2 - Etiopathogenesis of Osteoarthritis
Authors: Moskowitz, Roland W.; Altman, Roy D.; Hochberg, Marc C.; Buckwalter, Joseph A.; GoldberG, Victor M.
Title: Osteoarthritis: Diagnosis and Medical/Surgical Management, 4th Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > I - Basic Considerations > 2 - Etiopathogenesis of Osteoarthritis
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2
Etiopathogenesis of Osteoarthritis
A. Robin Poole
Farshid Guilak
Steven B. Abramson
Osteoarthritis (OA) is a condition that represents a pathological imbalance of degradative and reparative processes involving the whole joint and its component parts, with secondary inflammatory changes, particularly in the synovium, but also in the articular cartilage itself (Fig. 2-1). Idiopathic primary OA may involve one particular joint, or it may be generalized or involve multiple joints in erosive inflammatory forms1,2 (Table 2-1). The presentation of this pathological condition in joints may be a consequence of the biomechanics within the joint which reveal otherwise masked systemic genetically determined changes. The mechanical pressures within the joint may therefore reveal weaknesses in tissue maintenance that are more widespread than previously considered.
Most forms of OA fall into two categories, depending on the predominant background: those that are primary, and often idiopathic, with abnormalities of joint biomaterial and biomechanically faulty joint structure that may result from a recognizable mutation, and those that are secondary and result from superimposed risk factors affecting distribution and severity of loading forces acting on specific joints, such as joint injury.
Risk Factors for Osteoarthritis
Risk Factors Associated with Abnormalities in Joint Biomaterial and Biomechanical Properties, Chemical Injury, or Endocrine Disorders
Familial OA (Table 2-1) may result from abnormal cartilage structure and properties such as a consequence of a mutation in the type II collagen COL2A1 gene (localized on chromosome 12), which causes not only cartilage dysplasia but also a severe form of OA with defective collagen.3,4 Onset is usually soon after cessation of growth. (See Chapter 6 for other gene defects relevant to OA associated with dysplasias and joint laxity.) Chronic abnormalities of growth plate development and bone growth leading to altered congruity of articulating surfaces can also cause OA. OA can develop in patients after traumatic injury or damage to chondrocytes associated with abnormal deposits in the cartilage matrix found in metabolic diseases such as hemochromatosis, ochronosis or alkaptonuria, Wilson disease, and Gaucher disease. OA can also result from disturbances in cartilage metabolism caused by endocrine disorders, such as acromegaly5 (see Chapter 13).
Risk Factors Related to Abnormalities in the Quality and Distribution of Loading Forces on a Joint
Cartilage damage due to trauma, impact injuries, abnormal joint loading, and excessive wear, or as part of an aging process, can lead to changes in the composition, structure, and material properties of the tissue (Fig. 2-2). These alterations can compromise the ability of cartilage to function and survive in the strenuous mechanical environment normally found in load-bearing joints. Joint injury and subsequent joint instability, from loss of ligamental or meniscal support, are significant risk factors for OA.6 Injury and abnormal loading, due to overexercise or abnormal joint use, are a risk for OA.7,8 In regard to underloading, disuse immobilization from chronic inanition, neurologic disorders, or postoperative casting can lead to cartilage disuse atrophy, with increased vulnerability to cartilage injury, unless exercise programs for rehabilitation are carefully controlled. Evidence for this is available from studies of casted animals and those subsequently subjected to controlled or excessive treadmill exercise. Immobilized joint cartilage exhibits arrest of cartilage proteoglycan aggrecan
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synthesis,8,9 altered biomechanical properties,10,11,12 and associated elevated metalloproteinases that may contribute to cartilage damage13(reviewed in Helminen et al.14). Deep ulcerative lesions with elevated protease activity can result from treadmill overexercise after disuse immobilization.15 Standard levels of exercise may cause site-specific changes in proteoglycan content and cartilage stiffness, although these changes are not believed to be deleterious16 and may potentially have a beneficial effect in the normal joint.17,18,19 Altered joint loading due to instability or injury of the joint is now well known to be a significant risk factor for the onset and progression of OA.8,20,21 Alterations in joint loading, brought about through ligament transection22 or meniscectomy,23 may lead to profound and repeatable changes in joint tissues which mimic changes seen in early human OA, including increased hydration and proteoglycan turnover, and decreased tissue stiffness in tension, compression, and shear.11,24,25,26,27,28 Obesity is a well-defined risk factor involving excessive joint loading29 as well as systemic metabolic changes that include low-grade chronic inflammation.30 In this respect, obesity is regarded as the number one preventable risk factor for OA.19,31 Evolutionary adaptations to the upright posture by humans have redistributed preponderant loading forces to new sites, predisposing to an increased risk for development of OA in hips, knees, bunion joints, and the lumbar spine.32
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Figure 2-1 Gross pathologic changes observed in OA joints during many years of degenerative change. |
Age-related changes in the magnitude and pattern of stresses on joint cartilage may arise from a number of factors, including altered gait, muscle weakness, changes in proprioception, and changes in body weight. A neuromus-cular control deficit is likely to contribute to the loss of normal attenuation of body weight-bearing forces during walking. This is manifested in OA patients as the digging of the heels on forceplate analysis.7 The development of experimental canine OA can be accelerated by posterior nerve root section at the spinal cord, which affects the afferent signals governing stereognostic control of the affected arthritic limb;33 this provides important insights into the pathophysiologic process of the Charcot joint. The mechanism of impact loading, in which energy is normally predominantly absorbed or attenuated by strong muscle groups in the thigh and leg, is also significantly impaired in OA patients,34 who exhibit decreased muscle strength. Quadriceps weakness is associated with knee pain, especially in OA.35 Biomechanical changes in the joint capsule as a consequence of genetic or post-translational changes, such as those affecting collagen fibers, may also influence joint loading.
Examination of nutritional factors in the etiopathology of OA has provided evidence for an increased risk of development of OA of the knee with vitamin E and C deficiencies,36 no doubt influencing matrix assembly and function. In Asia, Kashin-Beck disease, a form of OA, may be caused by dietary exposure to an endemic fungus.37 Hypothyroidism afflicts many of these patients because of a dietary selenium deficiency.38
Articular Cartilage
Composition
Normal articular cartilage consists of an extensive, hydrated extracellular matrix that is synthesized and maintained by a sparse population of specialized cells, the chondrocytes (Fig. 2-3). In the adult human, these cells may occupy as little as 2% of the total volume. The matrix consists mainly of collagen (mostly type II with lesser amounts of other collagen types) and proteoglycans, principally aggrecan, which is large and aggregates with hyaluronic acid (HA).39 Types II, IX, and XI collagens of cartilage combine to form a fibrillar network that provides a structural framework of the matrix in the form of an inhomogeneous and anisotropic meshwork of fibers, which is surrounded by a highly concentrated solution of the proteoglycan aggrecan. A secondary microfibrillar
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network involving type VI collagen is concentrated in the pericellular matrix between the cell surface and the territorial matrix.
TABLE 2-1 CLASSIFICATION OF OSTEOARTHRITIS | ||||||||||||||||||||||||||||||||||||||
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Proteoglycans are complex macromolecules with a protein core to which are attached glycosaminoglycan chains, primarily of chondroitin sulfate and keratan sulfate. These glycosaminoglycans, which are negatively charged in solution, are responsible for the hydration and large swelling pressure of this tissue.40,41 Many other smaller proteoglycans and other molecules are present within the tissue, some of which may be directly associated with the collagen fibrils. For more details, please see Chapter 4.
Biomechanics of Articular Cartilage
Articular cartilage serves as a low-friction, wear-resistant surface for load support, load transfer, and motion between the bones of the diarthrodial joint. Under normal circumstances, this tissue, bathed in synovial fluid, is able to withstand millions of cycles of loading each year at stresses that may reach 18 MPa,42 while exhibiting little or no wear. These unique properties are endowed by the composition and structure of the major constituents of articular cartilage, and their associated spatial variations provide a complex and inhomogeneous set of material properties.
From a biomechanical standpoint, articular cartilage can be viewed as a fiber-reinforced, porous, and permeable composite material that is saturated with an interstitial fluid, water.43 These characteristics provide for mechanical properties that are viscoelastic (time- or rate-dependent), anisotropic (dependent on direction), and nonlinear (dependent on magnitude of strain). Accordingly, the biomechanical properties of cartilage have been widely studied using models that take into account the multiple phases (collagen solid matrix, interstitial fluid, and mobile and fixed ionic groups) and the interactions among these phases.43,44,45
The largest constituent, water, provides load support through fluid pressurization and energy dissipation by fluid flow in response to applied loading.43 The second largest constituent, the collagen fibril, provides articular cartilage with its nonlinear properties in tension,46,47 which are inhomogeneously distributed with depth from the tissue surface. However, these tensile properties decrease progressively with increasing age after 30 years in articular cartilages, such as of the hip, that most commonly develop OA.48 Age-related changes in cartilage tensile properties are believed to arise in part from the accumulation of advanced glycation end products (AGE) which increase the brittleness of the cartilage, increasing the potential for tissue fracture and aging-associated biomechanical dysfunction.49
The high concentration of negative charges associated with the proteoglycans in cartilage has a significant effect on the mechanical behavior of the tissue. The negatively charged nature of cartilage arises primarily from the glycosaminoglycans, namely, the many chondroitin sulfate and keratan sulfate chains that are present on aggrecan molecules.50 The large size of aggrecan and its interactions with HA to form macromolecular aggregates serve to retain aggrecan molecules in the extracellular matrix so that their negative charges are fixed. These fixed charges are responsible for the physicochemical and electrokinetic properties of this tissue, such as a large osmotic pressure and associated propensity to swell and exhibit streaming potentials, streaming currents, and electro-osmotic effects.41,45 As a result, the mechanical behavior of articular cartilage exhibits an interdependence on physicochemical factors, such as the structural organization and properties
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of the collagen fibrillar network, the proteoglycan aggrecan concentration, and the type or distribution of counterions.44 These physicochemical properties significantly contribute to the function of articular cartilage.45 The swelling pressure is believed to largely contribute to residual stresses in the cartilage matrix that enhance the support and distribution of applied loads.51,52 The loss of tensile properties and swelling pressure as collagen and proteoglycans are degraded and lost in OA results in mechanical decompensation and an ensuing increase in the magnitude of tissue strains under similar magnitudes of physiologic loading,10,28,53 particularly at the cellular level.54
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Figure 2-2 Potential mechanisms involved in the etiopathogenesis of OA. |
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Figure 2-3 Changes observed in articular cartilage in OA involving chondrocytes and extracellular matrix. |
Articular cartilage endows the synovial joint with frictional properties that remain unmatched by man-made joints. The coefficient of friction (ratio of frictional force to compressive force) of cartilage gliding on cartilage has been reported to be as low as 0.002.55 The mechanisms by which the synovial joint achieves these properties involve a combination of biomechanical and biomolecular factors.56
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For example, joint congruity and cartilage deformation serve to distribute loads over a larger contact area, thereby minimizing contact stresses. The high water content and low hydraulic permeability of the cartilage extracellular matrix provide a unique mechanism of supporting loads whereby fluid pressurization within the tissue can bear nearly 90% of the load and thus minimize stresses on the solid extracellular matrix.57,58 Synovial fluid plays multiple roles in joint lubrication by providing a high viscosity squeeze film layer that delays cartilage-to-cartilage contact under compression59 but also serves as a source of boundary lubricant molecules within the joint.
Boundary lubricants are molecules that may be adsorbed or bound to the cartilage surface and decrease friction in cases when the tissue surfaces actually contact one another. In the past two decades, there have been significant advances in our understanding of the composition, structure, and properties of biomolecular components of the synovial fluid that serve as the primary boundary lubricants for the joint. Lubricin, a ~ 227 kDa glycoprotein, was first identified from bovine synovial fluid by density gradient sedimentation and gel-permeation chromatography.60 This molecule was first identified as a product of synovial fibroblasts expressing the gene for megakaryocyte stimulating factor (MSF, also termed PRG4). Subsequent investigations have identified a 345 kDa protein, termed superficial zone protein (SZP), as an additional product of the MSF gene.61,62 The importance of these molecules in the health of the joint have been demonstrated by the rare autosomal recessive disorder, camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome, which has been attributed to mutations in the PRG4 gene.63 The loss of SZP function in CACP is associated with a severe juvenile-onset joint failure that is noninflammatory in nature.
Biomechanical Regulation of Cartilage Metabolism
A number of in vivo studies have emphasized the relationship between mechanical loading and the health of the joint, and suggest that a critical level and pattern of mechanical stress is required to maintain the normal balance of cartilage synthesis and breakdown. Under normal physiological conditions, the components of the extracellular matrix are in a state of slow turnover, retained in a homeostatic balance between the catabolic and anabolic events of the chondrocytes. These activities are controlled through the processing of both genetic and environmental information, which includes the action of soluble mediators (e.g., growth factors and cytokines), extracellular matrix composition, and physical factors such as mechanical stress. Indeed, many studies have shown that the mechanical stress environment of the joint is an important factor that influences (and presumably regulates) the activity of the chondrocytes in vivo.14,64
Considerable research effort has been directed toward understanding the processes by which physical signals are converted to a biochemical signal by the chondrocyte population. Clarification of the specific signaling mechanisms in normal and inflamed cartilage would not only provide a better understanding of the processes which regulate the physiology of cartilage, but would also be expected to yield new insights on the pathogenesis of OA. In this respect, in vitro explant models of mechanical loading provide a model system in which the biomechanical and biochemical environments can be better controlled as compared to the in vivo situation. Explant models of cartilage loading have been utilized in a number of different loading configurations, including unconfined compression, indentation, tension, shear, and osmotic and hydrostatic pressure (reviewed in Guilak et al.64). The general consensus of these studies is that static compression suppresses matrix biosynthesis, and cyclic and intermittent loading stimulate chondrocyte metabolism (e.g., Gray et al.,65 Sah et al.,66 Guilak et al.,67 Torzilli et al.68). These responses have been reported over a wide range of loading magnitudes, and exhibit a stress-dose dependency. Excessive loading (e.g., high magnitude, long duration) seems to have a deleterious effect, resulting in cell death, tissue disruption, and swelling.69,70,71
The cellular transduction mechanisms responsible for converting mechanical stress into a biochemical response are the subject of much study but are not fully understood. Currently, there is significant evidence that chondrocytes may transduce mechanical signals into biochemical responses through various intracellular and intercellular signaling pathways, including activation of the traditional second messenger pathways such as cyclic AMP (cAMP), inositol trisphosphate, or calcium ion (see Guilak et al.64 and Stockwell72 for reviews).
The Degeneration of Articular Cartilage in Osteoarthritis
The classic loss of articular cartilage observed in OA may be initiated as a focal process that first appears to manifest at the articular cartilage surface. These lesions, which are commonly observed in aging human populations, have all the biochemical features of OA cartilages at arthroplasty.73 They may progressively enlarge to involve specific compartments, inducing alterations in other articulating surfaces by producing changes in loading. Some of the clues as to whether these focal lesions enlarge may have been revealed by recent studies on these lesions in the ankle versus the knee joint. In knee lesions, the emphasis in the cartilage is on matrix degradation, whereas in the ankle it is on matrix synthesis.39 Moreover, in the ankle the response involving increased matrix turnover is more generalized, whereas in the knee it is associated with the lesion.39,73 These fundamental differences in the response and in the lesions could help explain why knee OA is much more common. More widespread changes in loading after traumatic injury may involve the whole joint cartilage, in which alterations in cartilage matrix turnover are detectable within days, weeks, or months after damage to the anterior cruciate ligament or meniscus.74,75 In particular, joint injuries that involve fracture of the articular surface tend to accelerate more rapidly to a degenerative state of post-traumatic arthritis.76
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Cartilage degeneration is first observed at the articular surface in the form of fibrillation (Fig. 2-3). Splits are initially parallel to the articular surface; later, they vertically penetrate the damaged cartilage, eventually reaching subchondral bone. Cell cloning is observed early around the splits but is confined to more superficial sites. Many of these cells have become hypertrophic. Progressive loss of cartilage thickness, starting at the surface, is observed.
In large joints, idiopathic OA is ordinarily believed to be a slow process that may take as long as 20 to 30 years, but it is accelerated in cases of joint injury75,77,78,79 or may present clinically on cessation of growth as in familial OA.80 Degeneration is often more pronounced in the tibial cartilage, particularly in the medial compartment. This characteristic is observed in both human and in experimental OA.
Other examples of long-term development of OA come from experimental studies of anterior cruciate ligament transection in dogs, in which bone, ligament, and synovial changes are also observed early28,81,82 (see Chapter 5), presenting as an advanced lesion after a period of only 3 or more years. The earliest changes in the unstable knee that can be seen in articular cartilage in injured joints in animals and humans feature cartilage swelling (also called a hypertrophic reaction), with enhanced synthesis of matrix with an increased content of aggrecan.24 This is followed by a phase of increased matrix turnover, with net depletion of principal matrix components. Finally, severe damage to and loss of the collagen network is observed.11,28,75,83,84 The hypertrophic stage, not to be confused with chondrocyte hypertrophy, clearly precedes the occurrence of the lesional stage with its characteristic deep focal loss of cartilage. In the dog, the biomechanical properties correlate well with a reduction in proteoglycan aggregation and the loss of hyaluronan and link protein.84,85 The presence of smaller proteoglycan aggregates in uncovered or unprotected areas of tibial plateau cartilage in normal control subjects, coupled with the presence of elevated protease activity after surgery, may result in part from a shift of load-bearing sites during the development of OA in this model.86,87
Proteinases of Osteoarthritis Cartilage
Metalloproteinases (MMPs) are generally considered to play a principal role in the cleavage of matrix macromolecules, including type II collagen and the cartilage proteoglycan aggrecan. Collagenases cleave type II collagen, which contains a long triple-helical domain, at a specific site approximately three quarters from the amino terminus. This results in unwinding (denaturation) of the -chains, which are then susceptible to secondary cleavage by collagenases and other MMPs such as stromelysin 1(MMP-3) and the gelatinases MMP-2 and MMP-9. Aggrecan is cleaved by different MMPs and by the aggrecanases (adamolysins) ADAMTS-4 and -5.
Four collagenases may be active in articular cartilage, namely, MMP-1, -8, -13, and -14 (Table 2-2). MMP-13 is the most efficient at cleaving type II collagen.88 It may be involved in type II collagen cleavage in articular cartilage more than any other collagenase.89,90 Overexpression of constitutively active MMP-13 in cartilage induces the early onset of OA in mice.91 MMP-2 and -9 have also been reported to have collagenase activity. Most MMPs are secreted as latent proenzymes and are then activated. MMP-1 and -13, for example, can bind to collagen fibrils where they can be activated. MMP-3 and MMP-14 are involved in activating other MMPs. Like other MMPs, these activators may themselves be activated by plasmin generated from plasminogen by urokinase-type activator produced by chondrocytes or by cysteine proteinases such as cathepsin B,92 or by MT1-MMP (MMP-14), which possesses a furin cleavage site, which means that it is usually activated within the cell before secretion. Cathepsin K, a cysteine proteinase, can also cleave triple-helical collagen but in primary sites different from the primary cleavage produced by collagenases.93 It is expressed by superficial chondrocytes in increased amounts in OA cartilage.94 There is unpublished evidence thatthis proteinase is involved in collagen cleavage in OA articular cartilage in culture (V. Dejica, J.S. Mort, and A.R. Poole, unpublished data).
In OA, there is increased expression and content of various MMPs, including MMP-1, MMP-3, MMP-13, and MMP-28 (epilysin), but not ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs) or ADAMTS-5, the latter being downregulated.95 Others have observed that increased MMP-13 expression is the most dominant of the collagenases, being stronger in late stage disease when MMP-3 is downregulated; of the aggrecanases, only ADAMTS-5 was clearly expressed.96 This increased expression is first observed at or close to the articular surface very early in the degenerative process.97,98 Similarly there is increased expression of MMP-2, MMP-9, MMP-8,99,100 MMP-11,101 MMP-14,102,103 and matrilysin.104 Plasminogen activator105 and cathepsin B106,107 are also upregulated in human and experimental OA cartilage.
Cleavage and denaturation of type II collagen by collagenases are first observed around chondrocytes in these superficial sites where MMP-1 and -13 are present in increased amounts.97,108,109 This change is also seen with aging but more so in OA. It extends into the territorial and interterritorial matrix and then progressively extends into the mid and deep zones with lesion development.97 Collagenase activity, the denaturation of type II collagen, and the associated loss of type II collagen73,110 are much increased in OA cartilages.73,89,108 These changes in articular cartilage are seen within months of anterior cruciate ligament rupture, which is a major risk factor for OA development in a joint.75,111
In established OA of the knee, the synthesis of type II collagen is simultaneously increased markedly.39,112,113,114 However, these new molecules, as well as resident pre-existing collagen, are the subject of excessive proteolysis.90 The same applies to aggrecan.115
The core protein of aggrecan is cleaved by different proteinases.50 Cleavage sites are common in the interglobular domain between the G1 and G2 domains as well as in the chondroitin sulfate-rich region. In the interglobular domain, two principal cleavage sites have been identified: the aggrecanase site, where proteinases such as cell surface-associated
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aggrecanases or ADAMTS-4 and -5 can cleave;116 the MMP cleavage site is a target for multiple MMPs.92 There is evidence for enhanced degradation of aggrecan at both these cleavage sites in cartilage matrix in OA.117
TABLE 2-2 EARLY CHANGES IN THE STRUCTURE AND COMPOSITION OF ARTICULAR CARTILAGE IN HUMAN OSTEOARTHRITIS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Of the aggrecanases, ADAMTS-5 has been shown to be the major enzyme responsible for aggrecan loss in experimental murine OA118 and inflammatory joint disease.119 These proteinases are also activated outside the cell, probably at the cell surface.119,120
A variety of cleavage products of aggrecan accumulate in OA cartilages. Early in cartilage degeneration (Mankin score of 1 to 6), the excessive proteolysis leads to a reduction in molecular size of aggrecan fragments that have accumulated with aging as a result of degradation, probably during a period of many years.115 With increased degeneration, the sizes of aggrecan fragments increase.115 This may reflect altered proteolysis, but is more likely the partial degradation of more recently synthesized larger molecules. That new aggrecan synthesis and incorporation occur is reflected by the appearance of epitopes on chondroitin sulfate that are normally only commonly found in actively biosynthetic fetal cartilages.115,121,122,123 Some of these epitopes that increase in OA in synovial fluid, such as the 846 epitope,124,125 are thought to present on newly synthesized molecules that have been released by matrix degradation.126
The Causes and Regulation of Cartilage Matrix Degradation
The reasons for this increased proteolysis have been widely studied. Degradation products of matrix molecules may themselves stimulate degradation through chondrocyte and synovial cell receptor-mediated activation, forming a chronic cycle (Fig. 2-4). Different fragments of fibronectin can stimulate chondrocyte-mediated cartilage resorption by cell surface receptor activation127,128,129 just as in synovial fibroblasts, where RGD-integrin receptor activation is involved.130 Fibronectin is produced in increased amounts in OA cartilage.131 Its degradation may therefore play an important role in establishing positive feedback generation of proteolysis. Cellular responses in OA cartilage involve the production of cytokines such as interleukin (IL)-1, which are known to stimulate degradation50 and also play an essential autocrine and paracrine role132 in fibronectin fragment-mediated degradation (Fig. 2-4). Fragments of type II collagen can, when present in sufficient concentration, also induce matrix resorption.133,134
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Figure 2-4 Responses of chondrocytes to mechanical forces, cytokines, and matrix degradation products generated by MMPs. |
In OA, there is increased expression on chondrocytes of the receptors for IL-1135 and of IL-1 itself, even more than in rheumatoid arthritis,136 as well as the receptor for tumor necrosis factor a (TNF- )99,137 (Table 2-2). The
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presence of the TNF- p55 receptor (but not the p75) on OA chondrocytes correlates with the susceptibility of cartilage explants to TNF- -induced proteoglycan loss.137
IL-1 and TNF- are potent activators of cartilage degradation in vitro.50 In combination with oncostatin M, IL-1 is even more potent in causing cartilage resorption, but levels of oncostatin M, a member of the IL-6 family, are not usually elevated in synovial fluid in OA.138 Inhibition of IL-1 or TNF- by biologic antagonists can suppress cartilage matrix resorption in articular cartilage in culture. It can also stimulate an increase in aggrecan content,139 probably by inhibiting degradation of newly synthesized molecules.
Inducible nitric oxide synthase (iNOS, or NOS2) is upregulated in OA chondrocytes140 more so than in rheumatoid articular cartilage,136 leading to an increased generation of nitric oxide. IL-1 , IL-1b , and TNF- are potent stimulators of nitric oxide production in cartilage141 in a manner that can be arrested by osteopontin,142 which is also upregulated in OA cartilages.143 The expression by chondrocytes of iNOS, TNF-a, IL-1 , and IL-1 are correlated in arthritis136 (Fig. 2-4). Nitric oxide mediates the inhibition of aggrecan synthesis induced by IL-1.144 However, protease activity and proteoglycan degradation are enhanced when nitric oxide production is blocked,145,146 suggesting that nitric oxide may also play a protective role. Nitric oxide can also induce apoptosis in chondrocytes,147 but only in the presence of other reactive oxygen species. Inhibition of iNOS reduces the progression of experimental OA.148 Nonexpression of IL-1 or IL-1 converting enzyme or iNOS can also accelerate the development of surgically-induced murine OA. These observations together point to the importance of physiological amounts of these molecules to maintain a healthy joint,146 and suggest that complete suppression of activity could be detrimental from a therapeutic dosing standpoint.
Changes in matrix loading can also induce the production of a variety of pro-inflammatory mediators and promote matrix degradation as well as alter the synthesis of matrix molecules50,78 (Fig. 2-4). Mechanical compression causes a dose-dependent increase in the synthesis of nitric oxide and prostaglandin E2 through the activation of NOS2 and cyclooxygenase 2 (COX2), respectively, with significant interaction between the NOS2 and COX2 pathways.149,150 Injurious mechanical compression of cartilage explants at high loading rates and magnitudes results in significant upregulation of MMPs and aggrecanases151,152 that are also associated with increased loss of proteoglycans as well as other biomarkers of OA.153
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Figure 2-5 Changes observed in cartilage and bone in OA and factors that protect against, accelerate, or are associated with the OA process. |
The pathologic changes in cartilage matrix structure in OA are likely to cause fundamental disturbances in the normal balance resulting from controlled mechanical loading and cytokine and growth factor signaling, which leads to changing gene expression of matrix macromolecules, signaling molecules, and enzymes (Fig. 2-5). Activities of these MMPs are regulated not only at the levels of transcriptional activation, translation, and extracellular proenzyme activation, but also extracellularly at the level of inhibition by tissue inhibitors of metalloproteinases (TIMPs). Four such inhibitors have been described, namely, TIMP-1, -2, -3, and -4. These react with the active MMP in a 1:1 molar ratio. In OA, there is a deficiency of TIMP activity154,155 favoring excessive proteolysis (Table 2-2). TIMP-3, which is the only TIMP that can bind to extracellular matrix, is capable of inhibiting aggrecan degradation in hyaline cartilage.156
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Its expression is upregulated in OA cartilage whereas TIMP-1 and -4 are downregulated.95
TGF- 1 can downregulate MMP-1 and -13 as well as IL-1 and TNF receptors on OA chondrocytes.99 Yet, it can stimulate ADAMTS-4 expression and aggrecan degradation.157 TGF- 2 can rather selectively suppress the cleavage of type II collagen by collagenases in OA cartilage in culture and reduce the expression of MMPs and proinflammatory cytokines: this also involves suppression of hypertrophy associated genes.158 The Chitinase 3-like protein glycoprotein 39 (GP39), which is upregulated in OA cartilage, can suppress chondrocyte induction of proinflammatory cytokines, chemokines, and collagenases by IL-1 and TNF- 159
General Changes in Cartilage Matrix Protein Content and Gene Expression
The early damage to the more superficial matrix in early OA is accompanied by an increased content of biglycan and decorin160 and aggrecan (A.R. Poole and A. Reiner, unpublished data) in the mid and deep zones, no doubt to compensate for the increased loading on the chondrocytes and the damage to and loss of these molecules from the more superficial cartilage. This accompanies the marked increase in the synthesis of type II procollagen in these deeper sites,114 mainly type IIB as revealed by experimental studies113 but also some type IIA,161,162 which is normally observed only before chondroblast differentiation early in development.163 Overall there is a loss of type II collagen, starting in the more superficial cartilage.108 There is limited expression and synthesis of type III collagen.112 Type VI content is, however, increased164,165,166 and its filamentous structure is altered,167 presumably as a result of pericellular remodeling which frequently results in an enlargement of the pericellular matrix.168 These changes are also reflected as a loss of mechanical properties of the pericellular matrix,169,170 which results in significant alterations in the biomechanical environment of the chondrocytes.54
Aggrecan and link protein synthesis or expression are upregulated in response to the increased damage.50,115,121,171 There is a general increased expression and synthesis of the proteoglycans versican, fibromodulin, lumican, decorin, and biglycan.171,172 This is associated with an increase in insulin-like growth factor 1 (IGF-1)173 and its receptor.174 IGF-1 is a potent stimulant of aggrecan synthesis and may be responsible for this increase. This increased synthesis is often seen in the same sites where degradation is enhanced. Although bone morphogenetic proteins play key roles in promoting matrix synthesis, BMP-3 is markedly downregulated in OA.175
There are changes in the distributions and contentsof many other matrix molecules in OA.50 Cartilage oligomeric protein (COMP) is altered in distribution.176 Contents of cartilage matrix protein,177 tenascin,178 osteonectin,143 and fibronectin131 and other molecules are increased with the result that the cartilage reverts in part to a more fetal tissue. These changes are summarized in Table 2-2 and Figure 2-3.
The Chitinase 3-like protein GP 39 (YKL-39), but not YKL-40, is also markedly upregulated in OA cartilage. This protein can modulate IL-1 activity as well as suppress apoptosis and stimulate cell division. It therefore seems to offer protection against degeneration.159,179 The significance of a variety of early changes in gene expression in OA detected in articular cartilage and of genes that are expressed in cartilage which change in expression in peripheral blood cells in early OA remains to be determined.180
The Regulation of Cartilage Matrix Assembly in Osteoarthritis
Throughout the development of OA, synthetic processes are probably much influenced by the degradative cytokines IL-1 and TNF- , the major anabolic growth factors IGF-1, the transforming growth factor- (TGF- ) family,181 the bone morphogenetic proteins (particularly BMP-2 and -7), and the anti-inflammatory or modulatory cytokines of the synovium, cartilage, and other tissues, including platelet-derived growth factor, fibroblast growth factor-2, IL-4, IL-6, IL-10, and IL-13. These and other regulatory molecules contribute in many different ways to anabolism.50,181,182 Cytokines such as IL-1 can inhibit matrix synthesis whereas IGF-1 can suppress this inhibition.183 IGF-1 and mRNA levels are increased in OA articular tissue.184 IGF-1 can decrease the degradation and inhibition of synthesis induced by IL-1.185 IGF-1 release from chondrocytes is in fact stimulated by IL-1 and TNF- 186 In spite of the increase in IGF-1 in OA, OA chondrocytes are hyporesponsive to this growth factor. This may be because IGF-1 activity is excessively restricted by IGFBPs, which are also upregulated174,187 by cytokines such as IL-1. Proteases can also cleave these binding proteins, regulating their activity.186,188 Fibroblast growth factor-2 stimulates cell proliferation in articular chondrocytes but does not stimulate synthesis of glycosaminoglycans.189,190 Synergistic relationships have been demonstrated between growth factors and cytokines in articular cartilage, which help regulate important cellular processes. Chondrocyte proliferation can be amplified by combinations of IL-6 and TGF- or of fibroblast growth factor and IGF.186
Moreover, TGF- stimulates type II collagen and aggrecan gene expression and inhibits metalloproteinase mRNA expression in synovial fibroblasts and chondrocytes.181,182 It can suppress IL-1 expression and type collagen cleavage in cartilage,158 stimulate production of plasminogen activator inhibitor protein 1,191 and also TIMP synthesis,50 thereby regulating proteolysis and enhancing synthesis. However, injection of TGF- in the knee joint of mice results in increased osteoarthritic degeneration, possibly due to increased bone formation and remodeling.192,193 The balance between these pro-proliferative, anabolic, and catabolic molecules is very complex and clearly fundamentally perturbed in OA and by injury that leads to an altered mechanical environment of the chondrocytes, affecting the biosynthesis of these molecules. Studies of Guinea pig strains with different rates of natural OA development have revealed from serum measurements of cartilage molecular markers of type II collagen synthesis and degradation that the ratio of the markers favors degradation over synthesis in more rapid progressors194 (N. Gerwin, K. Rudolphi, A.R. Poole, et al., unpublished data).
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Changes in the Chondrocyte Phenotype in Relationship to Cell Death, Matrix Degradation, and Calcification in Osteoarthritis
In previously uncalcified articular cartilage in OA, there is induction of type X collagen expression and synthesis.195 Expression of this and other hypertrophy-related genes including MMP-13 is seen very early in micro-lesion development.98 Hypertrophy is normally only seen in the growth plate when the extracellular collagen network is partially resorbed by MMP-1350,97,196 and then calcified as cells die as a result of apoptosis. In OA, these events including apoptosis197,198 reappear in degenerate OA cartilage although some expression data argue against this.199 The increase in apoptosis corresponds to a reduced cell density and expression of caspase 3.200 These changes are in association with expression of the cell surface type II collagen receptor annexin V,201 also highly expressed by early hypertrophic chondrocytes. Parathyroid hormone-related peptide (PTHrP), which is also produced by prehypertrophic cells in the growth plate and suppresses hypertrophy, is also upregulated in OA cartilage.202,203 The calcium-sensing receptor, expressed by hypertrophic cells, is upregulated with the onset of OA in the guinea pig together with PTHrP.204
These changes are initially observed in OA cartilage mainly in the more superficial and mid zones where damage to collagen is most pronounced205 (Fig. 2-3), and may represent a chondrocyte response to a damaged extracellular matrix with the reversion to a more fetal phenotype. There is also a marked increase in expression of type II collagen112,113,114 and MMP-13,88,206,207 which are also a feature of the shift to hypertrophy in the growth plate.208 An inhibitor of MMP-13 can suppress hypertrophy,97 suggesting that MMP-13 is a key proteinase in this process and that excessive collagen cleavage is a trigger for further chondrocyte differentiation.
In the partially calcified OA cartilage delimited by the tidemark and bordered by the subchondral bone, there is a reactivation of endochondral ossification characterized by upregulation of type X collagen expression and duplication or replication of the tidemark, separating this zone from uncalcified cartilage. Vascular invasion from subchondral bone is reinitiated, resembling that seen in endochondral ossification. Moreover, osteophyte formation, an endochondral process, is initiated peripheral to the articular cartilages, leading to bone spurs capped with articular cartilage (Fig. 2-1). Thus, there is a major shift in the physiology of the articular cartilage characteristic of a superimposition of endochondral changes within and associated with articular cartilages. We know that TGF- signaling is essential to prevent hypertrophy since mice with a functionless type II receptor209 or a deletion in a Smad signaling component210 develop a rapid degeneration of articular cartilage associated with extensive chondrocyte hypertrophy and the formation of large osteophytes. PGE2, generated when TGF- 2 is added to OA cartilage, suppresses hypertrophy and collagenase activity.158 A transcription factor, early growth response protein-1 (Egr-1), which can stimulate TGF- expression and suppress apoptosis, is very down-regulated in OA, favoring a drop in TGF- content.211
Hypertrophy is accompanied by calcification of the normally uncalcified extracellular matrix of articular cartilage. More than 90% of OA subjects show evidence for limited calcification of articular cartilages;212 there is also a high incidence of hydroxyapatite crystals in joint fluids.213,214 In calcium pyrophosphate deposition (CPPD) disease, joints affected by mineral deposition, such as the shoulders, wrists, and metacarpophalangeal joints, are different from those affected in idiopathic OA215 (see Chapter 13).
Although CPPD and hydroxyapatite crystal aggregates can, under some conditions, be markedly phlogistic in both animal models and cell culture, there is equivocal evidence in cartilage that crystals can injure chondrocytes directly.216,217,218 As in growth cartilage matrix, matrix vesicles have been detected in OA articular cartilages, often with associated minerals as well as cellular generation of pyrophosphate.219 Apoptotic cell particles may also generate minerals in the presence of adenosine triphosphate.220 These changes in OA cartilage are summarized in Table 2-2 and Figure 2-3.
Physiologic concentrations of extracellular pyrophosphate (PPi) regulate calcification that results in basic calcium phosphate crystal deposition. Hydrolysis of excess PPi promotes crystal formation in OA via elevated inorganic phosphate generation.221 PPi is generated from nucleoside triphosphates by nucleotide pyrophosphatase phosphodiesterase PC-1. The extracellular concentration of PPi is regulated via the trans-membrane protein ANK. In OA cartilage, ANK is upregulated.222 This would this favor the elevation of extracellular PPi. Interestingly, increased ANK expression promotes MMP-13 expression,222 providing a link between calcification and increased MMP-13 expression, both of which are features of chondrocyte hypertrophy.50
The Remodelling of Subchondral Bone in Osteoarthritis
Pronounced changes in subchondral bone occur in OA, and may even occur in sites remote from the affected joints. Femoral neck bone is less stiff and less dense in hip OA, but not as reduced in density as in osteoporosis.223 Bone mineral density remote from degenerate joints in arms and spine is elevated.224,225 Bone loss is elevated in men with hip OA.225 Women with incident knee OA have a higher bone mineral density in the spine and hip than those without disease.226 In generalized OA, there is also hypermineralization;227 yet in hand OA in women, there is evidence that with increasing grade of OA, bone mass is decreased.228 Subchondral bone in hip OA is less mineralized and has more osteoid indicative of incomplete mineralization.229,230 The elevated content of osteoid is accompanied by increased synthesis and content of type I collagen and increased alkaline phosphatase content.230 Together, these changes are indicative of increased turnover of bone in hip OA. TGF- a bone growth factor, is also increased in content.230 Such changes are also seen in remote sites, such as in the iliac crest, where osteocalcin, IGF-1, IGF-2, and TGF- contents are increased.227
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These observations raise the possibility that bone turnover may be different in people before the development of OA and that these changes may vary according to the type of OA. They may clearly contribute to or even cause the onset of OA. Analyses of type II procollagen production in OA articular cartilages reveal increased synthesis reflected by elevated C-propeptide concentration. Yet in the peripheral blood of OA patients, there is a significant reduction of the C-propeptide. This also suggests a systemic alteration in cartilage type II collagen synthesis, which again may be a risk factor for the onset of OA.114 Observations of this kind raise questions as to whether idiopathic OA may result more from specific fundamental differences wherein local factors (such as biomechanical) precipitate joint disease via interactions with systemic metabolic factors in any given individual. Thus systemic bone or cartilage changes alone may predispose people to these degenerative changes in joints where the mechanical environment may reveal such abnormalities. It is interesting to note that peak bone mass is increased in the hips of daughters of women with hand OA.231 Clearly there would appear to be genetic linkages in the etiology of this disease.
The degeneration of articular cartilage may be accompanied or possibly preceded by increased subchondral bone turnover, as suggested by bone scintigraphy. In the absence of MRI, it is not possible to be clear as to whether the bone changes preceded those in articular cartilages. Such bone changes are predictive of the development of hand OA,232 the progression of knee OA,233 and generalized nodal OA.234 Studies in humans and animals, such as the aging guinea pig, using histologic analyses and magnetic resonance imaging, suggest that degenerative changes in articular cartilages are accompanied by local changes in subchondral bone that involve cyst formation and altered trabecular and osteoid thickness and bone formation and turnover.235,236,237,238
The development of osteophytes so often seen peripherally in an OA joint involves the formation of a cap of new articular cartilage as well as new bone formation as part of an endochondral process. Experimentally, it has been shown to be correlated with articular cartilage loss elsewhere in the joint.239 These changes and relationships are often compartmental, suggesting localized events. The overall increase in bone turnover in OA and resultant changes are reflected by increases in bone-specific deoxypyridinoline cross-links in urine as a result of enhanced osteoclastic resorption of bone.126,240 These changes in urine may also result from more extensive systemic change.
Changes in both the articular cartilages and the subchondral bone of a degenerate joint no doubt reflect the interdependence of these tissues within the joint. Changes in one tissue would influence mechanical loading of the other and alter tissue turnover. Thus, it is not surprising that such changes may occur simultaneously. The presence of bone marrow abnormalities on MRI has been reported to be associated with cartilage remodeling based on a type II collagen biomarker assay.241 Whether this marker reflects changes in uncalcified cartilage or in the calcified cartilage adjacent to subchondral bone or both is not known. It is noteworthy that in the ankle, where OA is much less common than in the hip or knee, cartilage degeneration of the talar is not associated with an increase in subchondral bone density,242 indicating different responses in ankle joints that may influence OA development. Studies of bone changes in familial OA (caused by a cartilage collagen mutation, for example) compared with idiopathic OA may be of use in determining whether these cartilage changes occur together with or independently of those in bone.
In osteoporosis, a condition that results in excessive resorption and a net loss of bone mineral density, it is uncommon to observe OA (Fig. 2-5), and vice versa.243,244,245 The structure, turnover, and density of bone would therefore appear to influence articular cartilage turnover and play a significant role in the pathogenesis of OA. Thus, a controlled reduction in bone density may help in controlling joint degeneration.
The interrelationships between bone and cartilage changes in OA may also result from the molecular effects of the products of one tissue on another. Bone cell cultures from OA subchondral bone, but not from nonarthritic bone, can stimulate proteoglycan release from nonarthritic human articular cartilage.246 Further studies of this kind are needed.
Calcitonin suppresses osteoclastic resorption of bone, a key component of the remodeling of bone. It can also reduce both cartilage pathology85 and suppress bone changes247 in experimental dog OA. Whether this effect is achieved through the control of bone changes or also involves a more direct stimulation of proteoglycan synthesis by chondrocytes248 is unclear. Alendronate, another potent inhibitor of bone resorption, can also reduce cartilage degeneration and osteophyte formation in experimental OA in the rat,249 again suggesting that bone remodeling in OA plays an important role in the degenerative process.
Synovitis and Inflammation in Osteoarthritis
OA is not considered an inflammatory arthritis, and the synovial fluid leukocyte count is characteristically less than 3000 cells/mL. To the extent that acute synovial fluid leukocytic inflammation does occur in OA, it is often the result of secondary crystal-induced synovitis (either calcium apatite or calcium pyrophosphate dihydrate). However, low-grade inflammatory processes nevertheless occur in osteoarthritic synovial tissues that contribute to disease pathogenesis, and many of the clinical symptoms and signs seen in OA joints clearly reflect synovial inflammation (e.g., joint swelling and effusion, stiffness, occasionally redness). Synovial histological changes include synovial hypertrophy and hyperplasia with an increased number of lining cells, often accompanied by infiltration of the sublining tissue with scattered foci of lymphocytes. Cartilage breakdown products, derived from the articular surface as a result of mechanical or enzymatic destruction of the cartilage, can provoke the release of collagenase and other hydrolytic enzymes from synovial cells and macrophages.250
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Cartilage breakdown products are also believed to result in mononuclear cell infiltration and vascular hyperplasia in the synovial membrane in OA.251 A consequence of these low-grade inflammatory processes is the induction of synovial IL-1 and TNF- , which are likely contributors to the degradative cascade.
Recent studies have also demonstrated that, even in the absence of clinical signs of synovitis, there is frequently localized synovitis in patients with OA, which may be most pronounced immediately adjacent to the OA lesion of the articular cartilage. For example, arthroscopy has demonstrated localized synovial proliferative and inflammatory changes in up to 50% of patients with knee OA.252,253 Proteases and cytokines produced by activated synovium have been suggested to accelerate deterioration of contiguous cartilage lesions.253 Areas of increased radionuclide uptake ( hot spots ) on bone scintigraphy have also been reported to identify joints more likely to progress by radiographic criteria or to require surgical intervention over a 5-year period.233
Synovial tissues and cartilage also synthesize anti-inflammatory cytokines, including IL-13, IL-4, and IL-10. Indeed, synovial fluid of OA patients contains increased levels of these factors, which can decrease PGE2 release, IL- , TNF- , and MMPs while upregulating TIMP.254,255 Another anti-inflammatory molecule produced by joint tissues is the IL-1 receptor antagonist (IL-1Ra), which, like soluble IL-1 receptors discussed above, competes with cell surface receptors for IL-1 and thereby reduces nitric oxide production, PGE2 synthesis, or protease secretion. Although the production of IL-1Ra is increased in OA, increased production is insufficient to reverse the catabolic effects of augmented IL- .
A number of investigations have revealed that serum HA is upregulated in patients with rheumatoid arthritis and is related to joint inflammation and radiologic progression.256 HA is also often increased in OA patients.257 Those with persistently elevated serum HA levels exhibit more rapid disease progression.258 HA levels also indirectly correlate with minimal joint space.258,259 COMP is synthesized by synovial cells as well as by chondrocytes. COMP synthesis is stimulated by TGF- 1, which is produced in inflammation.260 Patients who show serum elevations of COMP often exhibit progression of joint damage.261,262,263 Serum/plasma levels appear to be closely associated with hip synovitis241 and knee OA.264 Elevation of both HA and COMP is associated with a greater risk of progression in hip OA.265
A glycosylated derivative of the pyridinoline collagen cross-link is enriched in human synovium and present in low levels in cartilage and other soft tissues.266 It can be detected in urine. Its close association with the presence of knee OA and severity267 suggests the presence of synovitis, a feature of which is increased content of type I and III collagens and their turnover.
MMP-3 and MMP-9, which are elevated in synovial cells from patients with rapidly destructive hip OA, are also elevated in synovial fluid, plasma, and sera in these patients.268,269 The elevation of MMP-9 is markedly reduced a year after arthroplasty, pointing to the joint cartilages and/or bone as the cause of this elevation, probably by triggering a synovitis. This may involve an immune reaction since T lymphocyte immunity to cartilage aggrecan and link protein is enhanced in OA.270 In experimental OA, T cell immunity to fibrillar collagens also develops.271
Chemokines are also elevated. Macrophage inflammatory protein-1 is elevated in OA synovial fluid over serum as in RA.272 Eotaxin-1, RANTES, and MCP-1 areelevated in plasma of OA patients.273
Fas ligand, which induces apoptosis, is also present in synovial fluid in OA274 and may account in part for the enhanced apoptosis in articular cartilage in OA by engagement of the receptor for this ligand on chondrocytes and synovial cells. The presence of systemic inflammation in OA, albeit limited, is also revealed by the small but significant increase in the serum acute-phase molecule C-reactive protein,275 which is predictive of progression in early onset disease.276 These are but some examples of evidence for an inflammatory process in OA that in some cases may be more pronounced within a joint and may accelerate joint degeneration by the release of cytokines, chemokines, proteinases, and other mediators that cause joint degeneration.
Pain in Osteoarthritis
Arthritis pain is the most common cause of pain in aged populations277 and arguably the most debilitating aspect of OA. Although the presence of knee pain increases with radiographic disease severity in most studies, it is apparent that the severity of abnormalities by routine radiography does not correlate with pain severity in the individual patient. MRI studies have indicated that in patients with knee OA, knee pain severity was associated with subarticular bone attrition, bone marrow lesions, synovitis/effusion, and meniscal tears.278
Pain severity in persons with OA is not a simple phenomenon, and can arise from any of several innervated tissues. The joints of the appendicular skeleton are innervated by the peripheral nervous system in every tissue except cartilage where innervation is peripheral in the periosteum, synovium, capsule, ligaments, and subchondral bone. Here nociceptors monitor the environment. Neuro-innervation can determine disease onset. Limbs paralyzed by hemiplegia or poliomyelitis are often spared in the development of OA or RA.279,280 Patients with different joint involvement in OA can exhibit pronounced hyperalgesia to thermal and mechanical stimuli including uninvolved joints.281,282,283 Following total hip arthroplasty, there is a return to normal pain thresholds in the contralateral hip.284 The association of movement with pain suggests the contribution of central mechanisms.285 Nerve growth factor plays a major role in inflammatory hyperalgesia: IL-1 contributes to the upregulation of this neurotrophin and hyperalgesia.286 There is evidence for an association between pain, synovitis, and changes in subchondral bone.287 Neuropeptides generated by nerve fibers are messengers that link the peripheral nervous system and
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inflammation. C-fiber stimulation causes Substance P release, which in turn induces mast cell and platelet degranulation with histamine, serotonin, bradykinin, and platelet activating factor release, capable of not only causing vasodilation and vasopermiabilisation but of stimulating nociceptors and amplifying and prolonging afferent discharge into the central nervous system.288 Prostaglandins can also contribute to painful afferent sensory responses.289,290 Substance P can directly activate synovial cells to induce collagenase and PGE2 release291 and stimulate monocytes/macrophages and other inflammatory cells to produce IL-1, TNF- and IL-6.292
Neuropeptides can also perform various regulatory functions. Calcitonin gene-related peptide and vasoactive intestinal peptide (VIP) can each inhibit synovial cell proliferation and the expression of proinflammatory cytokines and MMP-2.293 Somatostatin can modulate the production of MMP-1 and MMP-9.294 The parasympathetic vagus nerve, which innervates all major organs, can control TNF- synthesis. It has sensory (input) and motor (output) fibers to sense and suppress inflammation. The sensory nerve can detect IL-1 and respond by releasing acetylcholine which suppresses TNF- and IL-1 generation by macrophages. Electrical stimulation of this nerve prevents TNF release from macrophages. Surgical section removes this protection.295 This is because the acetylcholine normally released by the nerve activates 7 nicotinic acid receptors on macrophages which suppress the release of these proinflammatory cytokines.296 The sympathetic nervous system mediates unloading-induced bone loss through the suppression of bone formation by osteoblasts and enhanced resorption by osteoclasts.297 Leptin has an anti-osteogenic function that is mediated by sympathetic neural pathways that control bone remodeling. This occurs by sympathetic signaling of 2 adrenergic receptors on osteoblasts. In mice deficient in the receptor Adrb2, the sympathetic system favors bone resorption; this occurs by an increase in Rankl expression on osteoblast progenitor cells. Leptin controls the expression of the neuropeptide cocaine amphetamine regulated transcript 9CART, which inhibits bone resorption by modulating Rankl expression. Thus leptin regulated neural pathways control both aspects of bone remodeling.298
Neuropeptides can also help explain some of the effects of the nervous system on the skeleton. VIP potentiates IL-6 production by osteoblasts induced by proinflammatory osteotropic cytokines, including IL-1.299 Substance P stimulates osteoclast formation.300 Chondrocytes express functional -opioid receptors that can be activated with -endorphin301 causing increased IL-1 and TNF- generation.302
Ipsilateral and contralateral joint involvement whereby joint inflammation in a single joint can induce distal bilateral degeneration of articular cartilage has also been ascribed to neurogenic mechanisms and neuropeptides by using an antagonist of neurokinin-1 and spinal compression to inhibit the involvement of the other joint.280
Thus it can be seen with these examples that neurological mechanisms influence not only the perception of pain that is altered in OA but also regulate skeletal turnover and inflammation. There is still much to be learned of this much neglected area of research in our understanding of the pathogenesis of OA.
Therapeutic Targets for the Management of Osteoarthritis
Cartilage is clearly a principal target because of its paramount importance in joint articulation. Despite the tremendous impact of this disease, however, current therapies are palliative and there are no disease-modifying OA drugs (DMOADs) currently available for clinical use. Nonetheless, a number of promising molecular targets exist in the development of pharmacologic therapies for OA, and useful and comprehensive review of such therapeutic approaches has recently been published.303
For example, there has been significant emphasis on targeting MMPs that cleave collagen because collagen degradation is clearly indicated in OA pathogenesis. The collagenase MMP-13 is thought to be an important target for the control of collagen fibril damage in articular cartilage. To date, doxycycline is the only molecule that can regulate collagenase activities in vitro,304 control the progression of experimental OA,305 and be used without serious side effects in the treatment of knee OA.306
Cartilage proteoglycan aggrecan degradation by aggrecanases is also of very much interest as a target. Although the aggrecanase ADAMTS-5 may be rate limiting in the degradation of this molecule in animals (see section on Proteinases of OA Cartilage), it remains to be seen whether it is in humans. This is because aggrecan, unlike type II collagen, is susceptible to cleavage by many proteinases such as those of the ADAMTS family. Based upon experiments in knockout mice, ADAMTS-5 has been reported to be the primary aggrecanase responsible for aggrecan degradation in a murine model of OA, and could be a potential target for therapeutic intervention in human OA.119
Another approach is to restore the balance between synthesis and degradation by enhancing cartilage matrix synthesis. A clearer identification of the key growth factors involved in matrix assembly is a priority, particularly since some of these can suppress degradation. IGF-1 is of obvious importance in view of its potency and upregulation in OA,173 but there may be more potent growth factors or combinations thereof that can be used to renew matrix assembly and control degradation. A combination of MMP inhibitors and enhanced stimulation of matrix synthesis may prove most effective.
Work with bone morphogenetic protein 7 has revealed its capacity to promote matrix assembly in articular cartilage and to inhibit the degradative effects of IL-1.307 We have already discussed how TGF- 2 is a potent stimulant of matrix synthesis,50 and can suppress the cleavage of collagen by collagenases and chondrocyte hypertrophy in OA cartilage in culture.158 Still other approaches have targeted the pro-inflammatory mediators such as nitric oxide through selective inhibition of NOS2 and animal models of OA.148 These studies have shown significant promise for inhibiting disease progression by decreasing chondrocyte
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apoptosis as well as cartilage catabolism via inhibition of NOS2. While the mechanisms for these findings are not fully understood, they may involve the local suppression of other inflammatory cytokines such as IL-1 or TNF- .
Brandt et al. recently reported that doxycyline slows joint space narrowing (JSN) in patients with OA of the medial tibiofemoral compartment.306 In this placebo-controlled trial, 431 obese women (ages 45 to 64 years) with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with doxycycline 100 mg or placebo twice daily. Doxycycline reduced JSN in the OA knee by approximately 30% at 30 months; however, the mean progression of JSN in both groups was limited (0.30 0.60 mm vs. 0.45 0.70 mm).
IL-1 has attracted significant interest as a target for disease modification in OA. The intra-articular injection of recombinant human IL-1Ra attenuates the development of cartilage lesions and the expression of MMPs in the canine experimental OA model.308 Two groups have also demonstrated that in vivo transfer of the IL-1Ra gene prevents disease progression in the meniscectomy rabbit model of knee OA.309,310 In human OA, the benefit of intra-articular IL-1Ra injection for symptomatic knee OA has been reported in an open-label 12-week study;311 however, in a follow-up controlled trial by these authors, intra-articular injection of IL1-Ra reduced knee pain at day 4, but was not more effective than placebo at 1 month. In addition to biological IL-1 antagonists, small molecule drugs are in development that interfere with the conversion of intracellular precursor IL-1 to active IL-1 by inhibiting caspase-1, the iNOS. Fundamental changes in bone in OA and the relative absence of OA in patients with osteoporosis (and vice versa) raise issues as to the possibility of controlling cartilage degeneration by modifying bone turnover and density. This hasalso been reviewed in the section on bone changes. Would controlled loss of bone density slow the process of degeneration? To date, DMOAD trials using the bisphosphonate to slow progression of knee OA have had mixed results.312
Regulation of synovitis is another target. About 10% of the OA population is thought to have a pronounced synovitis, comparable in numbers to the total rheumatoid population. We know that the incidence of much of the hip and knee OA is greater in women than in men, but we know almost nothing of the reasons for this. Clearly, much needs to be done to determine whether sex hormones regulate cartilage turnover.
None of these treatments will be effective if we rely on existing clinical assessments for the degenerative process. When most patients present with an OA joint, the disease is usually advanced and much damage has been done. For the future, it is important to detect and treat the disease early by employing new detection systems such as new imaging and biomarker modalities be they protein or gene based. Only then will therapy be most likely to succeed. Inevitably, this will mean the introduction of screening programs to identify these early changes. Otherwise, we must be content for now with halting further degeneration and slowing OA development elsewhere. We must also not forget the opportunities to treat single large joints such as the knee. This is an attractive consideration in view of the experience gained with intra-articular therapy with HA preparations and steroid usage. It also offers an opportunity to avoid or minimize possible side effects.
If we can effectively control the pain of OA, we will have already made a great stride forward. Much research has pinpointed new targets to control the pain of arthritis. Pharmacologic stimulation of the vagus nerve cholinergic anti-inflammatory pathway offers new therapeutic opportunities.313 These discoveries are being very actively pursued. We will probably find that many disease modifying drugs lack symptomatic relief for the patient. Inevitably, combination therapy will be needed in such cases.
Conclusions
In the last two decades, we have made significant progress in our understanding of the pathophysiology of OA. This has revealed a complex series of molecular changes at the cell, matrix, and tissue levels and complex interactions between tissues that make up the joint. Some of these are summarized in Figure 2-2 and Figure 2-5. We can now better understand how these changes develop and progress, as well as the fact that tissues other than cartilage are involved in the disease process. Opportunities for the management of disease progression and targets for therapeutic intervention have been identified and can now be tested for the first time. The future of OA research is extremely promising, and some real opportunities for the effective therapeutic management of OA are now available.
Acknowledgments
The authors work has been funded by Shriners Hospitals for Children; the Canadian Institutes of Health Research and the Canadian Arthritis Network (A.R.P.); and the National Institutes of Health (A.R.P., F.G., S.B.A.).
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