Osteoarthritis

Chapter 61Osteoarthritis



John P. Caron


Joints are highly differentiated structures composed of a number of connective tissues including bone, articular cartilage, and periarticular soft tissues, all of which contribute to normal joint function and undergo changes in structure and metabolism in disease.1,2 From the point of view of joint diseases, perhaps the most important of these components is articular or hyaline cartilage, composed principally of a precisely organized arrangement of collagens and proteoglycans. This tissue is responsible for the load-distributing functions of the joint, and, in health, cartilaginous surfaces glide over one another in a virtually frictionless manner, even when under substantial load. In joint trauma or osteoarthritis (OA), the normal structure and function of articular cartilage are deranged, leading to biochemical, structural, and biomechanical abnormalities in all joint tissues. If the trauma is uncorrected, the result is progressive joint destruction, a process likened to organ failure in other body systems. Joint disease is a particularly prevalent cause of lameness and as such is an expensive equine health problem.3-5 An understanding of the biology and pathobiology of joints enables the clinician better to diagnose joint disease and to provide appropriate treatment and prevention recommendations.



Structure and Function of Normal Joints



Synovium and Synovial Fluid


The synovium is a vascular connective tissue lining the inner surface of the joint and consists of the cells of the synovial intima and a subsynovial stroma; the latter is composed of various amounts of fibrous, areolar, and fatty tissues. The synovium covers all articular surfaces, excluding articular cartilage and localized areas of bone. However, synovium is not uniform throughout the joint, and dense connective tissue may be found in its place in areas predisposed to trauma. Because the synovial lining bears neither true epithelium nor conventional basement membrane separating the joint cavity from the synovial vasculature, no true synovial membrane exists. Rather the intima and subsynovial tissues comprise a structural and functional continuum that acts as a macromolecular sieve.


The synovial intima is lined by a diverse population of synoviocytes, which have been classified according to their ultrastructure and with the use of specific antisera.6-8 The three cell types are type A cells, of macrophage origin; fibroblast-derived type B cells; and type C cells, which appear to be an intermediate between A and B forms.7,9-11 The most abundant are the type B cells, which synthesize a variety of important macromolecules, including collagen and hyaluronan.12,13 The viscosity of synovial fluid is largely the result of the concentration and degree of polymerization of hyaluronan, which serves a vital function in soft tissue lubrication. Type A cells, comprising only 10% to 20% of the lining cells, are predominately phagocytic. However, apparently some overlap in function between the two principal cell types exists.14,15 Importantly, synoviocytes synthesize a variety of soluble mediators implicated in the pathogenetic events of OA, including cytokines (e.g., interleukin-1 [IL-1]),16-18 eicosanoids (e.g., prostaglandin E2),19,20 and proteinases.21 That the synovial lining is capable of expressing these substances supports a role for the synovium in the pathogenesis of OA.


Deep to the synovial lining, the subsynovial region possesses a rich blood supply that is essential to generating synovial fluid, facilitates the exchange of nutrients and metabolic wastes of the synovium, and provides the sole source of nutrition to adult articular cartilage. Because of the specialized structure and functions of the synovial lining and subsynovial stroma, synovial blood flow is subject to a complex regulatory system involving extrinsic control and locally produced factors such as angiotensin II, endothelin-1, and nitric oxide.2



Periarticular Soft Tissues


The periarticular soft tissues include muscles, tendons, ligaments, and joint capsule. Muscles effect movement and, via complex reflexes, are vital to providing joint stability and protecting the joint from supraphysiological excursion. Muscle mass is more abundant near joints with a wide range of movement, such as the shoulder and the hip, and less so around joints that move in a single plane. Tendons serve as a bridge between muscle and bone, and ligaments provide stability between bones composing a joint. Tendons and ligaments are of similar, although not identical, composition, consisting mainly of water, an organized array of collagen bundles (predominantly type I), and a sparse population of fibroblasts. Ligaments contain more elastin fibers and have greater elasticity than tendons.22 Importantly, the molecular composition of these tissues responds to physical stimuli, and immobilization elicits catabolic events leading to tissue weakening.23 The composition of capsular structures parallels that of ligaments. Indeed, some ligaments can be recognized only as hypertrophied portions of the joint capsule. The fundamental role of the capsule is to provide stability; however, its specific nature varies with anatomical location and joint position. For example, the caudal capsule of the human knee is lax in flexion but exerts an important stabilizing force when the joint is in extension.24



Subchondral Bone


Although subchondral bone is histologically and biochemically similar to bone in other locations, the organization of the subchondral plate is specific. The plate is thinner than cortical bone found at other locations, and its Haversian systems are oriented parallel to the joint surface rather than parallel to the long axis of the bone.25 Similarly the organization of subchondral cancellous bone varies between joints, reflecting predominant biomechanical forces and adaptation to exercise.26,27 The deformability of the subchondral cortical and epiphyseal trabecular bone exceeds that of the diaphyseal cortical shaft by many times and has the important function of force attenuation. As such, possibly the bone stiffening (sclerosis) observed in OA contributes to disease progression.28,29



Articular Cartilage


Cartilage is the principal working tissue of the joint and allows simultaneous motion and weight-bearing with negligible friction. Cartilage covers the subchondral plate of bones composing the joint, to which the cartilage is firmly attached. Its thickness varies between joints and at different locations within them. Cartilage is composed of water, collagen, and proteoglycans that are present in respective proportions of 65% to 80%, 10% to 30%, and 5% to 10% of its wet weight. Chondrocytes account for less than 2% of its volume in most species. In adults, cartilage is avascular, alymphatic, and aneural; thus cartilage is nourished mainly via the synovial fluid (see the following discussion). Because articular cartilage is aneural, lesions restricted to cartilage are nonpainful, and the innervation of the underlying bone and adjacent periarticular soft tissues is responsible for providing information on joint position.


Cartilage possesses a number of zones or layers including the following:


• The superficial (tangential or gliding) zone, in which the cells are elongated and oriented parallel to the joint surface

• A middle (transitional) zone, in which the cells are rounded and appear randomly distributed

• A deep (radial) zone, containing cells arranged in columns oriented perpendicular to the surface

• A calcified zone, in which cells are heavily encrusted with hydroxyapatite crystals (Figure 61-1)

image

Fig. 61-1 Photomicrograph illustrating regional organization of mammalian cartilage. The four main zones from the articular surface to the subchondral plate include the superficial (tangential) (S), the middle (transitional) (M), the deep (radial) (D), and the calcified (C) zones. The deep and calcified zones are separated by the tidemark (TM). Pericellular matrix regions, distinguishable by their histological and ultrastructural differences and located at progressively greater distances from chondrocyte lacunae, are the pericellular, territorial, and interterritorial regions (×50). SCB, Subchondral bone.


The latter two zones are separated by an irregular line, visible on standard histological preparations, called the tidemark, the specific function of which is unclear.30 The density of chondrocytes in the matrix varies with depth from the articular surface, as does the macromolecular composition of the matrix surrounding the chondrocytes. These regional differences can be identified histologically and have been designated as the pericellular, territorial, and interterritorial regions.


The unique functional properties of articular cartilage are reflected in its biochemistry. Articular cartilage is composed of an abundant, specialized extracellular matrix maintained by the aforementioned sparse population of chondrocytes (Figure 61-2). Its water content varies with age but may be as high as 80%.31 This water is freely exchangeable with that in the synovial fluid and is maintained in the matrix in the form of a gel, with matrix collagens and proteoglycans. Water movement is believed to be pivotal to the capacity of cartilage to absorb and distribute compressive load and for its lubrication.


image

Fig. 61-2 Organization of the major extracellular matrix components in articular cartilage. The principal collagen of cartilage is type II, and a network of these fibrils provides much of the tensile strength of the tissue. Aggrecan is composed of a linear protein with three globular domains (G1 to G3) to which are attached numerous glycosaminoglycan chains of chondroitin sulfate (CS) and keratan sulfate (KS) (see also Figure 61-4). Supramolecular aggregates are formed by the noncovalent interaction of aggrecan with hyaluronan (HA) and stabilized by link protein (Link). The negatively charged glycosaminoglycans (CS and KS) attract several times their weight in water, and this proteoglycan-water composite is responsible for the compressive stiffness of cartilage. Cartilage also has a number of minor proteoglycans and collagens (e.g., decorin and dermatan sulfate [DS], the functions of which are not fully characterized). Fragments of aggrecan, remaining bound to hyaluronan, are depicted to illustrate the effects of proteolytic activity in cartilage.


(From Koopman WJ, editor: Arthritis and allied conditions: a textbook of rheumatology, ed 13, vol 1, Baltimore, 1997, Williams & Wilkins.)



Collagens


The collagens of articular cartilage differ from those found in most other locations in the body. Several collagens, fibrillar and nonfibrillar, are present in this tissue and are thought to provide cartilage with structural support. These proteins also interact with other matrix components to contribute to cartilage architecture and function.32-34 Collagen fibrils are oriented parallel to the joint surface in the superficial zone and act as a protective layer, whereas larger, radially oriented fibrils in the deeper layers anchor the cartilage to the underlying articular end plate.


Type II collagen is the most abundant in cartilage, accounting for about 90% of the fibrillar network and half of the dry weight of cartilage.2,35 Type II collagen consists of three identical amino acid chains arranged in a triple helix, is less soluble, possesses a higher proportion of hydroxylysine residues, and is more richly glycosylated than type I collagen.36,37 Unlike type I, which typically forms fibers, type II collagen is organized in the form of fibrils that are composed of molecules aligned with a 25% overlap or quarter stagger (Figure 61-3). This structure is stabilized by chemical bonds between specific amino acids in each chain, called hydroxypyridinium cross-links.38 Fibrils are not uniform in size throughout the matrix; they tend to be larger in the middle and deep zones of the matrix, which reflects regional biomechanical demands.39 This protein is arranged in arcades, which form the three-dimensional network or skeleton of the cartilage matrix. Type II collagen is produced by the chondrocytes, and whereas significant degradation and resynthesis of fibrils occur during growth and development, limited turnover occurs in adults.40,41


image

Fig. 61-3 Schematic representation of collagen fibril organization and its proteolytic degradation in cartilage. Cartilage collagen is arranged in fibrils of cross-linked, triple-helical molecules overlapping at regular intervals. Collagenases cleave intact helical collagen and produce characteristic “image” fragments. Other proteases (e.g., stromelysin) degrade collagen in nonhelical regions.


(From Koopman WJ, editor: Arthritis and allied conditions: a textbook of rheumatology, ed 13, vol 1, Baltimore, 1997, Williams & Wilkins.)


Minor collagens are present in modest amounts in cartilage, and the specific roles of these collagens in its structure and function have yet to be defined fully. Type XI is a fibrillar collagen that is found within type II fibrils. Its function is unclear, but likely it plays a role in type II collagen fibril assembly and organization because a mutation in the type XI gene in mice leads to a disorganized matrix, with abnormally thick collagen fibrils.42 Type VI is a microfibrillar collagen that may act as a bridge between fibrillar collagen and other matrix components.43,44 So-called fibril-associated small collagens include collagens IX, XI, and XIV. Type IX collagen molecules bound covalently to the surface of type II fibrils may serve to stabilize the latter.45 Types XII and XIV collagen also are associated with fibrillar collagen, but the specific functions have yet to be identified.



Proteoglycans


By definition, proteoglycans are composite molecules consisting of protein and glycosaminoglycan (polysaccharide) components. This definition is broad because some of the aforementioned minor collagens (e.g., type IX) have a single glycosaminoglycan side chain and thus can be designated as proteoglycans. A number of proteoglycans are found in articular cartilage. Aggrecan, the largest and most abundant, has a well-defined function in the extracellular matrix; however, the specific roles of the smaller proteoglycans remain to be characterized fully.


Aggrecan is the primary proteoglycan of articular cartilage that interacts with hyaluronan to form aggregates (see Figures 61-2 and 61-3; Figure 61-4). The individual or monomeric form of this molecule consists of a linear core protein interrupted by three globular domains. The first of these globular domains is designated G1, exists at the amino-terminal portion of the molecule, and is the site at which the proteoglycan attaches to hyaluronan. As many as 100 aggrecan monomers may be attached to the same hyaluronan chain to form supramolecular aggregates of micrometer dimensions (see Figure 61-2).46 The interaction of aggrecan with hyaluronan is noncovalent but is stabilized by a link protein that binds to the G1 domain and hyaluronan with equal affinity.47 Equine link protein was characterized and is similar to that found in human cartilage.48 The specific functions of the G2 and G3 domains are unclear; however, because the G3 domain is present in only about one third of the aggrecan monomers in adult cartilage, it is unlikely that it plays a pivotal role in the extracellular matrix.49


image

Fig. 61-4 Schematic representation of an aggrecan monomer. Proteolytic cleavage of the molecule in vivo usually first occurs in the G1 to G2 interglobular domain (IGD). The specific sites involved vary among the enzymes implicated in the process. Keratan sulfate (KS) and chondroitin sulfate (CS) regions are positioned on the periphery of the molecule.


(From Koopman WJ, editor: Arthritis and allied conditions: a textbook of rheumatology, ed 13, vol 1, Baltimore, 1997, Williams & Wilkins.)


In the region between the second and third globular domains, glycosaminoglycan chains of variable length and composition are attached radially to the protein core (see Figure 61-4). Immediately adjacent to the G2 domain is a region rich in keratan sulfate, and this portion of the proteoglycan, detectable by monoclonal antibodies, has served as a tissue marker of matrix turnover.50 Farther peripherally on the core protein is the chondroitin sulfate–rich region, where up to 100 chondroitin sulfate chains may be found attached radially to the core protein. These chondroitin sulfate chains vary in length, which is the main reason for heterogeneity in the size of aggrecan. Importantly, these glycosaminoglycan chains contain numerous carboxyl and sulfate groups, so that aggrecan is highly negatively charged and can bind up to 50 times its weight in water.46,51,52 This highly hydrated matrix gives cartilage its compressive stiffness and ability to dissipate load.



Matrix Proteins


Cartilage, like other connective tissues, contains a number of noncollagenous proteins, many of which are proteoglycans. Among the best characterized of the small proteoglycans are decorin, biglycan, lumican, and fibromodulin, all of which are similar in molecular organization. These proteins have been shown to interact with a number of matrix constituents, including cartilage collagens, and in many cases these interactions involve a number of different collagens and appear to regulate a variety of metabolic processes.46,52 For example, decorin and fibromodulin inhibit fibrillogenesis of type II collagen, a process that may regulate the size of collagen fibrils in the matrix.53 Some of these small matrix proteins also may contribute to the antiadhesive properties of articular cartilage.54,55


Cartilage also contains a number of small proteins that are neither collagens nor proteoglycans,56,57 and most are involved in interactions with a variety of matrix molecules and chondrocytes. For example, anchorin is found on the surface of chondrocytes and within the cell membrane and has a high affinity for type II collagen fibrils. These properties suggest that anchorin may act as a mechanoreceptor, providing chondrocytes with information on changes in stresses experienced by the matrix. Fibronectin is a minor component of cartilage that is thought to contribute to matrix assembly, via interactions with chondrocytes and elements of the extracellular matrix. Fibronectin fragments are present in elevated quantities in OA and may contribute to catabolic events in affected cartilage.58,59 Cartilage oligomeric matrix protein (COMP), also known as thrombospondin-5, is abundant in articular cartilage and is formed by the association of five identical subunits. COMP is most abundant in the proliferative cell layer of growth cartilage, where it is thought to regulate cell growth.



Chondrocytes


Studies of cartilage metabolism contradict the seemingly inert histological appearance of this relatively acellular tissue. Despite the fact that chondrocytes represent a small percentage of the volume of cartilage, they are responsible for extracellular matrix synthesis, including all the collagens and proteoglycans. They are also capable of elaborating a variety of proteolytic enzymes effecting degradation of matrix macromolecules. The rate of turnover of the various matrix components is not uniform. At least a portion of the proteoglycan pool is renewed at a relatively rapid rate, whereas the rate of collagen turnover is minimal.60-62 Chondrocyte metabolism is influenced by intrinsic and extrinsic mechanical influences. For example, cyclic loading and alterations in matrix pressure, as a result of changes in solute content, materially influence proteoglycan synthetic rates.63,64 Thus the maintenance of the cartilage matrix involves the chondrocyte-mediated processes of synthesis and degradation, and the cartilage loss in OA appears to be attributable to a disequilibrium in favor of matrix degradation.



Nutrition


Unlike the cartilage of growing animals, in which articular cartilage receives some blood supply from subchondral vasculature, adult articular cartilage contains no blood vessels. As a result, the chondrocyte exists under relatively hypoxic and acidic conditions, with an extracellular pH typically 7.1 to 7.2.65 Nutrients migrate from subsynovial vessels to the synovial fluid and subsequently penetrate the dense connective tissue matrix of the cartilage, while metabolic wastes are simultaneously cleared in the opposite direction. The density of the matrix appears not to hamper diffusion because molecules as large as hemoglobin (65 kDa) can penetrate normal articular cartilage.66 The highly charged proteoglycans contained in the matrix do not inhibit the diffusion of small, uncharged molecules.67 Entry of solutes into the matrix occurs by simple diffusion or may be facilitated by compression-relaxation cycles. Intermittent loading of cartilage is vital to its health, as is evidenced by the deleterious effects of immobilization.68



Joint Lubrication


Although several mechanisms for cartilage-on-cartilage lubrication have been hypothesized, two main systems are accepted: a hydrostatic or weeping system that functions at high loads, and a boundary system that functions at low loads.69 Hydrostatic lubrication of opposing cartilaginous surfaces is effected by a thin film of water liberated from the matrix during cartilage compression. Because little movement of water can occur from cartilage to the subchondral bone, most is squeezed from the opposing cartilages onto the surface, immediately peripheral to the zone of impending contact.70 With the release of compressive force, the cartilage expands, and water is drawn back into the matrix.


Whereas hydrostatic mechanisms function well under relatively heavy loads, boundary lubrication occurs under low-load conditions. Boundary lubrication is accomplished by specialized materials including lubricin71 (a glycoprotein of synovial origin) and hyaluronan. These molecules bind to opposing articular cartilage surfaces and prevent the direct contact of these surfaces under low loads. Coefficients of friction were unchanged after hyaluronidase treatment of synovial fluid, suggesting that hyaluronan has no place in cartilage-on-cartilage lubrication.72,73 However, others have found that hyaluronan actually does function as a boundary lubricant.74,75


Articular soft tissues require lubrication because they contribute most of the frictional resistance to joint movement. Indeed, the energy requirement for the stretching of articular soft tissues is 100 times that of the frictional resistance of opposing cartilage surfaces.76 The synovium is lubricated by a thin film of synovial fluid, rich in hyaluronan, its principal boundary lubricant.77



Intraarticular Volume and Pressure


Intraarticular volume varies and is influenced by joint position (see Chapter 66). Specifically, volume and pressure are respectively minimal and maximal near the extremes of flexion and extension.78-81 This effect is exacerbated in horses with synovial effusion, providing a physiological rationale for diagnostic flexion tests in equine lameness examinations. Moreover, the pointing of an equine limb in which there is joint effusion likely parallels the observation that in the human knee there is a maximum of intraarticular volume (and minimum of intraarticular pressure and pain) at 30 degrees of flexion.82,83


Whereas intraarticular pressure varies during movement, pressure within a normal joint is subatmospheric at rest.84,85 As a result, the normal synovial cavity is merely a potential space, the surfaces of which are coated with a thin film of synovial fluid to reduce friction during movement. Although the mechanisms by which this negative pressure occurs remain unclear, the phenomenon contributes measurably to joint stability.86

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Jun 4, 2016 | Posted by in EQUINE MEDICINE | Comments Off on Osteoarthritis

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