AAOS Comprehensive Orthopaedic Review
Section 1 - Basic Science
Chapter 6. Articular Cartilage
1. Articular cartilage consists mainly of extracellular matrix (ECM) (95%) and a sparse population of chondrocytes (5%) that maintain the ECM throughout life.
2. The major components of the ECM are water, collagen, and proteoglycans.
1. Water makes up 65% to 80% of articular cartilage.
2. The distribution is 80% at the superficial layers and 65% at the deep layers.
3. Most water is contained within the ECM and moved through the matrix by applying a pressure gradient across the tissue.
4. The frictional resistance of the water through the pores of the ECM and the pressurization of the water within the ECM are the basic mechanisms from which articular cartilage derives its ability to support very high joint loads.
5. Alteration of the water content affects the cartilage's permeability, strength, and Young modulus of elasticity.
6. The flow of water through the tissue also promotes the transport of nutrients and other factors through cartilage.
1. Collagen makes up more than 50% of the dry weight of articular cartilage and 10% to 20% the of wet weight.
2. It provides shear and tensile strength.
3. Type II collagen comprises 90% to 95% of the total collagen weight in hyaline cartilage.
a. Other minor types of collagen in articular cartilage include types V, VI, IX, X, and XI (
b. Type VI—Significant increase seen in early stages of osteoarthritis (OA).
c. Type X—Produced only in endochondral ossification by hypertrophic chondrocytes; is associated with cartilage calcification. Examples include the growth plates, fracture sites, calcifying cartilage tumors, and the calcified deep zone of cartilage.
4. The specialized amino acid composition of increased amounts of glycine, proline, hydroxyproline, and hydroxylysine help form the triple helix collagen molecules, which line up in a staggered fashion resulting in banded fibrils (
Intra- and intermolecular covalent cross-linking occurs between fibrils to help provide
[Table 1. Types of Collagen]
[Figure 1. A scheme for the formation of collagen fibrils. The triple helix is made from three α chains, forming a procollagen molecule. Outside the cell the N- and C-terminal globular domains of the α chains are cleaved off to allow fibril formation, which occurs in a specific quarter-stagger array that ultimately results in the typical banded fibrils seen under electron microscopy.]
strength and form the resulting collagen fiber.
Types V, XI, and XI help mediate collagen-collagen and collagen-proteoglycan interactions.
5. Cartilage disorders linked to defects or deficiencies in type II collagen
b. Type II achondrogenesis-hypochondrogenesis
c. Spondyloepiphyseal dysplasia
d. Kniest dysplasia
1. Represent 10% to 15% of dry weight.
2. Provide compression strength to cartilage.
3. Proteoglycans are produced and secreted into the ECM by chondrocytes.
4. They are made up of repeating disaccharide subunits, glycosaminoglycans (GAG). Two subtypes are found in cartilage: chondroitin sulfate and keratan sulfate.
a. Chondroitin sulfate is the most prevalent GAG. With increasing age, chondroitin-4-sulfate decreases and chondroitin-6-sulfate remains constant.
Figure 2. A schematic diagram of the aggrecan molecule and its binding to hyaluronate. The protein core has several globular domains (G1, G2, and G3), with other regions containing the keratin sulfate and chondroitin sulfate glycosaminoglycan chains. The N-terminal G1 domain is able to bind specifically to hyaluronate. This binding is stabilized by link protein.]
b. Keratan sulfate increases with age.
5. Sugar bonds link GAG to a long protein core to form a proteoglycan aggrecan molecule (Figure 2).
6. Aggrecan molecules bind to hyaluronic acid molecules via link proteins to form a macromolecule complex known as a proteoglycan aggregate (
7. Proteoglycans entangle between collagen fibers to create the fiber-reinforced solid matrix that helps determine the movement of water in the ECM (
8. Proteoglycans also help trap water in the ECM by way of their negative charge.
1. Represent 5% of dry weight.
2. Chondrocytes are the only cells found in articular cartilage and are responsible for the production, organization, and maintenance of the ECM.
3. Mesenchymal cells aggregate and differentiate into chondroblasts, which remain in lacunae to become chondrocytes.
4. Chondrocytes produce collagen, proteoglycans, and other proteins found in the ECM.
5. Compared to the more superficial levels of cartilage, chondrocytes in the deeper levels are less active and contain less rough endoplasmic reticulum and more intracellular degenerative products.
[Figure 3. A, A diagram of the aggrecan molecules arranged as a proteoglycan aggregate. Many aggrecan molecules can bind to a chain of hyaluronate, forming macromolecular complexes that effectively are immobilized within the collagen network. B, Electron micrographs of bovine articular cartilage proteoglycan aggregates from (i) skeletally immature calf and (ii) skeletally mature steer. These show the aggregates to consist of a central hyaluronic acid filament and multiple attached monomers (bar = 500 μm).]
F. Other matrix molecules
1. Noncollagenous proteins
a. These molecules play a role in the interactions between the ECM and chondrocytes.
b. They include chondronectin, fibronectin, and anchorin.
2. Lipids and phospholipids
1. Articular cartilage can be divided into different layers, or zones, at various depths.
2. Division is based on descriptive information such as collagen orientation, chondrocyte organization, and proteoglycan distribution.
B. Layers/zones (
Figures 5 and
1. Superficial (tangential, or zone I)
a. Lies adjacent to the joint cavity.
b. Forms the gliding surface.
c. Characterized by collagen fibers and disk-shaped chondrocytes uniformly aligned parallel to the articular surface along with a low proteoglycan concentration.
d. High collagen and water concentrations are found in this zone.
2. Middle (transitional, or zone II)
a. Characterized by thicker, obliquely oriented collagen fibers, round chondrocytes, and marked proteoglycan content.
[Figure 4. Diagram of aggrecan, collagen.]
b. Constitutes most of the cartilage depth.
3. Deep (radial, or zone III)—Characterized by collagen fibers oriented perpendicular to the articular surface, round chondrocytes arranged in columns, and a high proteoglycan content.
4. Calcified cartilage (zone IV)
a. Characterized by radially aligned collagen fibers
[Figure 5. A, Histologic section of normal adult articular cartilage showing even Safranin 0 staining and distribution of chondrocytes. B, Schematic diagram of chondrocyte organization in the three major zones of the uncalcified cartilage, the tidemark, and the subchondral bone. STZ = superficial tangential zone.]
[Figure 6. Diagram of collagen fiber architecture in a sagittal cross section showing the three salient zones of articular cartilage.]
and round chondrocytes buried in a calcified matrix that has a high concentration of calcium salts and very low concentration of proteoglycans.
b. Hypertrophic chondrocytes in this layer produce type X collagen and alkaline phosphatase, helping to mineralize the extracellular matrix.
c. The borders of the calcified cartilage layer include the tidemark as the upper border and the cement line, which formed during growth plate ossification at skeletal maturity, as the lower border.
C. Extracellular matrix
1. The ECM can also be characterized based on its proximity to the surrounding chondrocytes.
2. Each region has a different biochemical composition.
a. Pericellular matrix—Thin layer that completely surrounds chondrocyte and helps control cell matrix interactions.
b. Territorial matrix—Thin layer of collagen fibrils surrounding pericellular matrix.
c. Interterritorial matrix
i. Largest region
ii. Contains larger collagen fibrils and a large content of proteoglycans.
1. Cartilage is an avascular structure in the adult.
2. It is believed that nutrients diffuse through the matrix from the surrounding synovial fluid, from the synovium, or from the underlying bone.
Figure 7. The events involved in the synthesis of collagen, showing the intracellular sites that are used for each procedure.]
1. Chondrocytes synthesize and assemble cartilaginous matrix components and direct their distribution within tissue.
2. The processes include the synthesis of matrix proteins and GAG chains, and their secretion into the ECM.
3. Each chondrocyte is responsible for the metabolism and maintenance of the ECM under avascular and at times anaerobic conditions.
4. The maintenance of the ECM is dependent on the proper incorporation of components into the matrix as well as the balance between synthesis and degradation of matrix components.
5. Chondrocytes respond to both their chemical and physical environments.
a. Chemical (growth factors, cytokines)
b. Physical (mechanical load, hydrostatic pressure changes)
1. Collagen synthesis (Figure 7)
a. Most knowledge about collagen synthesis has originated from studies of major fibrillar types (ie, types I through III).
b. Hydroxylation requires vitamin C; deficiencies (eg, scurvy) can result in altered collagen synthesis.
2. Collagen catabolism
a. The exact mechanism is unclear.
b. Breakdown occurs at a slow rate in normal cartilage.
c. In degenerative cartilage and cartilage undergoing repair (eg, during skeletal growth), there is evidence of accelerated breakdown.
d. Enzymatic processes have been proposed, such as the cleaving of metalloproteinases to the triple helix.
1. Proteoglycan synthesis
a. A series of molecular events—beginning with gene expression, messenger RNA transcription, translation, and aggregate formation—are involved in proteoglycan synthesis (
b. The chondrocyte is responsible for the synthesis, assembly, and sulfation of the proteoglycan molecule.
c. The addition of GAG and other posttranslational modifications can result in tremendous variation in the final molecule.
d. The control mechanisms for proteoglycan synthesis are very sensitive to biochemical, mechanical, and physical stimuli (eg, lacerative injury, OA, nonsteroidal anti-inflammatory drugs).
2. Proteoglycan catabolism (
a. Proteoglycans are continually being broken down; this is a normal event in the maintenance of cartilage.
b. Catabolism occurs during remodeling in repair
[Figure 8. Diagram depicting the various stages involved in the synthesis and secretion of aggrecan and link protein by a chondrocyte. (1) The transcription of the aggrecan and link protein genes to mRNA. (2) The translation of the mRNA in the rough endoplasmic reticulum (RER) to form the protein core of the aggrecan. (3) The newly formed protein is transported from the RER to the (4) cis and (5) medial trans-Golgi compartments, where the glycosaminoglycan chains are added to the protein core. (6) On completion of the glycosylation and sulfation, the molecules are transported via secretory vesicles to the plasma membrane, where (7) they are released into the extracellular matrix. (8) Hyaluronate is synthesized separately at the plasma membrane. (9) Only in the extracellular matrix can aggrecan, link protein, and hyaluronate come together to form proteoglycan aggregates.]
processes and appears to be accelerated during degenerative processes.
c. Catabolism can be affected by soluble mediators (interleukin [IL]-1) and joint loading (loss of proteoglycans during joint immobilization).
d. GAG chains and other proteoglycan chains are released into synovial fluid during degradation. These may be quantified and could provide a diagnostic measure of catabolic activity in the joint.
E. Growth factors
1. Polypeptide growth factors regulate synthetic processes in normal cartilage and have been implicated in the development of OA.
2. Platelet-derived growth factor (PDGF)—In OA, and especially in lacerative injury, PDGF may play an increased role in healing.
3. Basic fibroblast growth factor (bFGF)
a. bFGF is a powerful stimulator of DNA synthesis in adult articular chondrocytes and is a potent mitogen.
b. bFGF may play a role in the cartilage repair process.
4. Transforming growth factor-beta (TGF-β)
a. TGF-β appears to potentiate DNA synthesis stimulated by bFGF, epidermal growth factor, and insulin-like growth factor (IGF)-1.
b. TGF-β also appears to suppress type II collagen synthesis.
c. TGF-β stimulates the formation of plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase (TIMP), preventing the degradative action of these enzymes.
5. Insulin-like growth factors (IGF-1 and IGF-2)—IGF-1 has been demonstrated to stimulate DNA and matrix synthesis in the immature cartilage of the growth plate as well as adult articular cartilage.
1. The breakdown of the cartilage matrix in normal turnover and in degeneration appears to be by the action of proteolytic enzymes (proteinases).
2. The overactivity of proteinases may play a role in the pathogenesis of OA.
a. These proteinases include collagenase, stromelysin, and gelatinase.
b. They are synthesized as latent enzymes (proenzymes) and require activation via enzymatic activation.
c. The active enzymes can be inhibited irreversibly by TIMP. The molar ratios of metalloproteinases and TIMP determine if there is net metalloproteinase activity.
G. Aging and articular cartilage (
a. Immature articular cartilage varies considerably from adult articular cartilage.
b. With aging, chondrocytes become larger, acquire increased lysosomal enzymes, and no longer reproduce.
c. Cartilage becomes relatively hypocellular in comparison with immature articular cartilage.
d. Proteoglycan mass and size decrease with aging in articular cartilage, with decreased concentrations of chondroitin sulfate and increased concentration of keratin sulfate.
e. Water and proteoglycan content decrease with aging.
f. As age advances, cartilage loses its elasticity, developing increased stiffness and decreased solubility.
IV. Lubrication and Wear
1. Synovial tissue is vascularized tissue that mediates the diffusion of nutrients between blood and synovial fluid.
2. Synovium is composed of two cell types.
a. Type A is important in phagocytosis.
b. Type B comprises fibroblast-like cells that produce synovial fluid
3. Synovial fluid lubricates articular cartilage.
a. Synovial fluid is composed of an ultrafiltrate of blood plasma and fluid produced by the synovial membrane.
[Figure 9. Representation of the mechanism of degradation of proteoglycan aggregates in articular cartilage. The major proteolytic cleavage site is between the G1 and G2 domains, making the glycosaminoglycan-containing portion of the aggrecan molecule nonaggregating. This fragment can now be released from the cartilage. Other proteolytic events also can cause the G1 domain and link protein to disaggregate and leave the cartilage.]
b. Synovial fluid is composed of hyaluronic acid, lubricin, proteinase, collagenases, and prostaglandins. Lubricin is the key lubricant of synovial fluid.
c. The viscosity coefficient of synovial fluid is not a constant; its viscosity increases as the shear rate decreases.
d. Hyaluronic acid molecules behave like an elastic solid during high-strain activities.
e. Synovial fluid contains no red blood cells, hemoglobin, or clotting factors.
B. Elastohydrodynamic lubrication is the major mode of lubrication of articular cartilage.
C. The coefficient of friction of human joints is 0.002 to 0.04.
[Table 2. Changes in Articular Cartilage Properties With Aging and Osteoarthritis]
Figure 10. Models of fluid film lubrication: Hydrodynamic (A), squeeze-film (B), weeping (C), and boosted (D).]
1. Fluid film formation, elastic deformation of articular cartilage, and synovial fluid decrease friction.
2. Fibrillation of articular cartilage increases friction.
D. Two forms of movement occur during joint range of motion: rolling and sliding. Almost all joints undergo both types of movement during range of motion.
1. Pure rolling—Instant center of rotation is at rolling surfaces.
2. Pure sliding—Pure translational movement without an instant center of rotation.
E. Types of lubrication (Figure 10)
a. This is the major mode of lubrication during dynamic joint motion.
b. Deformation of articular surfaces and thin films of joint lubricant separate surfaces.
2. Boundary—also known as "slippery surfaces"
a. The load-bearing surface is largely nondeformable.
b. The lubricant only partially separates articular surfaces.
a. Lubricating fluid pools in regions contained by articular surfaces in contact with one another.
b. The coefficient of friction is generally higher than in elastohydrodynamic lubrication.
4. Hydrodynamic—Fluid separates the articular surfaces.
5. Weeping—Lubricating fluid shifts toward load-bearing regions of the articular surface.
V. Mechanisms of Cartilage Repair
A. The repair of significant defects in articular cartilage is limited by a lack of vascularity and a lack of cells that can migrate to injured sites.
B. Cartilage also lacks undifferentiated cells that can migrate, proliferate, and participate in the repair response.
C. Repair of superficial lacerations
1. Superficial lacerations that do not cross the tidemark, the region between uncalcified and calcified cartilage, generally do not heal.
2. Chondrocytes proliferate near the site of injury and may synthesize new matrix, but they do not migrate toward the lesion and do not repair the defects.
3. The poor healing response is believed to be partly due to the lack of hemorrhage and the lack of an inflammatory response necessary for proper healing.
D. Repair of deep lacerations
1. Cartilage defects that penetrate past the tidemark into underlying subchondral bone may heal with fibrocartilage.
2. Fibrocartilage is produced by undifferentiated marrow mesenchymal stem cells that later differentiate into cells capable of producing fibrocartilage.
3. In most situations, the repair tissue does not resemble the normal structure, composition, or mechanical properties of an articular surface and is not as durable as hyaline cartilage.
E. Factors affecting cartilage repair
1. Continuous passive motion is believed to have a beneficial effect on cartilage healing; immobilization of a joint leads to atrophy and/or degeneration.
2. Joint instability (eg, anterior cruciate ligament transection) leads to an initial decrease in the ratio of proteoglycan to collagen (at 4 weeks) but a late (12 weeks) elevation in the ratio of proteoglycan to collagen and an increase in hydration.
3. Joint instability leads to a marked decrease in hyaluronan, but disuse does not.
Figure 11. Osteoarthritic changes seen on a knee radiograph illustrating extensive loss of articular cartilage in the medial and patellofemoral compartments. Prominent osteophytes and subchondral cysts are also present.]
1. OA, which eventually leads to destruction and loss of articular cartilage, is the most prevalent disorder of the musculoskeletal system.
2. The disease process leads to limitation of joint movement, joint deformity, tenderness, inflammation, and severe pain.
B. Radiographic findings (Figure 11)
1. Joint space narrowing
2. Subchondral sclerosis and cyst formation
3. Osteophyte formation
C. Macroscopic findings
1. Articular cartilage may show areas of softening (chondromalacia), fibrillation, and erosions.
2. With severe degeneration, there may be focal areas of ulceration with exposure of sclerotic, eburnated subchondral bone.
D. Histologic findings (
1. Early alterations include surface erosion and irregularities.
2. Other changes include replication and deterioration of the tidemark, fissuring, and cartilage destruction with eburnation of subchondral bone.
E. Biochemical changes
1. OA is directly linked to a loss of proteoglycan content and composition with increased water content.
[Figure 12. A, Low-power magnification of a section of a glenohumeral head of osteoarthritic cartilage removed at surgery for total shoulder replacement. Note the significant fibrillation, vertical cleft formation, the tidemark, and the subchondral bony end plate. B, A higher power magnification of surface fibrillation showing vertical cleft formation and widespread large necrotic regions of the tissue devoid of cells. Clusters of cells, common in osteoarthritic tissues, also are seen.]
Figure 13. The cascade of enzymes and their activators and inhibitors involved in interleukin-1-stimulated degradation of articular cartilage.]
2. Proteoglycans exist in shorter chains with an increased chondroitin/keratin sulfate ratio.
3. Proteoglycans are largely unbound to hyaluronic acid because of proteolytic enzymes and decreased number of link proteins.
4. Collagen content is maintained, but its organization and orientation are severely disturbed, presumably due to collagenase.
F. Molecular mechanisms of OA (Figure 13)
1. Levels of proteolytic enzymes are found to be elevated in OA cartilage.
a. Metalloproteinases (collagenase, gelatinase, stromelysin)
b. Cathepsins B and D
2. Inflammatory cytokines may exacerbate degeneration seen in OA.
3. IL-1 and other cytokines may further disrupt cartilage homeostasis and amplify the destructive actions of proteolytic enzymes.
Top Testing Facts
1. Articular cartilage consists mainly of extracellular matrix (ECM), with only a small percentage of chondrocytes, which are responsible for the synthesis, maintenance, and homeostasis of cartilage.
2. The major components of the ECM are water, proteoglycans, and collagen.
3. Articular cartilage is classified into four layers (superficial, middle, deep, and calcified) according to collagen orientation, chondrocyte organization, and proteoglycan distribution.
4. Cartilage is an avascular structure in the adult; this has implications for repair and healing.
5. The breakdown of the cartilage matrix in normal turnover and in degeneration appears to be the action of proteinases; their overactivity is implicated in OA.
6. The water content of cartilage decreases with aging and increases in OA.
7. Proteoglycan content and keratan sulfate concentrations decrease with OA; proteoglycan degradation and chondroitin-4-sulfate concentration increase.
8. Elastohydrodynamic lubrication is the principal mode of lubrication of articular cartilage.
9. Superficial lacerations to cartilage rarely heal; deeper lacerations may heal with fibrocartilage.
10. Inflammatory cytokine and metalloproteinases are responsible for macroscopic and histologic changes seen in OA.
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