Biology of Articular Cartilage
Rachel E. Miller, PhD
Anne-Marie Malfait, MD, PhD
Dr. Malfait or an immediate family member serves as a paid consultant to or is an employee of Merck and Vizuri; has received research or institutional support from Galapagis NV, GlaxoSmithKline; serves as a board member, owner, officer, or committee member of the Amercican College of Rheumatology, the Osteoarthritis Research Society International, and the Rheumatology Research Foundation. Neither Dr. Miller nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.
Keywords: aggrecan; articular cartilage; chondrocytes; collagen; extracellular matrix
INTRODUCTION
“The fabric of the joints in the human body is a subject so much the more entertaining, as it must strike everyone that considers it attentively with an idea of fine mechanical composition. Where-ever the motion of one bone upon another is requisite, there we find an excellent apparatus for rendering that motion safe and free.” Thus starts Of the Structure and Diseases of Articulating Cartilages, read by Scottish physician and anatomist William Hunter at a meeting of the Royal Society of London on June 2, 1743.1 In his delightful paper, Hunter provides us with the first detailed description of articular cartilage, which is hyaline cartilage, one of the three major types of cartilage tissue in the body. The two other types are elastic cartilage, which exists in the epiglottis and the Eustachian tube, and fibrocartilage, which can be found in the intervertebral disks, in the meniscus of the knee, and covering the mandibular condyles in the temporomandibular joints.
Articular cartilage is the white, smooth tissue that covers the surfaces of long bones where they articulate in diarthrodial joints (Figure 1). Adult articular cartilage mainly consists of extracellular matrix (ECM) (15% to 40% of the wet weight) and water (60% to 85% of the wet weight), in which chondrocytes are embedded. Chondrocytes, the only cell type present in articular cartilage, are derived from mesenchymal stem cells. Chondrogenesis requires the key transcription factor, SOX9, which secures chondrocyte lineage commitment, promotes cell survival, and transcriptionally activates the genes for many cartilage-specific structural components and regulatory factors.2
In synovial joints, hyaline articular cartilage covers the subchondral bone underneath, and its surface faces the joint cavity and the synovial fluid.3 Together with synovium, bone, ligaments, tendons, and—in the knee—the menisci, cartilage ensures the integrity of diarthrodial joints. Movement of the joints in daily life applies a complex set of forces to these tissues. The unique composition and structure of articular cartilage supply an almost frictionless surface for bones to move upon each other and provide tremendous load-bearing capabilities to the joint (up to several times the body weight). In addition, the unique zonal organization of cartilage as well as the interplay between the different components lends the tissue its ability to withstand shear, compression, and tensile forces.4 Loading is integral for cartilage health, and cartilage adapts to loading patterns over time. For example, the amount of extracellular matrix molecules in cartilage varies locally depending on individual gait patterns.
COMPOSITION OF ARTICULAR CARTILAGE
ZONAL ORGANIZATION OF ARTICULAR CARTILAGE
Chondrocytes account for approximately 1% to 5% of cartilage tissue volume,5 and a particular feature of articular cartilage is that chondrocytes lack cell-to-cell contact. Each cell can be thought of as a functional metabolic unit, isolated from neighboring cells and responsible for the elaboration and maintenance of the ECM in its immediate vicinity.6 The major macromolecules that make up the cartilage ECM are type II
collagen and the high-molecular-weight proteoglycan, aggrecan. Macroscopically, cartilage is a smooth white tissue that is resistant to compression (Figure 1). Microscopically, the supramolecular organization of its components changes in a depth-dependent fashion (“zones”), consistent with the differing functions of these cartilage zones (Figure 2, A). The first 10% of cartilage tissue underneath the surface is referred to as the superficial zone and is typified by chondrocytes that assume a flattened appearance, along with type II collagen fibers that run parallel to the cartilage surface. Proteoglycan content in the superficial zone is low.7 A major function of the superficial zone is to support cartilage surface lubrication and low-friction joint articulation. The orientation of the collagen fibers in this zone confers tensile strength, which is important for constraining the high osmotic swelling that occurs in cartilage. In the middle or transitional zone, chondrocytes—still appearing as single cell units—assume a more rounded appearance, and type II collagen fiber orientation is no longer parallel to the surface but is random (Figure 2, B). The middle zone, which has the highest content of chondroitin sulfate-modified proteoglycans, helps
provide resistance to cartilage shear strain and compression. Finally, in the deep or radial zone, chondrocytes appear as vertical columns of clusters of five to eight rounded cells (Figure 2), whereas collagen fibers are oriented perpendicularly to the cartilage surface. This zone has the highest content of proteoglycans and correspondingly has the greatest compressive strength.
collagen and the high-molecular-weight proteoglycan, aggrecan. Macroscopically, cartilage is a smooth white tissue that is resistant to compression (Figure 1). Microscopically, the supramolecular organization of its components changes in a depth-dependent fashion (“zones”), consistent with the differing functions of these cartilage zones (Figure 2, A). The first 10% of cartilage tissue underneath the surface is referred to as the superficial zone and is typified by chondrocytes that assume a flattened appearance, along with type II collagen fibers that run parallel to the cartilage surface. Proteoglycan content in the superficial zone is low.7 A major function of the superficial zone is to support cartilage surface lubrication and low-friction joint articulation. The orientation of the collagen fibers in this zone confers tensile strength, which is important for constraining the high osmotic swelling that occurs in cartilage. In the middle or transitional zone, chondrocytes—still appearing as single cell units—assume a more rounded appearance, and type II collagen fiber orientation is no longer parallel to the surface but is random (Figure 2, B). The middle zone, which has the highest content of chondroitin sulfate-modified proteoglycans, helps
provide resistance to cartilage shear strain and compression. Finally, in the deep or radial zone, chondrocytes appear as vertical columns of clusters of five to eight rounded cells (Figure 2), whereas collagen fibers are oriented perpendicularly to the cartilage surface. This zone has the highest content of proteoglycans and correspondingly has the greatest compressive strength.
 FIGURE 1 Macroscopic photographs of human knee and ankle cartilage. Legend adapted from Treppo et al: A, The distal femur taken inferiorly. The patellar surface of the distal femur (FP) and anterior (C) and posterior (P) of the femoral condyles with medial (M) and lateral (L) aspects labeled. B, The proximal tibial surface with the menisci removed (A = anterior; P = posterior). C, The talar surface of the talocrural joint. (A and B, reproduced with permission from Treppo S, et al: Comparison of biomechanical and biochemical properties of cartilage from human knee and ankle pairs. J Orthop Res 2000;18:739-748.) |
 FIGURE 2 A, Light microscopic overview of adult human articular cartilage taken from the medial femoral condyle. By definition, the superficial (S) and transitional (T) zones each constitute 10% of the height of the articular cartilage layer, the bulk of which (80%) is represented by the radial one (R). For analytical purposes, the latter is partitioned into an upper and a lower half, each of which is further subdivided into upper and lower portions. The layer of calcified cartilage (CC) and the subchondral bone plate (arrowheads) for relatively thin strata beneath the hyaline articular cartilage tissue. BM: bone marrow space. 100-µm-thick polished section of methacrylate-embedded tissue, surface-stained with McNeil’s tetrachrome, basic fuchsin, and toluidine blue O. Magnification bar = 500 µm. B, The collagen fiber architecture of articular cartilage is often categorized into three different zones: superficial, middle, and deep. Note that the fiber orientation is tangential in the superficial zone and radial in the deep zone, whereas it is less oriented in the middle zone. (A, Reproduced with permission from Hunziker EB, Quinn TM, Häuselmann H-J: Quantitative structural organization of normal adult human articular cartilage. Osteoarthr Cartil 2002;10(7):564-572. B, Reproduced with permission from Mow VC, Proctor CS, Kelly MA: Biomechanics of articular cartilage, in Noordin M, Frankel VH, eds: Basic Biomechanics of the Musculoskeletal System, ed 2. Philadelphia, PA, Lea & Febiger, 1989, pp 31-57). |
Beyond the deep zone, the “tidemark,” which appears as a thin undulating basophilic line on light microscopic sections of decalcified cartilage, separates articular cartilage from a thin layer of calcified cartilage underneath. The calcified cartilage, containing hypertrophic chondrocytes, anchors the articular cartilage to the subchondral bone underneath.8 The subchondral bone plate is vascularized, with vascular channels penetrating the calcified cartilage layer from underneath. Nerve fibers have also been shown in these vascular channels. The cartilage-bone interface is referred to as the osteochondral junction, and it is an area of active research in the context of osteoarthritis, where it has been proposed that the ingrowth of vessels and nerves at the osteochondral junction may contribute to disease pathogenesis and joint pain.9
CELLS OF ARTICULAR CARTILAGE: CHONDROCYTES
Articular cartilage is avascular and aneural. There is one cell type present in this tissue: chondrocytes. Cell density in adult human articular cartilage shows marked variations with tissue depth, being highest in the superficial zone, where it represents less than 10% of the tissue volume. Chondrocyte density decreases progressively in the deeper zones. In adult human femoral condyle cartilage, it has been estimated that the total number of chondrocytes in a 1 mm2 area is 23,674.10 In femoral condyle cartilage, the cellularity is inversely correlated with cartilage thickness, which in itself depends on the degree of load-bearing.10,11 The weight-bearing region in adult human femoral condyle cartilage is approximately 2.4 ± 0.4 mm thick, whereas the thickness of ankle articular cartilage is approximately 1.5 ± 0.2 mm.10,12 Cellularity and chondrocyte distribution in cartilage vary by joint, and in the ankle joint the superficial zone appears to be less distinct than in other joints, with cell numbers that are similar to the those in deep zone.10 Although the biological implications of these variations are unknown, one may speculate that the differences in articulation in the ankle versus the knee may place different structural demands on this top tissue layer. In contrast, the deep zone appears to be the most conserved region among different joints.
 FIGURE 3 Deep layer chondrocytes. A, Transmission electron micrograph illustrating multiple chondrocyte cell processes (arrowheads) extending across the pericellular matrix (Pm) to the loosely woven inner border of the pericellular capsule (Pc). The articular pole (AP) forms a compacted cupola, whereas the basal pole (BP) remains loosely woven. Groups of matrix vesicles are evident at the basal pole and throughout the matrix. Head of the index phalanx. Bar = 2 µm. B, Scanning electron micrograph showing a chondrocyte (C) suspended in the pericellular matrix space (Pm) and separated from radially aligned territorial collagen fibers (Cl) by a “felt-like” pericellular capsule (Pc). Medial femoral condyle. Bar = 2 µm. C, Detail of B illustrating macropores (large arrowheads) formed in the loose weave at the basal pole (BP) of the chondron above and micropores (small arrowheads) formed in the dense organization of the articular pole (AP). Bar = 1 µm. (Reproduced with permission from Poole CA, Flint MH, Beaumont BW: Chondrons in cartilage: ultrastructural analysis of the pericellular microenvironment in adult human articular cartilages. J Orthop Res 1987;5(4):509-522.) |
Despite the low numbers of chondrocytes in cartilage, these cells are capable of producing and maintaining the extensive ECM that surrounds them (Figure 3). This is in contrast to other types of tissues such as bone, where distinct cell types perform the tasks of synthesis (osteoblasts) and degradation/remodeling (osteoclasts). Although chondrocytes are the only cell type in articular cartilage, their phenotype changes
depending on their location within the tissue. As explained above, chondrocyte morphology and ECM composition change with depth, and thus the types of molecules that chondrocytes secrete change with depth. Superficial zone chondrocytes produce a molecule called lubricin (discussed below in more detail) that helps to provide a low friction coefficient for the cartilage surface and thus aids in smooth joint articulation.13,14 In contrast, middle and deep zone chondrocytes produce large quantities of type II collagen and aggrecan to provide structural stability and resistance to compression. Middle and deep zone chondrocytes form functional units called chondrons, which consist of the chondrocyte along with the immediately surrounding ECM, termed the pericellular matrix15,16 (Figure 3).
depending on their location within the tissue. As explained above, chondrocyte morphology and ECM composition change with depth, and thus the types of molecules that chondrocytes secrete change with depth. Superficial zone chondrocytes produce a molecule called lubricin (discussed below in more detail) that helps to provide a low friction coefficient for the cartilage surface and thus aids in smooth joint articulation.13,14 In contrast, middle and deep zone chondrocytes produce large quantities of type II collagen and aggrecan to provide structural stability and resistance to compression. Middle and deep zone chondrocytes form functional units called chondrons, which consist of the chondrocyte along with the immediately surrounding ECM, termed the pericellular matrix15,16 (Figure 3).
Articular cartilage has limited intrinsic healing capacity, and cartilage injury represents a major risk factor for cartilage degeneration. In recent years, a population of cartilage-derived stem cells or progenitor cells (CSPCs), similar to those found in many other adult tissues, have been observed in human, equine, and bovine articular cartilage.17 These cells can be isolated and characterized in vitro on the basis of their self-renewal, multilineage differentiation, and migratory abilities. It is thought that these progenitor cells emerge when cartilage is injured, migrate to the injury site, and participate in tissue repair activities. It has been proposed that these CSPCs may be a therapeutic target for cartilage injury and posttraumatic osteoarthritis, but the exact nature and origin of these cells is still uncertain and it has also been suggested that progenitor cells in the synovium play an important role.
EXTRACELLULAR MATRIX: FLUID AND STRUCTURAL MACROMOLECULES
The remarkable biomechanical properties of articular cartilage are in large part derived from its unique molecular organization and the specialized biochemical characteristics of its major constituents (listed in Table 1). In healthy cartilage, assembly and tissue distribution of ECM molecules vary according to the vicinity of the matrix to chondrocytes. Essentially, the cartilage matrix can be divided into three areas, the pericellular, the territorial, and the interterritorial matrix, each with its unique molecular organization (Figure 4). Collagen is differentially organized in these three areas. Directly surrounding each chondrocyte is the pericellular matrix, which consists of type VI collagen fibers that form a tightly woven, nest-like enclosure (2 to 4 µm thick) around each chondrocyte.16 The 5-to 10-µm-thick zone around the pericellular matrix is the territorial matrix, where thicker collagen fibers form radial bundles around one cell or a group of cells. Finally, the interterritorial matrix contains large collagen type II bundles (described in Benninghoff’s classic description as “arcades”18). Other proteins are also differentially expressed in these different
matrix zones. For example, the pericellular matrix is rich in fibronectin and the proteoglycans, biglycan and perlecan, which may regulate chondrocyte activity through cell-matrix interactions and growth factor sequestration.16 Cartilage oligomeric matrix protein (COMP) is expressed solely in the interterritorial matrix, where it plays a role in collagen cross-linking.19 Finally, the mechanical properties of these zones vary—the chondrocyte is the softest component, and these cells are softer than the pericellular matrix, which is softer than the surrounding ECM.16 As such, the pericellular matrix likely plays an important role as a mechanotransducer by filtering mechanical signals, so the chondrocytes can respond and react to mechanical forces. One way the chondrocyte may interact with the pericellular matrix is through the primary cilium, which is an organelle that projects from the cell membrane into the surrounding matrix, where it can interact with the matrix environment through integrins and ion channels such as transient receptor potential vanilloid 4 (TRPV4).16
matrix zones. For example, the pericellular matrix is rich in fibronectin and the proteoglycans, biglycan and perlecan, which may regulate chondrocyte activity through cell-matrix interactions and growth factor sequestration.16 Cartilage oligomeric matrix protein (COMP) is expressed solely in the interterritorial matrix, where it plays a role in collagen cross-linking.19 Finally, the mechanical properties of these zones vary—the chondrocyte is the softest component, and these cells are softer than the pericellular matrix, which is softer than the surrounding ECM.16 As such, the pericellular matrix likely plays an important role as a mechanotransducer by filtering mechanical signals, so the chondrocytes can respond and react to mechanical forces. One way the chondrocyte may interact with the pericellular matrix is through the primary cilium, which is an organelle that projects from the cell membrane into the surrounding matrix, where it can interact with the matrix environment through integrins and ion channels such as transient receptor potential vanilloid 4 (TRPV4).16
TABLE 1 Protein of the Cartilage Matrix | ||||||||||||||||||||||||||||||||||
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 FIGURE 4 The molecular organization of normal articular cartilage. The cartilage matrix surrounding chondrocytes in healthy articular cartilage is arranged into zones defined by their distance from the cell. The pericellular matrix lies immediately around the cell and is the zone where molecules that interact with cell-surface receptors are located; for example, hyaluronan binds the receptor CD44. Next to the pericellular matrix, slightly further from the cell, lies the territorial matrix. At largest distance from the cell is the interterritorial matrix. The types of collagens and the collagen-binding proteins that form the matrices are different in each zone. Abbreviations: CILP = cartilage intermediate layer protein; COMP = cartilage oligomeric matrix protein; CS = chondroitin sulfate; KS = keratan sulfate; PRELP = proline-arginine-rich end leucine-rich repeat protein. (Reproduced with permission from Heinegard D, Saxne T: The role of cartilage matrix in osteoarthritis. Nat Rev Rheumatol 2011;7(1):50-56). |
WATER
Normal cartilage has a water content ranging from 65% (deep zones) to 80% (surface) of its wet weight. The flow of water through the tissue is governed by mechanical and physicochemical laws, and it is this flow that allows the transport of nutrients through this avascular tissue, in addition to providing cartilage with its biomechanical properties (please refer to the chapter13). Articular cartilage holds water with avidity, through contact with the major macromolecules in cartilage, type II collagen, and proteoglycans.
COLLAGENS
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