et al. In vitro activation Magnetic resonance imaging of articular cartilage and evaluation of
of human chondrocytes and synoviocytes by a human interleukin- cartilage disease. Invest Radiol 2000;35:595– 601.
1-like factor. Arthritis Rheum 1984;27:654 – 662. 86. Xia Y. Magic-angle effect in magnetic resonance imaging of articular
69. Roughley PJ, Nguyen Q, Mort JS. Mechanisms of proteoglycan deg- cartilage: A review. Invest Radiol 2000;35:602– 621.
radation in human articular cartilage. J Rheum 1991;18(suppl 27): 87. Nehrer S, Minas T. Treatment of articular cartilage defects. Invest
52–54. Radiol 2000;35:639 – 646.
70. Kielty CM, Lees M, Shuttleworth CA, Woolley D. Catabolism of 88. Meachim G, Osborne GV. Repair at the femoral articular surface in
intact type VI collagen microfibrils: Susceptibility to degradation osteo-arthritis of the hip. J Pathol 1970;102:1– 8.
by serine proteinases. Biochem Biophys Res Commun 1993;191: 89. Gilbertson EM. Development of periarticular osteophytes in experi-
1230 –1236. mentally induced osteoarthritis in the dog. Ann Rheum Dis 1975;
71. Wu JJ, Lark MW, Chun LE, Eyre DR. Degradation of cartilage 34:12–25.
collagens by stromelysin. J Biol Chem 1991;266:5625–5628. 90. Bullough PG, Pagannath A. The morphology of the calcification front
72. Franchimont P, Bassleer C, Henrotin Y. Effects of hormones and drugs in articular cartilage. J Bone Joint Surg [Br] 1983;65:72–78.
on cartilage repair. J Rheumatol 1989;16:5–9. 91. Imhof H, Breitenseher M, Kainberger F, Trattnig S. Degenerative joint
73. Lotz M, Guerne PA. Interleukin-6 induces the synthesis of tissue disease: Cartilage or vascular disease? Skeletal Radiol 1997;26:
inhibitor of metalloproteinases-1/erythroid potentiating activity 398 – 403.
(TIMP-1/EPA). J Biol Chem 1991;266:2017–2020. 92. Dieppe P, Cushnaghan J, Young P, Kirwan J. Prediction of the
74. Mankin JH, Jennings C, Treadwell BV, Trippel SB. Growth factors progression of joint space narrowing in osteoarthritis of the knee by
and articular cartilage. J Rheumatol 1991;18(suppl 27):66 – 67. bone scintigraphy. Ann Rheum Dis 1993;52:557–563.