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Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Articular Cartilage. Part I: Tissue Design and Chondrocyte-Matrix Interactions*

J. A. BUCKWALTER, M.D., IOWA CITY, IOWA and H. J. MANKIN, M.D., BOSTON, MASSACHUSETTS

An Instructional Course Lecture, The American Academy of Orthopaedic Surgeons

	Introduction

Top Introduction Composition of Articular... Structure of Articular Cartilage Interactions between the... Overview References

 
In 1892, Walt Whitman observed that "the narrowest hinge in my hand puts to scorn all machinery."⁷⁸ Despite the remarkable advances in joint replacement, Whitman's observation stands unchallenged; no current prostheses come close to duplicating the function and durability of synovial joints. These complex structures, developed and progressively refined over hundreds of millions of years¹, are formed by an arrangement of multiple distinct tissues, including joint capsule, ligament, meniscus, subchondral bone, synovial tissue, and hyaline articular cartilage. These tissues are self-renewing, respond to alterations in use, and provide stable movement with a level of friction less than that achieved by any prosthetic joint. The tissue that contributes the most to these extraordinary functional capacities is the hyaline articular cartilage^15,19. It varies in thickness, cell density, matrix composition, and mechanical properties within the same joint, among joints, and among species²; however, in all synovial joints it consists of the same components, has the same general structure, and performs the same functions. Although it is at most only a few millimeters thick, it has surprising stiffness to compression and resilience; it also has an exceptional ability to distribute loads^52,53, thereby minimizing peak stresses on subchondral bone. Perhaps most important, it has great durability; in most people, it provides normal joint function for eighty years or more. No synthetic material approaches this level of performance.

Grossly and histologically, adult articular cartilage appears to be a simple inert tissue. When examined from inside a synovial joint, normal articular cartilage appears as a slick firm surface that resists deformation. Light microscopy shows that it consists primarily of extracellular matrix, with only one type of cell, the chondrocyte, and that it lacks blood vessels, lymphatic vessels, and nerves (Fig. 1). Compared with tissues such as muscle or bone, cartilage has a low level of metabolic activity and appears to be less responsive to changes in loading or to injury. Despite its unimpressive appearance and low level of metabolic activity, detailed study of the morphology and biology of adult articular cartilage shows that it has an elaborate, highly ordered structure and that a variety of complex interactions between the chondrocytes and the matrix actively maintain the tissue.

Fig. 1 Micrograph of articular cartilage from the medial femoral condyle of an eight-month-old rabbit. The tissue is organized into four layers, or zones. These consist of a superficial zone (S); a transitional zone (T); a middle (radial), or deep, zone (M); and a calcified cartilage zone (C) (bar = fifty micrometers). (Reprinted, with permission, from: Buckwalter, J. A.; Hunziker, E. B.; Rosenberg, L. C.; Coutts, R. D.; Adams, M. E.; and Eyre, D. R.: Articular cartilage. Composition and structure. In Injury and Repair of the Musculoskeletal Soft Tissues, p. 407. Edited by S. L-Y. Woo and J. A. Buckwalter. Park Ridge, Illinois, The American Academy of Orthopaedic Surgeons, 1988.)

	Composition of Articular Cartilage

Top Introduction Composition of Articular... Structure of Articular Cartilage Interactions between the... Overview References

 
Like other connective tissues, including tendon, ligament, and meniscus, articular cartilage consists of cells, matrix water, and a matrix macromolecular framework (Fig. 1), and like other connective tissues, articular cartilage derives its form and mechanical properties from its matrix^15,19. The cells contribute little to the volume of the tissue, about 1 per cent in adult human articular cartilage. (In other species, especially small animals such as mice, rats, and rabbits—which have thin articular cartilage—the cell density is many times greater than in humans^74,75.)

Chondrocytes
Within normal articular cartilage, there is only one type of cell: the highly specialized chondrocyte¹⁵ (Fig. 2). Chondrocytes from different cartilage zones differ in size, shape, and probably metabolic activity^3,4, but all of these cells contain the organelles necessary for matrix synthesis, including endoplasmic reticulum and Golgi membranes. They also frequently contain intracytoplasmic filaments, lipid, glycogen, and secretory vesicles, and at least some chondrocytes have short cilia extending from the cell into the matrix. These structures may have a role in sensing mechanical changes in the matrix. Chondrocytes surround themselves with their extracellular matrix and do not form cell-to-cell contacts. A spheroidal shape; synthesis of type-II collagen, large aggregating proteoglycans, and specific non-collagenous proteins; and formation of these molecules into cartilaginous matrix distinguish mature chondrocytes from other cells. Individual chondrocytes are surprisingly active metabolically (they have a glycolytic rate per cell similar to that of cells in vascularized tissues), but the total metabolic activity of the tissue is low because of the low cell density.

Fig. 2 Electron micrographs of chondrocytes from articular cartilage from the medial femoral condyle of a skeletally mature rabbit. a: superficial zone; b: transitional zone; c: middle (radial), or deep, zone; and d: calcified cartilage zone. N = nucleus, G = glycogen, IF = intermediate filaments, UM = unmineralized matrix, and MM = mineralized matrix (bar = three micrometers). (Reprinted, with permission, from: Buckwalter, J. A.; Hunziker, E. B.; Rosenberg, L. C.; Coutts, R. D.; Adams, M. E.; and Eyre, D. R.: Articular cartilage. Composition and structure. In Injury and Repair of the Musculoskeletal Soft Tissues, p. 415. Edited by S. L-Y. Woo and J. A. Buckwalter. Park Ridge, Illinois, The American Academy of Orthopaedic Surgeons, 1988.)

In adult animals, chondrocytes derive their nutrition from nutrients in the synovial fluid, which, to reach the cell, must pass through a double diffusion barrier: first the synovial tissue and synovial fluid, and then the cartilage matrix. This latter barrier is restrictive not only with respect to the size of the materials but also with respect to their charges and to other features such as molecular configuration²⁶. The nature of this system leaves chondrocytes with a low concentration of oxygen relative to most other tissues; therefore, they depend primarily on anaerobic metabolism.

The activity and function of articular cartilage chondrocytes during skeletal growth differ from those after completion of growth. In growing individuals, the chondrocytes produce new tissue to expand and remodel the articular surface; in skeletally mature individuals, they do not substantially change the volume of the tissue, but they replace degraded matrix macromolecules and they may remodel the articular surface^6,9. Cartilage first forms from undifferentiated mesenchymal cells that cluster together and synthesize cartilage collagens, proteoglycans, and non-collagenous proteins. The tissue becomes recognizable as cartilage under light microscopy when an accumulation of matrix separates the cells and they assume a spherical shape. During the formation and growth of articular cartilage, the cell density is high and the cells reach their highest level of metabolic activity, as the chondrocytes proliferate rapidly and synthesize large volumes of matrix. In growing mammalian articular cartilage, chondrocytes divide and produce new matrix in two zones: a peripheral zone, which enlarges and expands the articular surface, and a central zone, which also serves as the center of enchondral ossification of the epiphysis. With skeletal maturation, the rates of cell metabolic activity, matrix synthesis, and cell division decline. After completion of skeletal growth, most chondrocytes probably never divide but rather continue to synthesize collagens, proteoglycans, and non-collagenous proteins. This continued synthetic activity suggests that maintenance of articular cartilage requires substantial ongoing internal remodeling of the macromolecular framework of the matrix. Enzymes produced by chondrocytes presumably are responsible for degradation of the matrix macromolecules, and chondrocytes probably respond to the presence of fragmented matrix molecules by increasing their synthetic activity to replace the degraded components of the macromolecular framework. Other mechanisms must also influence the balance between synthetic and degradative activity. For example, the frequency and intensity of joint-loading influences chondrocyte metabolism. Immobilization of the joint or a marked decrease in joint-loading alters chondrocyte activity so that degradation exceeds synthesis of at least the proteoglycan component of the matrix^6,7. Persistent, increased use of the joint may also alter the composition and organization of the matrix, but this has not been demonstrated clearly in skeletally mature individuals^6,7. With aging, the capacity of the cells to synthesize some types of proteoglycans and their response to stimuli, including growth factors, decrease^{17,20,29,48,49}. These age-related changes may limit the ability of the cells to maintain the tissue and thereby contribute to the development of degeneration of the articular cartilage⁴⁸.

Extracellular Matrix
The matrix of the articular cartilage consists of two components: the tissue fluid and the framework of structural macromolecules that give the tissue its form and stability. The interaction of the tissue fluid with the macromolecular framework gives the tissue its mechanical properties of stiffness and resilience^10,52.

Tissue Fluid
Water contributes as much as 80 per cent of the wet weight of articular cartilage, and the interaction of the water with the matrix macromolecules substantially influences the mechanical properties of the tissue^{15,41,42,45,47,52}. This tissue fluid contains gases, small proteins, metabolites, and a high concentration of cations to balance the negatively charged proteoglycans. At least some of the water can move freely in and out of the tissue. The volume, concentration, and behavior of the water within the tissue depend primarily on its interaction with the structural macromolecules, particularly the large aggregating proteoglycans that help to maintain the fluid within the matrix and the concentrations of electrolytes in the fluid. Because these macromolecules have large numbers of negatively charged sulfate and carboxylate groups that attract positively charged ions and repel negatively charged ions, they increase the concentration of positive ions such as sodium and decrease the concentration of negative ions such as chloride. The increase in the total concentration of inorganic ions causes an increase in the osmolarity of the tissue—that is, it creates a Donnan effect. The collagen network resists the Donnan osmotic pressure caused by the inorganic ions associated with the proteoglycans^10,52.

Structural Macromolecules
The structural macromolecules of the cartilage, collagens, proteoglycans, and non-collagenous proteins, contribute 20 to 40 per cent of the wet weight of the tissue¹⁵. The three classes of macromolecules differ in their concentrations within the tissue and in their contributions to the tissue properties. Collagens contribute about 60 per cent of the dry weight of cartilage; proteoglycans, 25 to 35 per cent; and non-collagenous proteins and glycoproteins, 15 to 20 per cent. Collagens are distributed relatively uniformly throughout the depth of the cartilage, except for the collagen-rich superficial zone. The collagen fibrillar meshwork gives cartilage its form and tensile strength¹⁰. Proteoglycans and non-collagenous proteins bind to the collagenous meshwork or become mechanically entrapped within it, and water fills this molecular framework. Some non-collagenous proteins help to organize and stabilize the macromolecular framework of the matrix, while others help chondrocytes to bind to the macromolecules of the matrix.

Collagens
Articular cartilage contains multiple genetically distinct collagen types^24,25,68, specifically types II, VI, IX, X, and XI. Types II, IX, and XI form the cross-banded fibrils seen with electron microscopy (Fig. 3). The organization of these fibrils into a tight meshwork that extends throughout the tissue provides the tensile stiffness and strength of articular cartilage and contributes to the cohesiveness of the tissue by mechanically entrapping the large proteoglycans. The principal collagen, type II, accounts for 90 to 95 per cent of the collagen in articular cartilage and forms the primary component of the cross-banded fibrils. Type-IX collagen molecules bind covalently to the superficial layers of the cross-banded fibrils and project into the matrix, where they also can bind covalently to other type-IX collagen molecules. Type-XI collagen molecules bind covalently to type-II collagen molecules and probably form part of the interior structure of the cross-banded fibrils. The functions of type-IX and type-XI collagens remain uncertain, but presumably they help to form and stabilize the collagen fibrils assembled primarily from type-II collagen. The projecting portions of type-IX collagen molecules may also help to bind together the collagen-fibril meshwork^{5,22,24,25,66} and to connect the meshwork with proteoglycans⁶⁶. Type-VI collagen appears to form an important part of the matrix immediately surrounding the chondrocytes and to help chondrocytes attach to the matrix^31,46. The presence of type-X collagen only near the cells of the calcified cartilage zone of the articular cartilage and the hypertrophic zone of the growth plate (where the longitudinal cartilage septa begin to mineralize) suggests that it has a role in mineralization of the cartilage.

Fig. 3 Electron micrographs of the interterritorial matrix of articular cartilage from the medial femoral condyle of an eight-month-old rabbit. a: superficial zone; b: transitional zone; c: upper portion of the middle (radial), or deep, zone; and d: lower portion of the middle (radial), or deep, zone. The arrows indicate proteoglycans precipitated with ruthenium hexamine trichloride (bar = 0.5 micrometer). (Reprinted, with permission, from: Buckwalter, J. A.; Hunziker, E. B.; Rosenberg, L. C.; Coutts, R. D.; Adams, M. E.; and Eyre, D. R.: Articular cartilage. Composition and structure. In Injury and Repair of the Musculoskeletal Soft Tissues, p. 418. Edited by S. L-Y. Woo and J. A. Buckwalter. Park Ridge, Illinois, The American Academy of Orthopaedic Surgeons, 1988.)

Proteoglycans
Proteoglycans consist of a protein core and one or more glycosaminoglycan chains (long unbranched polysaccharide chains consisting of repeating disaccharides that contain an amino sugar)^32,63,64,66. Each unit of disaccharide has at least one negatively charged carboxylate or sulfate group, so the glycosaminoglycans form long strings of negative charges that repel other negatively charged molecules and that attract cations. Glycosaminoglycans found in cartilage include hyaluronic acid, chondroitin sulfate, keratan sulfate, and dermatan sulfate. The concentration of these molecules varies among sites within articular cartilage and also with age, injury to the cartilage, and disease.

Articular cartilage contains two major classes of proteoglycans: large aggregating proteoglycan monomers or aggrecans, and small proteoglycans including decorin, biglycan, and fibromodulin^{32,61,63,64,66,69}. Because it may have a glycosaminoglycan component, type-IX collagen is also considered a proteoglycan⁶⁶. Aggrecans have large numbers of chondroitin-sulfate and keratan-sulfate chains attached to a protein core filament. Cartilage also contains large non-aggregating proteoglycans that resemble aggrecans in structure and composition and may represent degraded aggrecans^17,64. Decorin has one dermatan-sulfate chain, biglycan has two dermatan-sulfate chains, and fibromodulin has several keratan-sulfate chains⁶⁶. The tissue probably also contains other small proteoglycans that have not been identified. Aggrecan molecules fill most of the interfibrillar space of the cartilage matrix, contributing about 90 per cent of the total cartilage matrix proteoglycan mass; large non-aggregating proteoglycans contribute 10 per cent or less; and small non-aggregating proteoglycans contribute about 3 per cent. Although the small proteoglycans contribute relatively little to the total mass of proteoglycans compared with the aggrecans, because of their small size they may be present in equal or higher molar amounts.

In the articular cartilage matrix, most aggrecans non-covalently associate with hyaluronic acid (hyaluronan) and link proteins (small non-collagenous proteins) to form proteoglycan aggregates^11,12,18 (Fig. 4). These large molecules have a central backbone of hyaluronan that can range in length from several hundred to more than 10,000 nanometers^11,12. Large aggregates may have more than 300 associated aggrecan molecules¹². Link proteins stabilize the association between monomers and hyaluronic acid and appear to have a role in directing the assembly of aggregates^16,76. The formation of aggregates helps to anchor proteoglycans within the matrix, preventing their displacement during deformation of the tissue, and helps to organize and stabilize the relationship between proteoglycans and the collagen meshwork.

View larger version (140K): [in this window] [in a new window]   Fig. 4 Electron micrograph showing proteoglycan aggregates from bovine articular cartilage. The aggregates consist of central hyaluronan filaments and multiple attached aggrecan molecules. A: aggregate from a calf, and B (inset): aggregate from a steer. Aggregates from older animals have shorter hyaluronan filaments and fewer aggrecans; in addition, the aggrecans are shorter and vary more in length (bar = 500 nanometers).

The small non-aggregating proteoglycans have shorter protein cores than do aggrecan molecules; unlike aggrecans, they do not fill a large volume of the tissue or contribute directly to the mechanical behavior of the tissue. Instead, they bind to other macromolecules and probably influence cell function. Decorin and fibromodulin bind with type-II collagen and may have a role in organizing and stabilizing the type-II collagen meshwork^34,35,37,66. Biglycan is concentrated in the pericellular matrix and may interact with type-VI collagen⁶⁶. The small proteoglycans also can bind transforming growth factor-ß and may influence the activity of this cytokine in cartilage⁴⁰.

Non-Collagenous Proteins and Glycoproteins
The non-collagenous proteins and glycoproteins are not as well understood as the collagens and proteoglycans. There is a wide variety of these molecules within normal articular cartilage, but thus far only a few of them have been studied. In general, they consist primarily of protein and have a few attached monosaccharides and oligosaccharides^38,39. At least some of these molecules appear to help to organize and maintain the macromolecular structure of the matrix. Anchorin CII, a collagen-binding chondrocyte surface protein, may help to anchor chondrocytes to the collagen fibrils of the matrix^50,57. Cartilage oligomeric protein, an acidic protein, is concentrated primarily within the territorial matrix of the chondrocyte and appears to be present only within cartilage and to have the capacity to bind to chondrocytes^23,36. This molecule may have value as a marker of cartilage turnover and of the progression of cartilage degeneration in patients who have osteoarthrosis^43,71,73. Fibronectin and tenascin, non-collagenous matrix proteins found in a variety of tissues, also have been identified within cartilage^{21,33,55,67,70}. Their functions in articular cartilage remain poorly understood, but they may have roles in matrix organization, cell-matrix interactions, and the responses of the tissue in inflammatory arthritis and osteoarthrosis.

	Structure of Articular Cartilage

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To form articular cartilage, chondrocytes organize the collagens, proteoglycans, and non-collagenous proteins into a unique, highly ordered structure¹⁵. The composition, organization, and mechanical properties of the matrix; cell morphology; and, probably, cell function vary according to the depth from the articular surface (Figs. 1, 2, and 3). The composition, organization, and function of the matrix also vary according to the distance from the cell (Fig. 5).

Fig. 5 Electron micrographs showing the matrix compartments of the articular cartilage of the medial femoral condyle of an eight-month-old rabbit. a: The image shows the pericellular matrix (arrowheads), the territorial matrix (asterisk), and the interterritorial matrix (double asterisk) (bar = three micrometers). b: Higher-magnification view of the compartments of the matrix, showing the relationship between the cell membrane and the pericellular matrix (bar = one micrometer). Note the short cell processes that extend through the pericellular matrix. (Reprinted, with permission, from: Buckwalter, J. A.; Hunziker, E. B.; Rosenberg, L. C.; Coutts, R. D.; Adams, M. E.; and Eyre, D. R.: Articular cartilage. Composition and structure. In Injury and Repair of the Musculoskeletal Soft Tissues, p. 416. Edited by S. L-Y. Woo and J. A. Buckwalter. Park Ridge, Illinois, The American Academy of Orthopaedic Surgeons, 1988.)

Zones
The morphological changes in chondrocytes and matrix from the articular surface to the subchondral bone make it possible to identify four layers, or zones. These consist of a superficial zone; a transitional zone; a middle (radial), or deep, zone; and a zone of calcified cartilage¹⁹ (Fig. 1). The relative size and appearance of these zones vary among species and among joints within the same species; although each zone has different morphological features, the boundaries between the zones cannot be sharply defined. Nonetheless, recent biological and mechanical studies have shown that the zonal organization has functional importance^3,15. The matrices differ with respect to concentrations of water, proteoglycan, and collagen and with respect to the size of the aggregates¹⁵. Cells in different zones differ not only in shape, size, and orientation relative to the articular surface (Fig. 2) but also in metabolic activity³. They may respond differently to mechanical loading, suggesting that the development and maintenance of normal articular cartilage depend in part on the differentiation of phenotypically distinct populations of chondrocytes.

Superficial Zone
The unique structure and composition of the thinnest zone of articular cartilage, the superficial zone, give it specialized mechanical and possibly specialized biological properties. This zone typically consists of two layers. A sheet of fine fibrils with little polysaccharide and no cells covers the joint surface. This portion of the superficial zone presumably corresponds to the clear film, often identified as the lamina splendens, which can be stripped from the articular surface in some regions. Deep to this acellular sheet of fine fibrils, flattened ellipsoid-shaped chondrocytes arrange themselves so that their major axes are parallel to the articular surface (Fig. 2). The chondrocytes synthesize a matrix that has a high concentration of collagen and a low concentration of proteoglycan relative to the other cartilage zones; studies of cultures of cells from the superficial zone have shown that these cells degrade proteoglycans more rapidly and synthesize less collagen and proteoglycans than do cells from the deeper zones³. Concentrations of fibronectin and water are also highest in this zone.

The dense matrix of collagen fibrils lying parallel to the joint surface in the superficial zone (Fig. 3) helps to determine the mechanical properties of the tissue and affects the movement of molecules in and out of the cartilage. These fibrils give this zone greater tensile stiffness and strength than the deeper zones, and they may resist shear forces generated during use of the joint^19,52,65. In vitro experiments have shown that the superficial zone also makes an important contribution to the compressive behavior of articular cartilage⁷². Removal of this zone increases the permeability of the tissue and probably increases loading of the macromolecular framework during compression; disruption or remodeling of the dense collagenous matrix of the superficial zone is one of the first detectable structural changes in experimentally induced degeneration of articular cartilage³⁰, suggesting that alterations in this zone may contribute to the development of osteoarthrosis by changing the mechanical behavior of the tissue. The densely packed collagen fibrils also create a so-called skin for the articular cartilage that may limit the ingress of large molecules such as antibodies or other proteins and the egress of large cartilage molecules. By acting as a barrier to the passage of large molecules between the synovial fluid and the cartilage, the superficial zone may effectively isolate cartilage from the immune system. Thus, disruption of this zone not only may alter the structure and mechanical properties of articular cartilage, but also may release cartilage molecules that stimulate an immune or inflammatory response.

Transitional Zone
As the name of this zone implies, the morphology and the matrix composition of the transitional zone are intermediate between the superficial zone and the middle (radial) zone. The transitional zone usually has several times the volume of the superficial zone. The cells have a higher concentration of synthetic organelles, endoplasmic reticulum, and Golgi membranes than do cells in the superficial zone (Fig. 2). Cells in the transitional zone assume a spheroidal shape and synthesize a matrix that has larger-diameter collagen fibrils, a higher concentration of proteoglycan, and lower concentrations of water and collagen than does the matrix of the superficial zone.

Middle (Radial) Zone
The chondrocytes in the middle zone are spheroidal in shape and tend to align themselves in columns perpendicular to the joint surface (Figs. 1 and 2). This zone contains the largest-diameter collagen fibrils, the highest concentration of proteoglycans, and the lowest concentration of water. The collagen fibers pass into the tidemark, a thin basophilic line seen on light microscopy sections of decalcified articular cartilage that roughly corresponds to the boundary between calcified and uncalcified cartilage. The nature of the tidemark remains uncertain⁵⁶. It may result from the concentration of basophilic calcified material at the interface between calcified and uncalcified matrix, possibly accentuated by tissue-processing, and thus may represent a so-called high watermark for calcification. Alternatively, one study revealed a band of fine fibrils corresponding to the tidemark⁶², suggesting that it represents a well defined matrix structure.

Calcified Cartilage Zone
A thin zone of calcified cartilage separates the radial zone (uncalcified cartilage) from the subchondral bone. The cells of the zone of calcified cartilage have a smaller volume than the cells of the radial zone, and they contain only small amounts of endoplasmic reticulum and Golgi membranes (Fig. 2). In some regions, these cells appear to be surrounded completely by calcified cartilage—that is, they are buried in individual "calcific sepulchers"—suggesting that the cells have an extremely low level of metabolic activity. However, recent work suggests that they may have a role in the development and progression of osteoarthrosis⁵⁶.

Regions of the Matrix
Variations in the matrix within zones allow the distinction of three compartments, or regions: a pericellular region, a territorial region, and an interterritorial region¹⁵ (Fig. 5). The pericellular and territorial regions appear to serve the needs of chondrocytes, binding the cell membranes to the matrix macromolecules and protecting the cells from damage during loading and deformation of the tissue. They may also help to transmit mechanical signals to the chondrocytes when the matrix deforms during joint-loading. The primary function of the interterritorial matrix (Fig. 3) is to provide the mechanical properties of the tissue.

Pericellular Region
Chondrocyte cell membranes appear to attach to the thin rim of the pericellular matrix that covers the cell surface. This region is rich in proteoglycans and also contains non-collagenous proteins, such as the cell-membrane-associated molecule anchorin CII^50,57, and non-fibrillar collagens, such as type-VI collagen^31,46. It has little or no fibrillar collagen. Cytoplasmic extensions from the chondrocytes project into and through the pericellular matrix to the territorial matrix.

Territorial Region
An envelope of territorial matrix surrounds the pericellular matrix of individual chondrocytes and, in some locations, pairs or clusters of chondrocytes and their pericellular matrices. In the radial zone, a territorial matrix surrounds each column of chondrocytes. The thin collagen fibrils of the territorial matrix nearest to the cell appear to adhere to the pericellular matrix. At a distance from the cell, they decussate and intersect at various angles, forming a fibrillar basket around the cells. This collagenous basket may provide mechanical protection for the chondrocytes during loading and deformation of the tissue. An abrupt increase in the diameter of the collagen fibril and a transition from the basket-like orientation of the fibrils to a more parallel arrangement marks the boundary between the territorial and interterritorial matrices. However, many collagen fibrils connect the two regions, making it difficult to identify precisely the boundary between them.

Interterritorial Region
The interterritorial matrix makes up most of the volume of mature articular cartilage (Fig. 1) and contains the largest-diameter collagen fibrils. Unlike the collagen fibrils of the territorial matrix, these fibrils are not organized to surround the chondrocytes and they change their orientation relative to the joint surface 90 degrees from the superficial zone to the radial zone (Fig. 3). In the superficial zone, the fibrils have a relatively small diameter and generally lie parallel to the articular surface; in the transitional zone, interterritorial fibrils assume more oblique angles relative to the articular surface; and, in the radial zone, they generally lie perpendicular (or radial) to the joint surface.

	Interactions between the Chondrocytes and the Matrix

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The interdependence of the chondrocytes and the matrix makes possible the maintenance of the tissue throughout life. The relationship between the chondrocytes and the matrix does not end when the cells secrete the matrix macromolecules. The matrix protects the chondrocytes from mechanical damage during normal use of the joint, helping to maintain their shape and phenotype. Nutrients, substrates for the synthesis of matrix molecules, newly synthesized molecules, degraded matrix molecules, metabolic waste products, and molecules that help to regulate cell function, such as cytokines and growth factors, all pass through the matrix, and in some instances they may be stored in the matrix. The types of molecules that can pass through the matrix and the rate at which they can pass depend on the composition and organization of the matrix, primarily the concentration, composition, and organization of the large proteoglycans.

Throughout life, chondrocytes degrade and synthesize matrix macromolecules. The mechanisms that control the balance between these activities remain poorly understood, but cytokines with catabolic and anabolic effects appear to have important roles^44,51,60,77. For example, interleukin-1 induces the expression of matrix metalloproteases that can degrade the matrix macromolecules, and it interferes with the synthesis of matrix proteoglycans at the transcriptional level. Other cytokines, such as insulin-dependent growth factor-I and transforming growth factor-ß, oppose these catabolic activities by stimulating matrix synthesis and cell proliferation. In response to a variety of stimuli, chondrocytes synthesize and release these cytokines into the matrix, where they may bind to receptors on the cell surfaces (stimulating cell activity by either autocrine or paracrine mechanisms) or may become trapped within the matrix. The anabolic activities appear in large measure to be responses to structural needs of the matrix or other stimuli, possibly including mechanical loading of the tissue detected by the chondrocytes. The degradative response, on the other hand, appears to be the result of a complex cascade that includes the activation or inhibition of interleukin-1, stromelysin, aggrecanase, plasmin, and collagenase by factors such as prostaglandins, transforming growth factor-ß, tumor necrosis factor, tissue inhibitors of metalloproteases, tissue plasminogen activator, plasminogen activator inhibitor, and other molecules.

The matrix also acts as a signal transducer for the chondrocytes. It transmits signals that result from mechanical loading of the articular surface to the chondrocytes, and the chondrocytes respond to these signals by altering the matrix, possibly through the expression of cytokines that act through autocrine or paracrine mechanisms. Experimental studies have shown that a persistent abnormal decrease in joint-loading or immobilization of a joint decreases the concentration of proteoglycan in articular cartilage and the degree of proteoglycan aggregation and alters the mechanical properties of cartilage^6,7,14. Resumption of use of the joint restores the composition and mechanical properties of the matrix toward normal; thus, maintenance of the normal composition of articular cartilage requires a minimum level of loading and motion of the joint^7,9. Repetitive loading and motion of the joint at greater-than-normal levels may increase the synthetic activity of chondrocytes, but the chondrocytes have limited, if any, ability to expand the tissue volume in adults.

The details of how the mechanical loading of joints influences the function of chondrocytes remain unknown, but deformation of the matrix produces mechanical, electrical, and physicochemical signals that may have major roles in stimulating chondrocytes^8,9,27,28. Compression of the articular surface deforms the matrix and may directly deform chondrocytes. Deformation of the matrix also produces electrical and physicochemical effects that may influence chondrocytes. It causes flow of the tissue fluid and the counter-ions relative to the fixed charged groups of the matrix macromolecules. This flow alters the charge density around the cells and produces a streaming potential. Changes in charge density within the matrix alter the Donnan osmotic pressure and the osmotic pressure gradients. Mechanically induced flow of the matrix fluid may also accelerate the flow of nutrients and metabolites through the matrix. Loading may also cause persistent changes in the molecular organization of the matrix, altering the response of the chondrocytes to subsequent loading. Thus, the matrix may not only transduce and transmit signals, it may record the loading history of the tissue and alter the response of the cells on the basis of the loading history.

	Overview

Top Introduction Composition of Articular... Structure of Articular Cartilage Interactions between the... Overview References

 
The unique biological and mechanical properties of articular cartilage depend on the design of the tissue and the interactions between the chondrocytes and the matrix that maintain the tissue. Chondrocytes form the macromolecular framework of the tissue matrix from three classes of molecules: collagens, proteoglycans, and non-collagenous proteins. Type-II, IX, and XI collagens form a fibrillar meshwork that gives the tissue its form and tensile stiffness and strength. Type-VI collagen forms part of the matrix immediately surrounding the chondrocytes and may help the chondrocytes to attach to the macromolecular framework of the matrix. Large aggregating proteoglycans (aggrecans) give the tissue its stiffness to compression and its resilience and contribute to its durability. Small proteoglycans, including decorin, biglycan, and fibromodulin, bind to other matrix macromolecules and thereby help to stabilize the matrix. They may also influence the function of the chondrocytes and bind growth factors. Anchorin CII, a non-collagenous protein, appears to help to anchor chondrocytes to the matrix. Cartilage oligomeric protein may have value as a marker of turnover and degeneration of cartilage, and other non-collagenous proteins, including tenascin and fibronectin, can influence interactions between the chondrocytes and the matrix. The matrix protects the cells from injury due to normal use of the joint, determines the types and concentrations of molecules that reach the cells, and helps to maintain the chondrocyte phenotype.

Throughout life, the tissue undergoes continual internal remodeling as the cells replace matrix macromolecules lost through degradation. The available evidence indicates that normal matrix turnover depends on the ability of chondrocytes to detect alterations in the macromolecular composition and organization of the matrix, including the presence of degraded molecules, and to respond by synthesizing appropriate types and amounts of new molecules. In addition, the matrix acts as a signal transducer for the cells. Loading of the tissue due to use of the joint creates mechanical, electrical, and physicochemical signals that help to direct the synthetic and degradative activity of chondrocytes. A prolonged severe decrease in the use of the joint leads to alterations in the composition of the matrix and eventually to loss of tissue structure and mechanical properties, whereas use of the joint stimulates the synthetic activity of chondrocytes and possibly the internal tissue-remodeling. Aging leads to alterations in the composition of the matrix and the activity of the chondrocytes, including the ability of the cells to respond to a variety of stimuli such as growth factors. These alterations may increase the probability of degeneration of the cartilage.

	Footnotes

 

*Printed with permission of The American Academy of Orthopaedic Surgeons. This article will appear in Instructional Course Lectures, Volume 47, The American Academy of Orthopaedic Surgeons, Rosemont, Illinois, March 1998.

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Funds were received in total or partial support of the research or clinical study presented in this article. The funding sources were the National Institutes of Health and the Veterans Administration.

Department of Orthopaedics, University of Iowa College of Medicine, 01013 Pappajohn Pavilion, Iowa City, Iowa 52242. E-mail address: joseph-buckwalter@uiowa.edu.

Orthopaedic Service, Gray 606, Massachusetts General Hospital, Boston, Massachusetts 02114.

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