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Osteoarthritis (OA) is a chronic joint disorder in which there is progressive softening and disintegration of articular cartilage accompanied by new growth of cartilage and bone at the joint margins (osteophytes) and capsular fibrosis. OA is the most common joint disease and often contributes to a high number morbidity. It differs from simple wear and tear in several ways: it is asymmetrically distributed and often localized to only one part of a joint; and it is related to abnormal loading rather than frictional wear. In its most common form, it is unaccompanied by any systemic illness and, although there are sometimes local signs of inflammation, it is not primarily an inflammatory disorder .
It is also not a purely degenerative disorder, and the term 'degenerative arthritis' - which is often used as a synonym for OA - is a misnomer. OA is a dynamic phenomenon; it shows features of both destruction and repair. Cartilage softening and disintegration are accompanied from the very outset by hyperactive new bone formation, osteophytosis and remodelling. In addition, there are various secondary factors which influence the progress of the disorder: the appearance of calcium-containing crystals in the joint; ischaemic changes (especially in elderly people) which result in areas of osteonecrosis in the subchondral bone; the appearance of joint instability; and the effects of prolonged anti-inflammatory medication.
The term 'primary osteoarthritis' is used, when no underlying cause is apparent. Patients are somewhat older, usually in their sixth or seventh decade, with a slight predominance of women, and often other areas (knees or spine) also are affected. The disease progress slowly. There may be evidence of chondrocalcinosis. The excessive and continuous use of certain joint will accelerate local degenerative process.
The term 'secondary osteoarthritis' is applied where there is an obvious underlying cause. Many types of injury, deformity, and disease are capable of producing the initial cartilage lesion that leads to the development of progressive secondary OA. Such ethiological factors will have a greater effect on aging cartilage than young cartilage. Secondary OA is more common in the weightbearing joints of lower limb than in non-weightbearing joints of upper limb. These patients are often in their third or fourth decade and the appearance of the joint reflects the preceding abnormality.
Pathogenesis and Pathology of OA
Whether OA is primary, secondary, or a combination of the two, the pathological process in the early stages is similar and represents a significant exaggeration of the previously described aging process. The local pathological process is best considered in relation to the various tissue components of the joint.
The earliest biochemical change of OA is always in the articular cartilage and consists of a loss of proteoglycan from the matrix. The resultant change in the physical, or biomechanical, properties of the cartilage is softening (chondromalacia) and loss of the normal elastic resilience that gives cartilage its shock-absorbing ability. Thus, the collagen fibrils of the cartilage, having lost some of their support and having become "unmasked," are rendered more susceptible to the friction of joint function. As a result, shredding of the tangential surface layers of cartilage is accelerated and the deeper vertical layers split, with consequent fissuring and fibrillation. The joint surface, which is normally bluish-white, smooth, and glistening, becomes yellowish, granular, and dull.
As Mankin has stressed, the pathogenesis of osteoarthritis, far from being a passive "wear and tear" phenomenon, is characterized by much cellular and metabolic activity within the articular cartilage. Not only does the cartilage become more cellular, but the adult chondrocytes (which normally no longer divide) begin once again to divide as evidenced by clustering of cells and even cell mitoses. These activated chondrocytes synthesize proteoglycans and collagen at a greatly accelerated rate. Despite this valiant effort, however, the proteoglycan content is diminished because of the progressive destruction by lysosomal proteases (cathepsins) and neutral metalloproteinase such as collagenase. Vascular invasion of the abnormal cartilage by vessels from the subchondral bone exposes the normally avascular cartilage to the systemic circulation for the first time and may lead to a type of self-perpetuating autoimmune disease that causes even further damage.
In the central area of the joint surface, which is exposed to the most friction, the softened, fibrillated cartilage is gradually abraded down to subchondral bone, which then serves as the articulating surface and gradually becomes as smooth as polished ivory (eburnation). The loss of articular cartilage is evidenced radiographically by a narrowing of the cartilage space.
In the peripheral areas of the joint, the cartilage responds by hypertrophy and hyperplasia to form a thickened rim of cartilage around the joint margin. This outgrowth of cartilage (chondrophyte) subsequently undergoes endochondral ossification to become a bony outgrowth (osteophyte), also referred to as "osteoarthritic lipping" or "a bony spur." Osteophytes may become sufficiently large that they actually restrict joint motion.
The loss of cartilage centrally and the building up of cartilage and bone peripherally produce incongruity of the joint surfaces which, in turn, alters both the distribution and the magnitude of the biomechanical stresses on the joint. Some areas are subjected to much more stress than normal, whereas others are subjected to less than normal stress. Thus, the pathological process is self-perpetuating and a vicious cycle is established.
Normal subchondral cancellous bone is stiffer than cartilage but much more resilient than dense cortical bone. As such, like cartilage, it also serves as a shock-absorber. The striking reaction of the subchondral bone in degenerative joint disease accounts for the synonyms osteoarthritis and osteoarthrosis. In the central area of maximum stress and friction, the subchondral bone, in addition to becoming eburnated, hypertrophies to the extent that it becomes radiographically dense (sclerotic). In the peripheral areas, however, where there is minimal stress, the subchondral bone atrophies and becomes radiographically less dense (rarefied, i.e., osteoporotic). Excessive pressure, particularly in weight-bearing joints such as the hip, leads to the development of cystic lesions within the subchondral bone marrow, possibly because of mucoid and fibrinous degeneration in the local tissues secondary to microfractures of trabeculae. These "cysts" may even communicate with the joint surface through defects in the subchondral bone, in which case they contain either fibrous tissue or synovial fluid. The increased vascularity associated with these bony reactions in a closed space within the bone may be a factor in the production of pain.
The redistribution of biomechanical stresses on the joint leads to a remodeling of the subchondral bone; bone is worn away centrally but deposited (by endochondral ossification of the deep layer of cartilage) peripherally. Such remodeling accentuates the previously mentioned joint incongruity and contributes to the vicious cycle of degeneration.
Synovial Membrane and Fibrous Capsule
Small fragments of abraded dead cartilage may float in the synovial fluid as loose bodies but tend to become incorporated in the synovial membrane which, in turn, reacts by undergoing hypertrophy and producing a moderate synovial effusion. The synovial fluid of such an effusion has an increased mucin content and consequently exhibits increased viscosity.
The fibrous capsule becomes greatly thickened and fibrotic, thereby further limiting joint motion. In the joints of the fingers, especially the distal interphalangeal joints, small areas of mucoid degeneration in the fibrous capsule at the joint margin form small subcutaneous protuberances which subsequently ossify and are known as Heberden's nodes. Nevertheless, Heberden's nodes are not necessarily a manifestation of OA because the cartilage of the subjacent joint is usually normal.
The muscles controlling the affected joint develop spasm in response to pain and eventually the stronger muscles (usually the flexors) undergo contracture with resultant joint deformity and further restriction of joint motion. With limited joint motion the excessive stresses are applied to a limited area of joint cartilage; this is another factor in the process of degeneration. The late result may be a fibrous ankylosis of the joint, but bony ankylosis seldom occurs spontaneously in OA.
Biomolecular Changes in OA
Cartilage has a poor intrinsic reparative potential and slow turnover of the extracellular matrix. However, cartilage displays responses that may be interpreted as reparative, during degenerative change or upon wounding. These response include elevated matrix synthesis and renewed chondrocyte proliferation. Indeed, it has recently been shown that the pro-inflammatory cytokines IL-1 and TNF-a stimulate production of BMP-2 in adult articular chondrocytes, and that BMP-2 is elevated in OA. Although the mechanism of mild inflammation could very likely lead to repair in normal and early OA cartilage, these responses are insufficient to heal even the small lesions. Overall, biosynthesis and activation of degradative enzymes provides activity that exceeds the biosynthesis of extracellular matrix.
The primary metabolic response of chondrocytes in osteoarthritis is an increased rate of synthesis of type II collagen by the articular chondrocytes. As will be seen in detail below, most extracellular matrix molecules are increased, as well as increased in the synthesis of degradative enzymes. These degradative materials will increase in concentration and destroy cartilage actively. Degradative materials such as MMP, IL-1, pro-stromelisin, procollagenase, proaggrecanase, plasminogen activator, and prostaglandin, all of these will produce collagenase, aggrecanase, and other materials to destroy matrix of cartilage. However, the degradative attempt will be obstructed by collagen synthesis which is aggravated by materials such as TGF-b, tissue inhibitors of matrix proteases (TIMP), and inhibitor of plasminogen activator. Nevertheless, this attempt isn't sufficient enough to keep up with the ongoing degradative process, still resulting gradual cartilage destruction. In addition, cells are also stimulated to divide, forming clusters of chondrocytes. Recently, apoptosis or programmed cell death has become an area of intense study. There are no single regulatory molecule or even group of molecules responsible for the induction of osteoarthritis has been found until now.
Figure 1. Hipothetical pathway of articular chondrocyte phenotypic changes in OA. Cited from reference no.3
In normal cartilage, the chondrocytes synthesize matrix components very slowly. A variety of anabolic cytokines and growth factors such as TGF-b, bone morphogenetic proteins, and IGF I will stimulate biosynthesis. In OA, many of these factors, as well as others such as inflammatory cytokines tumor necrosis factor-alpha (TNF- a) and interkeukin-1 (IL-1), are produced by the synovium and the chondrocytes. Normally, a careful balance between matrix synthesis and degradation is strictly regulated. In OA, this balance is disturbed. It is believed that the production of the catabolic and anabolic cytokines will activates the chondrocytes. Interestingly, no single cytokine can stimulate all the metabolic reactions observed in OA. TNF-a and IL-1 can enhance expression of matrix metalloproteinases (MMP) resulting increased proteolysis. Therefore, these factors can inhibit cartilage matrix biosynthesis.
Clements et al. investigate the possible role of candidate regulators of cartilage metabolism in OA by investigating the development of osteoarthritis induced by transection of the medial collateral ligament and partial medial meniscectomy in mice with deleted genes which responsible coding for either IL-1, IL-1-converting enzyme (ICE), stromelysin 1, or inducible nitric oxide synthase (iNOS). They observed that all knockout mice exhibited accelerated development of OA lesions compared to wild-type mice. This result shows that deletion of these genes changed homeostatic in regulation of balance between anabolism and catabolism, resulting in accelerated cartilage breakdown. It is apparent that inhibiting normal catabolism had deleterious effects, and caused increased susceptibility to lesion formation.
Nitric oxide (NO) is a free radical formed by combination of a guanidino nitrogen from arginine with molecular oxygen in a reaction catalyzed by NO synthase (NOS). There are three isoforms of NOS have been identified, and the one which can be induced and expressed only in injury and disease is the macrophage form. Surprisingly, inducible NOS (iNOS) was found in chondrocytes. NO is now implicated in OA since activated chondrocytes produce levels of NO and NOS. In this case, a single cytokine, IL-1, can induce the production of NO as much as macrophages per cell. The role of NO in OA is still not completely known, but it is belived that it can inhibit proteoglycan synthesis and may play a role in apoptosis of chondrocytes. Some studies indicating that NO may plays a role in the stimulation of apoptosis of chondrocytes.
Aggrecan Metabolism in Aging and Osteoarthritis
Aggrecan residing within cartilage has been shown to show changes with age. Some of the changes are related to cleavage within the CS-containing regions of the aggrecan monomer, resulting in the accumulation in the tissue of G1-containing, KS-rich, and CS-poor fragments of aggrecan. Aggrecan degradation was found to be a feature of intervertebral disk tissue with age, in which both metalloproteinase and aggrecanase-derived cleavage products have been observed. In older cartilage, aggrecan monomers are shorter and more variable in length, have shorter CS chain clusters, and have a shorter thin segment that may result from an increase in KS content. With age, aggregates are shorter with fewer KS monomers per aggregate. In osteoarthritis, aggrecan is lost from cartilage, and appears to be degraded by aggrecanases produced by the chondrocytes themselves. In OA cartilage, in contrast to aggrecan in aging cartilage, a high ratio of CS to KS has been observed as is typical of immature cartilage. These differences can be resolved by considering that there may be two phases in the disease process which relate to pathological degradation and attempted repair. In the first phase, there appears to be a general reduction in the size of aggrecan relative to normal, resulting from the loss of G3 and CS-2 domains. In the second phase, where fibrillation is extensive and the cartilage is degenerate in appearance, aggrecan monomers were found to be larger than normal, indicating the presence of newly synthesized intact aggrecan monomers. Altered reactivity of CS chains to antibodies has indicated that changes in the environment of the chondrocyte in OA cartilage may cause changes in CS synthesis.
Collagen Metabolism in Osteoarthritis
There are several studies showing that collagen synthesis in OA cartilage is increased compare to normal cartilage. These interesting results indicate that there may be an imbalance in the production of extracellular matrix. Distinct cellular phenotypes have been observed in OA cartilage. Attempts to characterize the phenotype of chondrocytes from OA cartilage have been made by analyzing their collagen synthesis or mRNA expression; the major type of collagen synthesized in OA is type II. Chondrocytes from OA samples were found to express type III collagen mRNA, as determined by in situ hybridization using a specific probe and by immunohistochemical analysis of the protein. This later observation suggests that chondrocytes can undergo dedifferentiation to a fibroblast-like phenotype. On the other hand, the expression of type I collagen mRNA, another marker for dedifferentiation, was absent in chondrocytes, arguing against the assumption of the fibroblastic phenotype. Although type I collagen was reported in human OA cartilage and in rabbit cartilage after mechanical trauma, the bulk of evidence demonstrates that chondrocytes, instead of dedifferentiating to a fibroblastic cell, favor the repair of cartilage matrix by expressing chondrocyte-characteristic collagens.
Girkontait et al demonstrated the onset of chondrocyte hypertrophy in the deep zone of OA cartilage as represented by the synthesis of type X collagen. Recently, type X collagen mRNA and protein have also been localized in certain cell populations of OA cartilage and correlated with clinical and radiological alterations. In this study of femoral heads obtained from following the hip joint replacement for femoral neck fractures, osteoarthritis or without hip-joint pathology, they showed that type X collagen is consistently found in osteoarthritic cartilage and is absent from normal adult cartilage. The collagen was primarily in the middle zone cells in advanced stages of OA, but only up to 20% of the cartilage was positive. Therefore, these authors suggest that type X collagen may not play a direct biomechanical role in the weakening of osteoarthritic cartilage, but may indicate a change in chondrocyte phenotype that consistently coincides with the formation of chondrocyte clusters, one of the first alterations in osteoarthritis visible on histologic examination.
Apoptosis and Osteoarthritis
Programmed cell death (apoptosis) is a mechanism by which cells are intentionally removed from tissue and is most evident during embryonic tissue remodeling. Apoptosis is believe to be the means by which hypertrophic cells are removed from the growth plate cartilage so that the hypertrophic cartilage can be removed by osteoclasts and new bone laid down. To examine the occurrence of apoptosis in human osteoarthritis cartilage, and to determine its relationship to cartilage degradation, osteoarthritic samples have been analyzed by flow cytometry, terrminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and electron microscopy. In one study, flow cytometry on cell suspensions showed that approximately 22% of OA chondrocytes and 5% of normal chondrocytes were undergoing apoptosis. Staining of cartilage sections demonstrated the presence of apoptotic cells in the superficial and middle zones. Cartilage areas that contained apoptotic cells showed proteoglycan depletion, and the number of apoptotic cells were significantly correlated with the OA grade. A second study found significant agreement with 51% of cells of OA chondrocytes and 11% of normal cells were apoptotic, primarily in the superficial and middle zones. Because apoptotic cells are not removed effectively from cartilage, the products of cell death such as pyrophosphate and precipitated calcium may contribute to the pathologic cartilage degradation.
One of the most remarkable and consistent features of joints affected with osteoarthritis, whether naturally occurring or experimentally induced, is the development of prominent osteochondral nodules known as osteophytes, osteochondrophytes, and chondro-osteophytes. Indeed, the presence of chondro-osteophytes in a joint, more than any other pathological feature, distinguishes osteoarthritis from other arthritides. It seems likely that both mechanical and humoral factors are involve in stimulating the formation of osteophytes, though the exact functional significance of osteophyte growth remains unclear. There is, however, direct evidence that osteophytes help stabilize osteoarthritic joints. Osteophytes are an example of new cartilage and bone development in osteoarthritic joints, which are ultimately characterized by articular cartilage degeneration. Close examination of the biosynthetic activity of developing chondro-osteophyte in the Pond-Nuki dog model of osteoarthritis revealed that the cells arise from tissue associated with the chondro-synovial junction, indicating that there is a population of pluripotential cells in the periosteum that is responsive to the mechanical and humoral sequelae of joint injury. The formation of chondro-osteophytes in OA joints is a unique example of adult neochondrogenesis that bears some similarities to growth plate elongation and fracture callus formation. Studies using in situ hybridization histochemistry to define the molecular phenotype of cells in active chondro-osteophytes have been performed in a dog model of early OA. Chondro-osteophytes are composed of fibrocytes and osteoblasts that express type I procollagen mRNA, mesenchymal prechondrocytes that express type IIA procollagen mRNA, and maturing chondrocytes that express type IIB procollagen mRNA. Based on the spatial pattern of gene expression and cytomorphology, the neochondrogenesis associated with chondro-osteophyte formation closely resembles that of the healing fracture callus and recapitulates events of endochondral bone formation. The fact that BMP-2 is a morphogenetic factor stimulated by pro-inflammatory cytokines, strongly suggests that this factor could stimulate differentiation in multipotent cells into osteophyte in the joint tissues.
Figure 2. Scheme of biomolecular changes in OA. Cited from reference no.5
Clinical Features of OA
There are no systemic manifestations of OA, the symptoms and signs are confined to individual joints. Patients usually present after middle age. Joint involvement follows several different patterns: symptoms centre either on one or two of the weightbearing joints (hip or knee), on the interphalangeal joints (especially in women), or on any joint that has suffered a previous affliction (e.g. congenital dysplasia, osteonecrosis or intra-articular fracture).
The predominant symptom in OA is pain that arises from bone and from the synovial mcmbrane, fibrous capsule, and the spasm of surrounding muscles. The pain is at first a dull ache and later is more severe; it is intermittent and aggravated by joint movement ("friction effect") and relieved by rest. Eventually, however, the patient may even experience "resting pain," which is probably related to the hyperemia and consequent "intraosseous hypertension" in the subchondral bone. Pain is often quite widespread, or it may be referred to a distant site - for example, pain in the knee from OA of the hip. It starts insidiously and increases slowly over months or years. Characteristically, the pain is worse when the barometric pressure falls just before a period of inclement weather. Paradoxically, the severity of the patient's pain is not necessarily related to the severity of the OA as evidenced by radiographic changes, but this may be caused by individual differences in pain threshold as well as differences in joint motion and the amount the joint is being used. Injuries, such as sudden strains or sprains, in an arthritic joint always aggravate the pre-existing symptoms.
The patient may become aware that the joint motion is no longer smooth and that it is associated with various types of joint crepitus such as squeaking, creaking, and grating. The joint tends to become stiff after a period of rest, a phenomenon referred to as articular gelling. Gradually, the involved joint loses more and more motion and eventually may even become so stiff that the pain (which is associated with motion) is decreased.
Loss of function, though not the most dramatic, is often the most distressing symptom. A limp, difficulty in climbing stairs, restriction of walking distance or progressive inability to perform everyday tasks or enjoy recreation may eventually drive the patient to seek help. Typically, the symptoms of OA follow an intermittent course, with periods of remission sometimes lasting for months.
Physical examination reveals swelling of the joint caused by a moderate effusion but there is relatively little synovial thickening; the joint swelling is more obvious because of the atrophy of surrounding muscles. There is no increased warmth of the overlying skin. Both active and passive joint motion are restricted and associated with joint crepitus, as well as pain and muscle spasm at the extremes of the existing range of motion. In the primary, or idiopathic, type of OA, Heberden's nodes are frequently seen at the distal interphalangeal joints; they are more common in women but their exact relationship to OA is not clearly understood. Similar nodular lesions in the proximal interphalangeal joints are known as Bouchard's nodes. Deformity may result from capsular contracture or joint instability. In the late stages, joint instability may occur for any of three reasons: loss of cartilage and bone, asymmetrical capsular contracture, and muscle weakness.