Arthritis & Allied Conditions
15th Edition

Chapter 108
Pathology of Osteoarthritis
Aubrey Johnston Hough Jr.
One purpose of studying a disease is to gain insight concerning its causation. Osteoarthritis (OA), despite widespread occurrence in the adult population, offers formidable obstacles to the acquisition of such understanding. The very term osteoarthritis is a misnomer because it implies an inflammatory process. The original usage of the term by John Spender in 1886 was as a synonym for rheumatoid arthritis (RA) and not as the disorder we recognize today (1). Initial credit for the use of the term in its modern sense probably belongs to Archibald E. Garrod (about 1910), although Edward Merrins of New York expressed similar ideas simultaneously (2). The term, therefore, has been used in the English-speaking world for several generations, and neither the pathologically more accurate term degenerative joint disease nor the European term osteoarthrosis has displaced it. OA has also suffered from a lack of consensus regarding its definition.
Different classification schemes for OA have emerged based on putative mechanical and biologic factors culminating in the disorder. The current working definition of OA incorporates these into a working formulation: stating “morphologic, biochemical, molecular, and biomechanical changes of both cells and matrix which lead to softening, fibrillation, ulceration, and loss of articular cartilage, sclerosis, eburnation of subchondral bone, osteophytes, and subchondral cysts” (3). In less comprehensive terms, OA is thus characterized by a deterioration of articular cartilage and formation of new bone at the joint surfaces (Fig. 108.1). However, the relationship between cartilaginous and bony changes has long been a source of contention. The nature of this relationship is central to the explanation of the pathologic changes seen in OA.
FIG. 108.1. Degenerative joint disease of the knee. Large areas of erosion of articular cartilage are present on the patellar facet and on the condyles of the femur. These erosions occupy principally the central portions of the joint surfaces and spare the marginal regions. The cartilage at the eroded edges is fibrillated. The irregular elevations at the periphery of the surfaces are osteophytes.
Remodeling is defined as the gradual alteration of the internal architecture of the skeleton in response to mechanical loading (4). The removal of bone from certain sites coincides with the simultaneous formation of new bone elsewhere (5). Remodeling of bone explains changes in the shape of the joints both with age and in OA. In experimental models, these forces can produce resorption of calcified cartilage in areas of decreased pressure and necrobiosis of chondrocytes in areas of increased pressure (4). Similar changes occur in human OA (6, 7). Likewise, rapidly destructive variants of OA that are associated with accelerated subchondral remodeling and osteocyte death also have been described (8, 9).

Accounts of early OA usually maintain that fibrillation of articular cartilage precedes the development of other lesions. Biopsies of cartilage in early OA show that fibrillation is the earliest gross pathologic change observed (10). Similar changes are seen in early OA induced by partial meniscectomy in rabbits (11) and anterior cruciate transection in dogs (12). Cartilaginous changes, however, may not occur first—changes in adjacent bony structures may precede them (13). The relationships between the cartilaginous and bony changes are complex, and the hypotheses relating them have been summarized by Sokoloff (4). OA can be viewed in isolation as a degeneration of articular cartilage progressively leading to denudation of the joint surface. If this purely chondrogenic theory were valid, little or no concomitant remodeling of bone would occur. This pattern does occur, most commonly in the hip joint, but is rather uncommon (4) and usually results from inflammatory lysis of cartilage rather than from mechanical overloading. In keeping with this hypothesis, the extent of remodeling in surgically resected femoral heads is generally greater in OA (coxa magna) than in RA (5). Similar lack of remodeling is seen in ochronotic arthropathy, perhaps owing to the cartilage lysis that characterizes the disorder.
A second hypothesis is that cartilage fibrillation (Fig. 108.2A) sets in motion a cascade of events leading to secondary bony remodeling of the joint (5). This concept is very difficult to substantiate from the cartilaginous pathology alone because other morphologic events often occur in cartilage and subchondral bone simultaneously. Furthermore, in clinical material, one customarily can only examine pathology at one point in time, usually later in the course of the disease. However, age-related remodeling (14,15,16) in the osteochondral junction may coexist with surface fibrillation, albeit at different sites. Remodeling of the basal calcified cartilage is usually more apparent in non-weight-bearing areas of the joint (15), in contrast to fibrillation, which is more prominent in the weight-bearing areas. Thus, direct causal relationships between these two early changes are difficult to establish. Microfractures of the calcified cartilage, however, may presage the development of later cartilage degeneration by penetrating into the underlying bone marrow (16,17,18), as can be seen in clinical material (Fig. 108.3).
FIG. 108.2. Fibrillation of articular cartilage. A: The most superficial dehiscences are oriented parallel to the surface and then arch downward in a more vertical direction. This pattern corresponds to the fibrous planes of the cartilage (hematoxylin and eosin stain, original magnification ×40.)B: Higher magnification (×240) of the fibrillated edge. The collagen fibrils at the surface have been “unmasked” from the hyaline matrix and appear frayed. Clusters of chondrocytes have proliferated to form so-called brood capsules.
FIG. 108.3. Relationship between a pseudocyst and a microfracture of the subchondral plate. This fortuitous slab section is from a recently fractured femoral head of a 77-year-old woman. Although moderate fibrillation is present elsewhere in the cartilage surface, the sole pseudocyst is located immediately beneath the minute discontinuity in the otherwise intact cartilage and osteochrondral junction. A: Gross appearance (about ×4).B: Roentgenogram, showing the gap in the subchondral plate and the sclerotic wall of the cyst.
A third hypothesis proposes that OA is a consequence of increased stiffness of subchondral bone (5). Radin and Rose

(19) postulated that changes in subchondral bone precede cartilage damage because bone, rather than cartilage, absorbs most of the energy of impact loading transmitted through the extremities. Microfractures have been described in association with OA (20, 21). Repair of these microfractures results in a net increase in bone stiffness, causing the overlying cartilage to absorb a greater proportion of the transmitted energy. This repartition of forces is postulated to result eventually in degeneration of the articular cartilage. Although this hypothesis has a distinct biomechanical logic, there are, as with the previous two hypotheses, certain limitations. The first is that the microfractures of the subchondral bony trabeculae may actually be a protective mechanism to maintain normal joint function because their numbers are decreased in OA, as compared with normal joints (22). This view holds that the remodeling of the subchondral trabeculae into thicker structures is the primary event rather than the microfractures. Bone morphometric studies of several types have confirmed that subchondral bone remodeling is consistently seen in OA (23,24,25,26). Another source of the confusion is the failure to distinguish between microfractures of the subchondral bony plate itself and those occurring at some distance in the underlying trabecular bone. The former are clearly involved in the formation of subchondral pseudocysts (Fig. 108.3). The latter are variously influenced by the systemic state of the skeleton, aging, and the extent of remodeling activities (5). Studies indicate that, in OA, trabecular histomorphometric changes of the iliac crest bone may not accurately reflect those occurring in subchondral bone in femoral heads (27). This may be due to the existence of distinct subpopulations of patients with atrophic and hypertrophic OA of the hip, the former being more likely to have thin bone trabeculae (28).
These degenerative and remodeling events are intertwined to the extent that identification of a unique initial event in the process of OA, if one exists, has not been possible. The same processes that culminate in destruction of the osteoarticular junction and abrasion of the cartilage surface also result in proliferation of new cartilage and bone at or near the joint surface (Fig. 108.4). Although the exact cause of this proliferation has not been established, the generation of the new cartilage in defects in the joint surface that penetrate into the subjacent bone marrow has been documented in experimental models (5). In humans, this abortive repair process produces islands of cartilaginous proliferation interspersed with foci of new bone formation in the subchondral bone marrow. Using this attribute of cartilage to advantage, autografts of cultured articular chondrocytes have been employed to repair full-thickness cartilage defects in the knee joints (29) (see Chapter 112). In a primate cartilage autograft model, direct contact with the underlying subcondral bone was necessary to avoid degenerative changes (30).
FIG. 108.4. Advanced osteoarthritis of the head of the femur. A: The weight-bearing surface (upper left) has been deformed by abrasion and corresponding eburnation. Marginal osteophytes are seen on both medial and lateral aspects. A wedge-shaped necrotic zone (W) lies deep to the eburnated surface and contains a rarefied, partially cystic area at the base. Residual articular cartilage (upper right) merges into the eburnated zone. B: Specimen radiograph of femoral head shown in A reveals eburnation, osteophytes in the soft tissue of the femoral neck and a rarefied zone corresponding to the apex of the wedge-shaped zone (×1.5). C: Whole-mount microscopic section of the femoral head seen in A shows rarefied zone contains no cystic lining and merges with overlying bone. Higher power microscopic view revealed secondary osteonecrosis of eburnated segment (hematoxylin and eosin stain, original magnification ×1.4).
Among the most prominent features of remodeling in OA are osteophytes (Fig. 108.4). Although osteophytes are a conspicuous feature of advanced OA, it would be erroneous to conclude that they represent purely a late change in the evolution of the joint lesions. Periarticular bone remodeling appears early in the course of experimental canine OA (31), parallel to changes in the composition of articular cartilage. In this regard, OA may be conceived as not so much the inability of the joint surface to initiate repair but rather the failure of repair to restore function (4).
Articular Cartilage
Early Microscopic Changes
Microscopic changes in articular cartilage are a consistent feature in early OA of both human and experimental animal subjects (5). However, opinions differ as to the relative importance of individual lesions in the overall pathogenetic schema. Correlation of these early changes with biochemical and molecular changes is hampered by regional variations in the types of response to injury. As an

example, repair cartilage, often of the fibrocartilaginous type, frequently overlies or is juxtaposed to degenerating hyaline cartilage in OA (Fig. 108.5F). Nevertheless, numerous specific lesions are described subsequently.
FIG. 108.5. Miscellaneous remodeling and degenerative changes; all sections are stained with hematoxylin and eosin. A: Reduplication of calcification tidemark (×95).B: Vascularization of base of articular cartilage; the dark-stained material in the capsules of the chondrocytes is calcific (×183). C: Weichselbaum lacunar resorption; small, geographic areas of hyaline cartilage are replaced by loose-textured, cellular fibrous tissue (×210).D: Early subchondral cystic degeneration; a small true cyst, filled with mucoid material, has a fibrous border. New bone formation is seen in the adjacent marrow (×90). E: Subchondral microfractures (arrows) of the femoral head in early osteoarthritis. Note proliferative callus (×70). F: Advancing ossification front has obliterated all but remnants of original articular cartilage (arrows). Reparative fibrocartilage occupies joint surface (×70).
Focal Chondromucoid Degeneration
Bennett and colleagues (32) first concluded that focal swelling of the cartilage matrix associated with increased affinity for hematoxylin constituted the initial event in the process of OA. This superficial mucoid transformation is associated with an increased number of chondrocytes adjacent to the alteration (33). This change is prominent in the precocious OA variant of the patellofemoral joint (chondromalacia patellae).
Some differences have been described between the histology of chondromalacia and progressive OA of older adults (34). Some authors have gone as far as suggesting that chondromalacia patellae without malalignment does not ordinarily progress to clinical OA (35).
Focal Loss of Metachromasia
Loss of metachromatic staining material, presumably chondroitin sulfate, from all but the deepest portion of the radial zone of articular cartilage has been proposed as a histologic counterpart of chondromalacia leading to OA (5). Decreased metachromasia is accompanied by a loss of affinity for hematoxylin, in contrast to the view of Bennett and colleagues (32). Quantitative and qualitative changes in matrix protein polysaccharides accompany the loss of metachromasia (36). Furthermore, severity of histologic change in cartilage correlates with proteoglycanase activity in human OA (37,38,39,40), and increased amounts of proteoglycan fragments circulate in plasma in OA (41, 42) as well as in chondromalacia patellae (43).
Proliferation of Chondrocytes
Small clusters of chondrocytes are common at the margin of minute fissures in the surface of the cartilage. These


chondrocytes (44) have apparently proliferated in response to the dehiscence of the tissue (Fig. 108.2). The preponderance of evidence supports focal mitotic activity as the source of the increased cellularity in these so-called chondrons (45, 46). Tetraploidy and unstable DNA also have been described in chondrocytes associated with osteoarthritic erosions (47), as have somatic mutations, particularly involving chromosome 7 (48). Whether these changes in DNA are involved in the pathogenesis of OA is unclear. However, in one recent study, the S-G2 index (a marker of proliferation) was much higher in severe or moderate stage OA than in mild stage disease (49), providing further evidence that proliferation is linked to matrix damage in progressive OA.
Weichselbaum Lacunar Resorption
Focal dissolution of matrix by chondroclastic cells in cartilage lacunae was once regarded as a specific feature of OA (Fig. 108.5C) but is more characteristic of RA (see Chapter 53). Evidence that cytokines (37, 38), particularly interleukin-1 (IL-1), can stimulate chondrocytes to release matrix-destroying proteases (50, 51) supports the observation that lacunar resorption is a significant pathologic process in cartilage destruction, regardless of disease specificity. Also, evidence has been presented that chondrocytes in OA are more sensitive to IL-1 action because of increased receptor density (52).
Diminution of Chondrocytes
Once adulthood is reached, the unit number of chondrocytes changes little in articular cartilage with simple aging uncomplicated by disease (53). In contrast to localized chondrocyte proliferation associated with fibrillation (44), diffuse chondrocyte loss, as identified by empty lacunae, is frequently found in all layers of articular cartilage in OA. Relics of disintegrated cells are often seen associated with microscars. Similar changes have been described in experimental (5) and spontaneous (54) animal OA. As a possible explanation for these histologic observations, increased numbers of apoptotic chondrocytes have been demonstrated in OA (6,7,55,56). Apoptotic chondrocytes, as defined by a variety of immunohistochemical techniques, are associated with degenerative changes in adjacent cartilage (7,57,58,59) and with abnormal patterns of calcification in articular cartilage (60) and subchondral bone (56). Whether this calcification is directly related to the remodeling of the calcified cartilage that is a consistent feature of OA (4,14,15,16) has not been established. However, apoptosis has also been observed in osteophyte cartilage in OA (61). The relationship of these apoptotic changes to chondrocyte death induced by abnormal pressures in experimental models (4) is at present unclear.
Fatty Degeneration
Fine fat deposits in the interterritorial matrix represent an early degenerative change in cartilage; these may become larger, forming coarse droplets at the “capsule” of the chondrocyte. The content of triglyceride and complex lipids increases with age in the cells and in cartilage matrix even before fibrillation. Similar lipid degeneration has been described in osteoarthritic joint capsular tissues that have undergone nodular chondroid metaplasia (62). Increased arachidonic acid, the precursor of prostaglandins, is confined to the tangential layer (5). Prostaglandin release from osteoarthritic cartilage has been described (63), as have qualitative and quantitative changes in gangliosides (64). Some have concluded that generalized OA could be in part the result of altered lipid metabolism (65), but this goes beyond present evidence. However, bone marrow mesenchymal cells from OA patients have shown reduced adipogenic activity (66).
Alteration of Collagen Fibrils
In aging articular cartilage, the general architecture and appearance of the collagen fibrils are preserved, although looser packing and occasional fragmentation are sometimes seen in the superficial layers. The aforementioned microscars increase in number as OA evolves. Some of the fragmented fibrils in these areas have a larger diameter. A progressive radial reorientation of the collagen fibrils has been noted by electron microscopy and by x-ray diffraction. Although amianthoid (asbestos-like) degeneration of the matrix has been described as a late feature of OA (67), this process typically occurs in costal and other extraarticular cartilage rather than in joint cartilage. In progressive OA, unraveling and disaggregation of collagen fibrils is usually apparent (68), although this may be secondary to changes in matrix protein polysaccharides.
Gross Changes
Localized areas of softening of the cartilage are associated with a fine, velvety disruption of the surface. In these areas, one sees dehiscence of the cartilage along the axes of the matrix collagen fibers. In disruption confined to the surface tangential layer, the process is referred to as flaking; when the process extends to the deeper radial layer, it is described as fibrillation (Fig. 108.2). Because these minute discontinuities in the surface are readily stained grossly by India ink (5), they lend themselves to quantitative study. Abrasion of the fibrillated cartilage results in progressive erosion that may expose the underlying bony cortex (Fig. 108.1). The sites of predilection for destruction of the joint surface are those subject to greatest load bearing or shearing stress. Earliest fibrillation, however, is often present in regions with presumably low compressive stress, such as

the infrafoveal portion of the femoral head. In the patella, the central facets are the sites most prone to erosion (5). Although not a weight-bearing joint, the patella is subjected to enormous loads by leverage when the knee is flexed, such as in stair climbing or squatting. Perhaps as a consequence, a normal patellar articular surface is rare in mature adults (69). Repair cartilage, often of fibrocartilaginous type, is demonstrable grossly owing to its bosselated, knobby appearance. As OA progresses, little original hyaline cartilage may remain. If osteophytes are present, these will be covered by a mixture of fibrocartilage and fibrous tissue. Hence, the translucent qualities of healthy hyaline cartilage will be absent.
Late Histologic Changes
In fibrillated regions, continuity of the surface of the articular cartilage is disrupted. The height of the fronds is in the range of 20 to 150 mm (4). Ground-substance metachromasia is reduced, and the matrix has a fibrillary, disheveled appearance. Birefringence of collagen fibrils is increased. Clusters of chondrocytes, long known as brood capsules, are located close to the margins of the clefts (Fig. 108.2B). The proliferative and proteoglycan-producing activities of these cells have been amply documented both in vivo and in vitro (45,46,70). Little or no collagen is seen within the clones, and it must be presumed that chondrolytic enzymes, including collagenases (37,71,72,73), have been generated to remove matrix to make room for the new cells. As an example, type VI collagen disappears from the pericellular matrix in these areas (74).
The ultimate fate of these cellular clusters has been the subject of debate. Although small areas of necrobiosis are seen, these are not necessarily limited to the cell clusters. Focal proliferation of chondrocytes is also seen in deeper areas when severe lesions have disrupted the surrounding matrix. The matrix in these areas has a pale, myxoid appearance. Evidence indicates that type II collagen degradation products are present in osteoarthritic cartilage (75), along with enhanced synthesis of type II collagen. Some immunohistologic studies have described a class switch to production of type I and III collagens occurring as osteoarthritic changes progress (76, 77). These collagens are predominantly deposited in the pericellular matrix (76, 77). In these proliferative clusters, type X collagen has also been identified and provides further evidence of chondrocyte hypertrophy (78, 79) in osteoarthritic cartilage. Quantitative polymerase chain reaction (PCR) measurements of gene expression of the various collagens in OA do not, however, support a general shift in cellular phenotype with advancing OA (80).
Suppression of matrix protein synthesis has been identified in the superficial zones of osteoarthritic cartilage (81). However, increases in biosynthetic activity of articular chondrocytes, even at some distance from the sites of overt damage to the cartilage, also have been described (5). Part of the confusion relates to the stage of OA from which cartilage has been obtained for study. In advanced lesions, the bulk of the cartilage is of a new and immature type. Thus, reparative cartilage typically is composed of a mixed hyaline and fibrocartilaginous tissue with more conspicuous fibrillary collagen and less intense staining for proteoglycan. Osteophytes are covered by a combination of a fibrocartilaginous surface with areas of overt fibrous tissue. In many cases, secondary degenerative change and fibrillation are then superimposed on the reparative cartilage, further complicating the histologic appearance. The histochemical and immunocytochemical features of the matrix are thus heterogeneous (5), reflecting the local pathology of that site.
In addition to changes described in the preceding paragraphs, degenerative changes in the basal calcified zone of articular cartilage are also a consistent feature. The junction of this calcified zone with the deep radial zone of articular cartilage is demarcated by an undulating hematoxyphilic line known as the tidemark. Reduplication of the tidemark (Fig. 108.5A) is exaggerated in the vicinity of the fibrillated cartilage and, more remotely, at the margin of the joint (5). Several types of degenerative change in the calcified zone have been described (14, 82). Calcium-containing crystals are deposited in the territorial matrix of the adjacent chondrocytes as forward remodeling occurs. These crystals appear as basophilic granules in demineralized sections (Fig. 108.5B) and within or around matrix vesicles in electron micrographs (14). The numbers and calcium-precipitating activities of matrix vesicle enzymes are increased in osteoarthritic cartilage compared with normal control articular cartilage (83). The association of calcification and matrix vesicles with apoptotic chondrocytes (60) in OA may be a factor in the remodeling of the basal zone. Osteonectin, a protein identified with early stages of calcification, was detected in chondrocytes above the calcified zone in osteoarthritic, but not in normal, cartilage (84). Osteopontin, a sulfated phosphoprotein normally expressed in epiphyseal plate chondrocytes, has also been identified in deep zone chondrocytes in OA (85). The process of pathologic advancement of the calcified zone contributes to bone production that consumes the articular cartilage from the subchondral aspect (Fig. 108.5F) and is an important component of the process leading to exposed bone (eburnation) at the joint surface.
New bone formation occurs in two separate locations in relation to the joint surface: in exophytic growths at the margins of the articular cartilage and in the immediately subjacent bone marrow (Fig. 108.4). Marginal osteophytes have two patterns of growth. One consists of a protuberance into the joint space, whereas the other develops within capsular and ligamentous attachments to the joint margins. In

each circumstance, the direction of the osteophyte is governed by the lines of mechanical force exerted on the area of growth, generally corresponding to the contour of the joint surface from which the osteophyte protrudes. The osteophyte consists in large part of bone that merges imperceptibly with the other cortical and cancellous tissue of the subchondral bone. The osteophyte is capped by a layer of hyaline and fibrocartilage continuous with the adjacent synovial lining. In advanced lesions, the landmarks are obliterated because the osteophytic surface itself undergoes degeneration, and fibrous tissue may cover the marginal portions of the osteophyte.
On the femoral head, proliferative tissue frequently occupies the fovea of the ligamentum teres and extends down along the femoral neck to form buttress osteophytes. These buttress osteophytes may obscure the normal boundary between the femoral head and the femoral neck. In most surgical specimens of the femoral head removed for OA, the combination of degenerative and proliferative activity has destroyed virtually all of the native articular cartilage.
The proliferation of bone in the subchondral tissue is most marked in areas denuded of their cartilaginous covering (5). In these regions, the articulating surface consists of bone that has been rubbed smooth. The glistening appearance of this polished sclerotic surface suggests ivory, hence the name eburnation. Nubbins of newly proliferated cartilage usually protrude through minute gaps in the eburnated bone. Proliferation of new bone at these sites is an integral part of eburnation (16, 86). Dense bone at the articular surface is accompanied by marked sclerosis of the underlying subchondral bone (87). Morphometric studies have confirmed the histologic impression of thickened trabeculae in the subchondral bone (25), and dual x-ray absorptiometry has established increased bone mineral content (24). These changes are more marked with increasing severity of OA.
“Cystic” areas of rarefaction of bone are commonly seen immediately beneath eburnated surfaces in the hip (Fig. 108.5D). Such structures are much less frequent in other joints. The cystic areas occur on both femoral and acetabular sides of the joint. The lesions are most frequently present on the superolateral weight-bearing surface. In severe instances, they may involve other regions of the hip as well (5). In a few cases, these lesions appear roentgenographically before narrowing of the joint space has given evidence of cartilage destruction. The lesions only infrequently contain pockets of mucoid fluid and thus are not truly cystic. The trabeculae in the affected areas disappear, and the bone marrow undergoes fibromyxoid degeneration. Fragments of dead bone, cartilage, and amorphous debris are often interspersed within them. Macrophages found in these cysts can differentiate into osteoclasts promoting enlargement (88). In time, the entire area is encircled by a rim of reactive new bone and compact fibrous tissue (Fig. 108.3B). Minute gaps in the overlying articular cortex, resulting from microfractures, are commonly seen at the apex of the pseudocysts (Fig. 108.3). These findings are consistent with an intrusion of pressure, if not of synovial fluid, from the joint cavity through a defect in the articular cortex into the subchondral bone marrow. Intraarticular pressures exceeding 1,000 mm Hg occur in hip joints with effusions (5). The increased pressure is dissipated radially into the adjacent bone marrow, compressing the medullary blood vessels and thereby leading to the retrogressive changes. This mechanism is not contradicted by observations that the intraosseous pressure is normal in osteoarthritic femoral heads at the time of arthroplasty. In these specimens, bulk pressures, rather than localized gradients, are measured. Furthermore, remodeling has compensated so that cysts are much less prominent in advanced lesions subjected to total hip arthroplasty. The “punched out” lesions observed radiographically in gout and the bone “cysts” in hemophilic arthropathy correspond pathologically to the pseudocysts in OA, except that they have specific exudates within the pseudocysts that are absent in OA.
New bone formation also occurs in the form of focal enchondral ossification at the base of the articular cartilage (82). Such metaplasia is a component of the remodeling process by which bone is added to a portion of the articular cortex while other areas of the joint undergo resorption of bone. During the period of active skeletal growth, this osteochondral junction underlying the calcified cartilage zone has an epiphysis-like function that permits actual enlargement of the bone through sequential ossification of the calcified cartilage. In adults, the interface between calcified and noncalcified hyaline articular cartilage is demarcated by a thin, undulating, hematoxyphilic line (the tidemark; Fig. 108.5A). In older persons, this line is usually transformed into several parallel discontinuous ones whose presence is clear evidence of the progression of the calcification front into the articular cartilage (14). The possibility that the progression of the basilar calcification might lead to thinning of the articular cartilage (senile atrophy) in the absence of pathologic new bone formation in OA has not been substantiated (5).
The role of osteonecrosis in the generation of OA has been the subject of considerable discussion. Much of the deformity in symptomatic OA results from collapse of the joint surface. Localized areas of necrosis are seen frequently in this location (Fig. 108.4), and occlusion of minute intramedullary arteries has been demonstrated in the past by angiography (5). However, distinctive histologic differences have been noted between subchondral vessels of resected femoral heads in osteonecrosis and OA (89).
Not infrequently, small secondary infarcts of eburnated bone are seen in surgically resected OA femoral heads (5,9,90). These changes are more frequent in severe OA (91), in which, in a recent study, 38.2% of 1,007 OA femoral heads demonstrated secondary osteonecrosis. A small percentage demonstrated deep, wedge-shaped infarcts, similar to those of primary osteonecrosis (9). In the past, extensive morphologic studies have led some to suggest that osteonecrosis might be involved in all cases of OA

of the hip, but this clearly exceeds the evidence (91). Hypercoagulability demonstrated in some patients with primary OA might also be operative in this complication (92). Nevertheless, rapidly destructive variants of OA are frequently accompanied by subchondral bone necrosis (93). Some patients with progressive OA have demonstrated sterile subchondral inflammatory foci histologically distinct from both pseudocysts and secondary osteonecrosis (94). These may also contribute to collapse of the articular surface. Primary and secondary osteonecrosis of the femoral head appear pathologically distinct from collapse of the articular surface owing to subchondral insufficiency fracture, another recently described entity (95, 96).
The frequency of chondrocalcinosis, especially in the older age group, has generated divergent opinions regarding the relationship of this condition to OA (see Chapter 116). Confusion over the exact role of chondrocalcinosis in OA is enhanced by the fact that calcium pyrophosphate dihydrate (CPPD) deposition disease, the most common form of chondrocalcinosis, occurs in both primary and secondary variants. The latter form of the disorder is associated with a wide range of conditions, including hemochromatosis, ochronosis, hepatolenticular degeneration, hyperparathyroidism, acromegaly, and hemophilic arthropathy. The primary form of CPPD is frequently found in association with OA, especially in older patients (97). However, chondrocalcinosis is also exceptionally common as an asymptomatic phenomenon in the knee joints of elderly persons (98). The experience of Sokoloff and Varma (99) indicates that meniscal chondrocalcinosis is present in roughly half of knees treated surgically for OA after 68 years of age. The risk for meniscal calcinosis in surgically removed knees was sixfold that of an age- and sex-adjusted postmortem population. A study of synovial fluid from patients undergoing total knee arthroplasty for OA demonstrated CPPD or basic calcium phosphate (BCP) crystals (or both) in 60% (100). In another study using atomic emission spectroscopy, calcium content of menisci correlated strongly with degeneration in OA (101). By contrast, CPPD crystals are rarely found in femoral heads removed for OA. Chondrocalcinosis also is relatively infrequent in fractured hips before the age of 85 years (5). Why the meniscus is the predominant site of involvement in OA of the knee, while the hyaline articular cartilages are largely spared, remains a matter of conjecture (102). Ordinarily, the deposition of CPPD in the osteoarthritic knee engenders no inflammatory reaction. Deposits of lipid are associated with CPPD deposits and are also present in the adjacent chondrocytes (5). The role of this lipid material in the deposition of crystals is unclear. In contrast to the articular chondrocytes that degenerate at sites of CPPD crystal deposition (103), meniscal fibrochondrocytes apparently remain metabolically active in the presence of these crystals (5). Several observers have noted that “joint mice” are more frequent in OA specimens with chondrocalcinosis than in those without crystal deposition.
In a recent study, serum nucleotide pyrophosphohydrolase activity was increased in patients with OA whether or not CPPD crystals were present in joints (104). To complicate the situation further, some cases of OA harbor CPPD crystals that are too small to be resolved by conventional polarizing microscopy (105). This leads to the possibility that the role of CPPD crystals in the pathogenesis of OA might be underestimated despite preoperative synovial fluid examination in patients undergoing total knee arthroplasty revealing a 60% prevalence of calcium crystals (100). Because apoptotic chondrocytes produced pyrophosphate in one study (60), a common basic mechanism of chondrocyte injury may be operative whether or not microscopically verifiable CPPD crystals are produced as the end result.
Another form of radiologic chondrocalcinosis is associated with deposition of BCP (apatite) crystals (see Chapter 118). The observation that BCP crystals are quantitatively associated with more severe cases of OA of the knee has promoted the theory that BCP crystals might be released from abraded eburnated surfaces (5), but this has not been established. However, BCP crystal deposition is characteristically associated with more severe arthropathy and occasional Charcot-like breakdown of joints. Unlike CPPD crystals, most of which can be seen with conventional polarizing microscopy, BCP crystals are too small (105) and require specialized techniques such as alizarin red staining of centrifuged synovial fluid for detection. Thus, it is difficult to establish the presence of BCP crystals in severe OA unless a specific search is employed.
Soft Tissue
During recent years, the inflammatory manifestations of OA have stimulated considerable discussion. By definition, OA is inherently a noninflammatory condition, but some degree of synovial villous hypertrophy and fibrosis is seen in most symptomatic cases (Fig. 108.6). A moderate focal chronic synovitis has been described in about one-fifth of surgically resected specimens (5). This synovitis is characterized by hyperplasia and enlargement of synovial lining cells and by the presence of lymphocytes and mononuclear cells (106). The infiltrate is generally mild and heterogeneous with respect to immunopathology (5). Polyclonal B lymphocytes compose part of the infiltrate, and extracellular deposits of complement component C3 also have been described (5). Fibronectin is deposited in exudative foci (5). Other tissue changes, such as hemosiderin deposition, foreign body reaction to joint detritus, and xanthoma-like changes around fat necrosis, may be seen. The stage of any particular case may be important because the synovial response has varied from an early inflammatory pattern in mild cases to a late fibrotic stage in advanced disease (107).

In a few cases, the synovial inflammation may be so pronounced as to resemble RA. Immunopathologic studies, however, show significant qualitative differences in the infiltrates characterizing the two diseases (108). Synovial macrophages are more frequent in RA (5). The mean nuclear density of cellularity is higher in RA, and immunoglobulin-producing plasma cells, common in RA, are rare in osteoarthritic synovia (5). Immunoblasts are not seen in the synovial fluid in OA (5). Helper-to-suppressor (CD4/ CD8) ratios vary between upper and lower synovial regions in RA but are uniform throughout the synovium in OA (5). Although CD4+ T cells are more numerous in RA synovium (109), those in OA also expressed an activated phenotype (110), indicating possible immune mechanisms. Natural killer cells with CD16/56+ phenotype are more frequent in OA than RA (111). In line with this latter observation, natural killer (NK) cell-associated granzyme expression is also increased in osteoarthritic synovial specimens (112). Mast cells occur in increased numbers in the synovium of patients (113) with OA and in one report were actually more numerous than in synovium from RA patients (114). Mast cells in OA are also of a tryptase-positive, chymase-negative phenotype associated with inflammation in other conditions (115).
FIG. 108.6. Synovial hypertrophy in severe osteoarthritis. The patient is a 63-year-old man whose left knee had been enlarged for 23 years following an automobile accident. A: A massive osteophyte (arrow) is seen at the medial border of the articular surface. The adjacent synovial tissue has undergone prominent papillary thickening. B: Histologically, the villous processes are made up of compact tissue not infiltrated by inflammatory cells (hematoxylin and eosin stain, original magnification ×16.)
Taken as a whole, these findings clearly differentiate the cellular inflammatory responses in OA from those in RA. However, the presence of inflammation in many cases of OA is undeniable. Epidemiologic studies have linked progression of early radiologic OA of the knee to higher serum levels of the inflammatory marker C-reactive protein

(116). Similar low-grade inflammatory responses occur in other joint diseases of nonphlogistic origin such as those accompanying acromegalic, ochronotic, and neuropathic arthropathies.
Autosensitization to joint detritus is an attractive consideration in the genesis of the inflammatory reaction. A so-called detritic synovitis is observed in many cases of severe OA requiring joint replacement, but is much less common in early cases treated with arthroscopic surgery (117). The synovial reaction to osteocartilaginous fragments not only causes inflammation but also may result in generation of cytokines and release of degradative enzymes such as cathepsin K by synovial macrophages (118). Such cytokines are associated with synovial inflammation in OA (119). Detritic synovitis also provides a possible mechanism for autosensitization to cartilage structural proteins. In fact, cartilage-derived molecules are present in sera of patients with OA (39,42,43,120).
Additional supportive evidence for autosensitization is the finding of autoantibodies directed against both native and denatured type II collagen in 50% of OA cartilage extracts (5). Analysis of DNA restriction enzyme patterns of T lymphocytes from osteoarthritic synovia shows an oligoclonal pattern of T cell receptor b-chain gene rearrangements, suggesting a response by a limited number of T cell clones (121), as might occur in a response to released indigenous articular cartilage molecules. Peripheral blood lymphocytes from OA patients are highly reactive in proliferation assays against human cartilage link protein (122). Evidence for an immune response in certain types of OA also includes the finding of immunoglobulin-complement complexes deposited in the superficial zones of osteoarthritic articular cartilage (123). Whether the deposits in OA are a primary phenomenon or merely a response to matrix damage is not known, but autoantibodies associated with deposition in articular cartilage are a recognized finding in generalized, nodal OA (124).
As previously discussed, another possible mechanism for the inflammatory changes in the synovium involves responses to CPPD or BCP crystals. Both species occur in the synovium, cartilage, and synovial fluid. Crystals have been proposed as one mechanism for induction of cytokine release. IL-1 stimulates synovial cells and articular chondrocytes to release neutral proteases capable of destroying cartilage matrix (52). Studies have also implicated tumor necrosis factor (TNF) in the process (125).
Other soft tissues also participate in OA. Minute tears in capsular tissue appear as slender, fibrovascular seams disrupting the principal axes of the collagen bundles. Secondary osteochondromatosis occurs at times but is much more characteristic of neuropathic arthropathy than of OA. In the hip joints, the ligamentum teres commonly disintegrates. In the knee joint, the cruciate ligaments and menisci also become frayed. Substantial clinical (126,127) and experimental (5) evidence suggests that meniscectomy leads to OA, especially when the meniscus is removed because of a degenerative (102), rather than a traumatic, (128) tear. Furthermore, postmeniscectomy OA of the knee shows a strong association with OA of the hands and opposite knee (129). Degeneration is more severe, however, on the operated side and is independent of age and sex. This study suggests that a predisposition to primary OA influences the development of secondary degeneration and makes a clear distinction between these two subsets of the disease more difficult. Others have found evidence of increased prevalence of generalized OA in individuals with severe knee (5) or hip (130) OA. Although meniscectomy can precipitate OA, underlying or systemic factors may contribute to its severity.
Among other soft tissue changes, fibrillation and fibrosis of the synovial surface and even mild cartilaginous metaplasia of the patellar tendon have been described. Lipochondral degeneration is seen in hip capsular tissues that have previously undergone nodular chondroid metaplasia (62). Amyloid deposits have been reported in the joint capsule in OA (131), but they also occur in joint capsules and articular cartilage of normal joints and in the intraarticular discs of older individuals (5). Serum amyloid A–activating factor increases expression of matrix metalloproteinases in OA cartilage (132). Amyloid or amyloid-like materials, however, have been described in several different tissues of aged individuals (5). Any claim for specificity for amyloid in cartilage requires a considerably more discriminatory technique than screening by green birefringence after Congo red staining, the usual histochemical method. Destructive amyloid arthropathy is characteristic, not of OA, but of dialysis-associated osteoarthropathy due to β2-microglobulin retention (133).
A progressive increase in the amount of fibrous tissue separating the synovial capillaries from the joint space has been described as an age-related finding. It is unlikely that this condition interferes with the nourishment of the cartilage, but distinction from amyloid must be made on histologic grounds. Focal hyaline sclerosis of minute vessels is a common finding even in joint tissues of young individuals (5). It is unlikely that this finding is directly related to OA. Periarticular muscle undergoes atrophy, with type 2 myofibers being affected primarily (5).
Biochemical Pathology of Osteoarthritis
Understanding of the biochemical changes in OA has rapidly advanced in recent years. The interpretation of biochemical data is subject to the same problems created by the heterogeneous nature of degenerative and reparative responses as is histology. When living tissue is required for metabolic studies, the source is frequently surgically resected femoral heads. Sampling of reparative rather than degenerated native cartilage from such specimens probably accounts for the major discrepancies noted between biochemical data from articular cartilage obtained from necropsy (5) and that from surgically resected specimens.

Similar variability can be introduced by using fractured femoral heads as a source of control cartilage because such tissue undergoes secondary changes after injury (5). The knee joint is recommended for study by some authors for this reason. Although the destructive process commonly is unicompartmental, the other condyle is not immune from the complex processes that are in part proliferative. Moreover, degradation of type II collagen, a key step in the chain of events in OA, quickly follows anterior cruciate ligament (ACL) rupture (75). Thus, cartilage obtained by arthroscopy during ACL repair would not be normal. Finally, biochemical properties in nonarticular cartilages show significant differences in some parameters (5). Thus, such findings are difficult to extrapolate to the pathobiology of articular cartilage.
The cellular and molecular biology of cartilage collagens also provides insight into the changes in structural proteins occurring in OA (see Chapter 9). Type II collagen accumulates in the matrix in early OA (5), accompanied by increased synthesis of the molecule (134). Although type II collagen continues to be produced in osteoarthritic repair cartilage, types I and III collagens are also demonstrated in more advanced cases of OA (76,77). Evidence is accumulating that changes in the distribution of minor collagens found in articular cartilage (types VI, IX, and XI) may predispose to breakdown of the principal collagen, type II (5). Type VI collagen is normally found in very small amounts in the pericellular domains (5) of normal cartilage but increases significantly in the interterritorial matrix in OA (74). Type X collagen, normally associated with hypertrophic epiphyseal chondrocytes, also appears in osteoarthritic cartilage (78). Cartilage matrix protein synthesis is suppressed in the more superficial zones of cartilage in OA as well (81). Immunohistochemical techniques are necessary to localize collagens and other proteins to specific areas because biochemical findings from fibrillated articular cartilage may differ considerably from those in nondegenerated areas. This is particularly so when cartilage from osteophytes is examined (135).
OA occurs widely in the vertebrate kingdom, regardless of the position of the species in the taxonomic scale. Osteophytic lesions, sometimes leading to ankylosis, were common in certain giant dinosaurs 100 million years ago (136). Degenerative spinal disease occurs in large felids (137). OA has been observed in large and small mammals, in animals that swim (cetaceans) rather than bear their weight on their extremities, and also, to a mild degree, in birds (138). It is of considerable economic importance in livestock commerce, the horse racing industry, and veterinary practice.
In small laboratory animals, it has been possible to study a number of pathogenetic concepts of OA. The importance of genetic factors has been established in mice. The inheritance appears to be polygenic and the overall behavior recessive. No evidence suggests major sex linkage, although male mice consistently develop more severe OA than do females. Obesity is not an important factor (4). In laboratory rodents, the knee and elbow joints are commonly affected severely, but the hips rarely. That inheritable biochemical defects are major factors in the development of OA is suggested by the frequency of osteoarthritic lesions in blotchy (BLO) mice carrying a mutant gene leading to inadequate cross-linking of collagen (139). Transgenic mice carrying deletions in the type II collagen gene (140) also develop OA. In the STR/ORT mouse, widely studied for its predisposition to OA (141,142,143), one report attributed knee joint changes to spontaneous patellar subluxation (5). Surgical containment of the subluxation prevented the development of OA. Others have postulated that the OA variant in male STR/ORT mice is due to chondroosseous metaplasia in paraarticular structures (144). Susceptibility to OA in these animals seems attributable to abnormal mechanical loading rather than to a cartilage metabolic abnormality. Although impressive, these data are difficult to reconcile with Sokoloff’s (4) observations that lesions in STR/IN mice were not confined to the knee but were more generalized. One study suggested that synovial acute and chronic inflammatory infiltrates of the patellofemoral joints in STR/ORT mice are so prominent that the use of this strain as a model of human OA should be questioned (141). More generalized cartilage degeneration has been observed in guinea pigs as well (145), especially in the Dunkin-Hartley strain (146).
The genetic aspects of OA are also manifested by variable susceptibility of different species to its development. Rats, for example, are generally resistant, whereas another rodent, Mastomys natalensis, develops a severe generalized OA by the age of 2 years. Another desert rodent, the Mediterranean sand rat (Psammomys obesus), develops a severe degenerative spondylosis with disc thinning and anterior vertebral hyperostosis reminiscent of human hyperostotic spondylosis (147). Genetic contributions to OA are also seen in certain breeds of cattle and swine. The fundamental pathogenetic problem is whether these genetic factors are local and articular, related to the configuration and mechanical forces exerted on the joint, as in the dysplastic hips of German shepherd dogs (148,149), or whether they are more generalized metabolic properties of the articular tissues. Such concerns complicate the use of spontaneous animal models of OA as paradigms of the human disease as well as influence the choice of various species and strains as subjects for experimental induction of OA.
Numerous animal models of OA have been developed. These have been extensively summarized by Smith and Ghosh (150). Some directly damage articular cartilage. Small surgically induced defects do not usually produce

OA. Larger defects deforming the joint contour, however, may result in OA, and direct damage to cartilage by heat, freezing, or other physical agents may also cause OA (5). Synovitis induced by intrasynovial instillation of irritants may eventuate in osteoarthritic changes, but these agents may have acted on the cartilage as well (5). Subluxation of the patella and hip dislocation have produced early remodeling and later OA. Surgical interruption of the cruciate ligaments, usually the anterior, is frequently used to induce OA in a relatively short time in both dogs (12,151) and rabbits (152,153). Partial meniscectomy is used in a similar way in rabbits (11,13,133,154). Meniscal transection in rats (155) and valgus tibial osteotomy in dogs also induce OA (156,157). Prolonged compression of the articular cartilages for even a few days causes death of chondrocytes, which may be followed by OA. This sequence is presumably due to prevention of percolation of interstitial fluids into the cartilage (5). Restriction of joint motion was found in some studies to lead to degeneration resembling OA, but one problem with such studies is that it is difficult to restrict joint mobility without altering joint loading (158). Others have found that motion in the absence of weight bearing does not maintain normal articular cartilage (4). In humans immobilized for long periods, contracture and fibrous ankylosis develop rather than OA (4). A similar pattern is seen in immature spastic cerebral palsy (159), although OA-like disease develops in rats that have undergone selective denervation of knee joint (160). The lack of correlation between the experimental model in rats and human disease may be due to the contribution of the dislocation of the proximal femur seen in cerebral palsy (159).
Repetitive impact loading has been used to induce degenerative changes resembling early OA in animal models (161). Intraarticular instillation of abrasive particles such as Carborundum induces superficial degeneration of articular cartilage and a foreign body reaction in the synovium. The similarity to the pattern of synovitis induced by cartilage detritus is apparent (117). Enzymes, such as bacterial collagenase, induce degenerative changes and osteophyte formation when injected into mouse joints (162). A variety of experimental manipulations that directly affect the viability of articular chondrocytes or the integrity of the surrounding matrix can result in OA-like disease. Other procedures placing abnormal mechanical stresses on joints can induce remodeling of articular contours (163). The application of any of these models to human disease requires discretion.
Degenerative changes in the spine affect two discrete, but interrelated, articular systems: the amphiarthroses (discs) and the diarthrodial (zygapophyseal or facet) joints. The former develop qualitative and quantitative changes (164) with increasing age, characterized by loss of ground substance metachromasia (5) and matrix water content, increased vascularization of the hyaline cartilage end plates, and disorderly and attenuated collagen fibrils (5). In many individuals, such degeneration leads to annulus fibrosis tears (165), disc herniation, and breakdown of the cartilaginous end plates with the development of spinal osteochondrosis (5). The prominent osteochondral osteophytes (166) that develop in this condition have led to the wide use of the term spondylosis deformans. Osteophytes are most commonly found at the T-9 to T-10 and L-3 interspaces (167). However, the cervical spine is very susceptible to the clinical manifestations of this condition (5).
The spinal diarthrodial joints develop osteoarthritic changes similar to those in peripheral joints. This distinction in terms should not lead to the conclusion that the two processes are unrelated because the pathologic findings in the joints are similar. The nucleus pulposus becomes fissured and deformed, and similar cracks appear in the annulus fibrosus (165). Fibrillary disintegration of the hyaline cartilage plates, through which the disc is attached to the vertebral bodies, cannot be distinguished histologically from the changes in diarthrodial OA (5). Eburnation of the subchondral bony plate develops in like manner. Marginal osteophytes arise under the mechanical stimulus of horizontal pulsion of the annulus fibrosus and its periosteal attachments as a result of collapse and spreading out of the nucleus pulposus. Traction forces by spinal muscles on the tendinous insertions in this region also have been implicated in this disorder. Furthermore, intervertebral disc disease shifts a greater proportion of the compressive and torsional loads on the apophyseal facet joints (5), contributing to further degenerative changes.
Another feature of spinal osteochondrosis is the development of nodules of cartilaginous and fibrous tissue beneath the subchondral plate of the vertebral bodies (Schmorl nodes). These nodules are usually attributed to the displacement of a nucleus pulposus into a vertebral body (5). These islands are often surrounded by a shell of bone and, except for their greater content of cartilage, are reminiscent of the subchondral cysts in osteoarthritic peripheral joints. Schmorl nodes are not a pathognomonic feature of vertebral osteoporosis because they occur commonly in degenerative disc disease not associated with osteopenia. Several studies have confirmed that degenerative disc disease and osteochondrosis are positively associated with increased bone mass (168,169,170). A similar relationship has been described for OA of the hands (171).
Although the marginal osteophytes develop most often on the anterolateral aspects of the vertebral bodies, posterior osteophytic protrusions occur and may affect the spinal cord and its roots. In the cervical region, spondylosis constitutes a hazard among older patients because of the resultant spinal stenosis. In the lumbar region, spinal stenosis develops with encroachment of osteophytes on the spinal canal and is frequently due to degenerative spondylolisthesis associated with OA of the apophyseal joints. Osteophytes in the Luschka (uncovertebral, neurocentral) joints

have been shown by anatomic and angiographic means to compromise the neighboring vertebral arteries. The narrowing of the vascular lumen is most marked during rotation of the head and provides the basis for the posterior cervical sympathetic or Barré-Lieou syndrome.
OA does not characteristically lead to ankylosis; however, in at least three forms of segmental disease of the senescent spine, bony bridges unite the vertebral bodies. The proclivity for ankylosis may be related to the inherent limited mobility of the intervertebral disc. These specific forms of degenerative spinal disease leading to ankylosis are discussed subsequently.
Hyperostotic Spondylosis
Of the vertebral ankylosing disorders, the best known entity goes by several names: hyperostotic spondylosis, senile ankylosing hyperostosis of Forestier and Rotes-Querol, and spondylorheostosis. Hyperostotic spondylosis nominally is distinguished from ordinary spondylosis by the absence of disc degeneration (5,172). The distal thoracic spine is the site of predilection (173). The ankylotic bridges are located on the anterolateral portions of the vertebral bodies and extend into the anterior longitudinal ligaments (Fig. 108.7). This appearance has often led to confusion with ankylosing spondylitis. However, ankylosing hyperostosis is not an inflammatory disorder, unlike the spondyloarthropathies. Ossification of the posterior longitudinal ligament is also frequently associated with vertebral hyperostosis (174), as is ossification of the stylohyoid ligament (175). In some instances, the vertebral lesion is accompanied by excessive osteophyte formation in peripheral joints, especially the pelvis, heel, elbow, and knee joints (173). From this feature comes still another term for this condition, diffuse idiopathic skeletal hyperostosis (DISH) (176,177,178). Currently, diagnosis is made on purely radiologic grounds because no tissue or serum markers exist. However, hyperglycemia is a common clinical finding in these patients (179). A possible relationship to relative excess of growth hormone has been postulated (180). Other studies have linked an increased likelihood of clinically palpable finger nodules (Heberden and Bouchard nodes) to DISH (181). Animal models of this disease exist in the Mediterranean sand rat (147) and the hyperostotic (twy/twy) mouse (182).
FIG. 108.7. Hyperostotic spondylosis in the thoracic spine of an elderly male. Unlike the lesions of ankylosing spondylitis (Marie-Strumpell arthritis), the vertebral bodies do not manifest a “squared” appearance. Ossification has developed in the intervertebral disks, and the disk space is also narrowed anteriorly. Ossification in the anterior longitudinal ligament has blended with a hyperostotic response of the anterior vertebral bodies forming a continuous bony bridge (×0.5). (Courtesy of Professor W. A. Gardner, M.D., University of South Alabama.)
Ankylosis, distinct from that of hyperostotic spondylosis, may accompany severe spondylosis in humans and other species. The disc space is narrowed. Destructive changes are present in the cortex of the anterior portion of the vertebral bodies (182). Dense new bone formation is seen in the anterior longitudinal ligament. The appearance suggests that the ligament is first avulsed from the osteophyte and then repaired.
Other Segmental Disease
Several patterns of dorsal protrusion and bridging of cervical vertebrae (posterior spondylotic osteophytes) may cause life-threatening cervical myelopathy (183). The relation of physiologic vertebral ligamentous ossification to the preceding disorder and to hyperostotic spondylosis is uncertain (174). It occurs in 7% of Japanese (184) and 0.3% of American adults (5). These lesions are asymptomatic in individuals with large spinal canals, but they require surgical decompression when spinal canals are small and myelopathy has developed (5). In women, ossification of the posterior longitudinal ligament of the spine has been associated with estrogen receptor and IL-1β gene polymorphisms (185).
Baastrup’s syndrome, an OA-like change that is due to bursitis between the distal portions of “kissing” lumbar dorsal spinous processes (5), is usually associated with severe spondylosis.
Heberden’s Nodes
Despite the relative antiquity of the description of Heberden’s nodes (2) and their frequency, comparatively little information is available on their histopathology, possibly because early lesions are seldom available (186). They usually manifest

as marginal osteophytes of the distal interphalangeal joints. In more advanced cases, these lesions are indistinguishable from those arising in osteoarthritic remodeling in other sites (Fig. 108.8). Ossific transformation of the tendinous insertion into the joint capsule creates the osteophytosis. In other instances, mucoid transformation of the periarticular fibroadipose tissue is associated with proliferation of myxoid fibroblasts and cyst formation. These types of Heberden’s nodes are usually associated with radiographically demonstrable distal interphalangeal osteophytes but not invariably so (187). These cysts, like the osteophytes, are not unique anatomic features of Heberden’s nodes. Indistinguishable changes may be present in other osteoarthritic joints and in other species. The process has certain morphologic similarities to ganglion formation or to cystic degeneration of the semilunar cartilages and to the subchondral pseudocysts of OA. Unilateral sparing from Heberden’s nodes after hemiplegia has been reported (188). This observation suggests the possibility of neurovascular contributions to the development of the lesion but does not exclude a biomechanical explanation. One study comparing groups of women with qualitatively similar manual tasks definitely related Heberden’s node formation to the quantitative use of the hands (189). The association of the paraarticular mucinous cysts of the distal interphalangeal joints with osteophytes has been emphasized because they are likely to recur after excision unless the osteophytes are also removed.
FIG. 108.8. Heberden node. The articular cartilage has completely disappeared from the surfaces of the distal interphalangeal joint. Bony osteophytes, directed toward the base of the finger, are present on the dorsal and palmar aspects of both articulating surfaces. Advanced osteoarthritic changes also are present in the proximal interphalangeal joint and form a so-called Bouchard node. (Hematoxylin and eosin stain, original magnification ×20.)
Erosive Osteoarthritis
The term erosive osteoarthritis has been applied to a disorder resembling OA in its predilection for the distal and proximal interphalangeal joints, but in which a distinct inflammatory component exists (190). A nonspecific, chronic synovial lymphocytic and mononuclear cell infiltrate is present. The nosologic status of the disorder is uncertain, and most reports deal with radiographic classification of the condition rather than pathology (191). One possibility is that this entity simply represents OA with a prominent, detritic synovitis. In a few cases, the lesion disseminates (5) to other joints and has been reported to evolve into RA. Such RA patients, however, are generally seronegative and show a much greater tendency toward osteophyte formation than patients with seropositive RA. Variants of nodal OA associated with chronic sialadenitis have also been described (192) whose relationships to erosive arthritis and seronegative RA are unclear. Bony ankylosis may occasionally occur in the finger joints in association with Heberden nodes, especially of the inflammatory type. Because of the difficulty in obtaining pathologic material from these sites, histologic studies are rare (186).
The generalized forms of OA are those variants having in common a marked tendency to polyarticular involvement. With the exception of most types of endemic arthritis, all have degrees of heritability, and some are now linked to specific molecular defects in structural or regulatory proteins.
Primary Generalized Osteoarthritis
Primary generalized OA was first defined as an entity by Kellgren and associates (5). Conspicuous features of the

disorder included a preponderance in middle-aged women, Heberden node formation, and involvement of the first carpometacarpal and knee joints. Hip joints were affected less commonly. Key features of the syndrome as described included signs of articular inflammation and radiologic evidence that proliferation of adjacent bone, rather than erosion of articular cartilage, was the primary event in the genesis of the lesions. The description of the syndrome was based on limited anatomic material, a situation not entirely corrected by succeeding studies (186,187,188,189,190,190,193).
The status of generalized OA remains controversial. Most patients with this pattern of disease do not present for surgical intervention. Thus, the condition is far more common in rheumatologic than in orthopedic practice. Some studies have confirmed an association of generalized OA with OA of the hips (194), whereas others have denied this relationship. The association of OA of the hands and knees has been established by radiologic studies (195). From the obverse viewpoint (5), patients requiring hip and knee surgery for localized OA are significantly more likely to have generalized disease as well. When hip disease is associated with Heberden nodes, particularly in patients with inflammatory features, it is of the concentric type (5) rather than the more common deforming type. Some authors maintain that this pattern of hip involvement is only a part of the generalized OA syndrome (5). The genetic predisposition to the development of generalized OA has been related to several types of markers. These include increased frequency of human leukocyte antigen (HLA)-DR2 (196,197), certain polymorphisms of the estrogen receptor gene (198), and abnormalities on chromosome 2q (199). Using radiographic hand and knee OA as the index condition, segregation analyses suggest a significant contribution from a major recessive gene together with possible environmental factors (200). This supports the observations made a generation previously by Kellgren (5) and recently confirmed elsewhere (201).
Osteoarthritis Caused by Heritable Collagen Defects
Other forms of polyarticular OA associated with mutant type II collagens have been described in several unrelated families (202,203,204,205). These disorders produce precocious generalized OA with accentuated involvement of weight-bearing joints. In one family, a mild spondylodysplasia with truncal shortening was present (202), and in others, more severe manifestations of spondyloepiphyseal dysplasia were noted (203). In the mildly spondylodysplastic family, a single point mutation at residue 519 in the triple helical domain substituted cysteine for arginine, producing abnormal posttranslational overmodification (204). The abnormal collagen has been isolated from cartilage remaining on a surgically excised femoral head from an affected family member (206) in which about one-fourth of the a1(II) chains contained the substitution. This was associated with severe precocious ulceration of articular cartilage. More recently, type II collagen with this particular point substitution has shown decreased affinity for binding type IX collagen (207). Electron microscopy of articular cartilage in one kindred demonstrated parallel lamellar arrays of collagen fibrils rather than the normal structure (205). Affected families showed definite or probable autosomal-dominant inheritance (202,203,204,205), with an age-dependent penetrance approaching 100%. Some other family studies have suggested an inherited defect in one of the introns or promoters for the procollagen II gene (208). Transgenic mice harboring copies of a transgene with mutations engineered into the mouse type II collagen gene develop early-onset knee joint degeneration along with other skeletal abnormalities (140,209).
Conversely, evidence to link defects in the type II procollagen gene to the common type of generalized nodal OA has not as yet been readily forthcoming (210). Molecular analysis of DNA from cases of generalized erosive nodal OA failed to disclose evidence of a single point mutation in collagen II a1(II) chain residue 519 (204). Sibling pair analysis in generalized nodal OA also fails to suggest linkage to loci encoding type II collagen (211). Some studies have suggested differential allelic expression from sequence dimorphisms of the type II collagen gene in osteoarthritic cartilage, but this could be a manifestation of somatic mutation (212), as has been described with abnormalities of chromosome 7 in synovia, osteophytes, and cartilage from patients with OA (213). Furthermore, the usual pattern in generalized OA does not include a clinically detectable spondyloarthropathy (see Chapter 110).
Ochronotic Arthropathy
Alkaptonuria is caused by a deficiency in homogentisic acid oxidase caused by a mutation on chromosome 3q (214) that eventually results in a generalized degeneration of joints similar to OA (see Chapter 120). Several differences are notable, however. External remodeling is less prominent than in idiopathic OA (5), and destructive spinal changes are more marked (215). This includes a calcification or ossification of the nucleus pulposus of the intervertebral discs and breakdown of the vertebral end plates. Osteophyte production is not a conspicuous feature of the spondylopathy either. In many cases, the spinal disease is so severe as to imitate that of a mucopolysaccharidosis or ankylosing spondylitis (216). Some investigators have postulated an increased prevalence of HLA-DR7 antigen in patients with clinical ochronosis (217). Moreover, the pigmented cartilage is extremely brittle, so that comminution with a resultant detritic synovitis is prominent. Pigmented cartilage fragments are found in the synovial fluid (218). Reactive polyps of the synovium containing these fragments are common and may be mistaken for loose bodies on radiographs. Fibrosis near ulcerated zones of the articular surface along with wavy alterations of the cartilage collagenous fibrillar ultrastructure has been noted (219). A

complicating feature is that both calcium pyrophosphate and BCP crystals have been identified in ochronotic cartilage (5). Homogentisic acid, the substance that accumulates in cartilage in ochronosis, has been shown to cause chondrocyte toxicity in vitro (220), possibly by producing oxidative DNA damage (221) because this effect can be delayed by ascorbic acid, glutathione, and D-penicillamine (220).
The arthropathy of gout develops as a consequence of the deposition of monosodium urate monohydrate crystals in and around joint tissues (see Chapter 114). Monoarticular, oligoarticular, and polyarticular forms occur. The character of the lesions depends on the amount, location, and duration of the deposits. Acute inflammatory episodes are a hallmark of the disease. These are likely to affect the small joints of the feet, particularly the first metatarsophalangeal joint, but large weight-bearing joints also can be involved.
Although tophaceous deposits can cause massive disorganization of articular structures, most cases with recurrent acute gout result in secondary OA of the postinflammatory type. Even in the absence of clinical acute inflammation, urate crystals may still be detected by polarized light microscopy of synovial fluid (222), particularly in patients not maintained on hypouricemic agents (223). Pathologically, the urate crystals are deposited not only in and on the surface of the articular cartilage but also in the subchondral marrow. Chondrocytes are characteristically necrotic and often surrounded by an oxyphilic matrix in areas of urate crystal deposition. Urate crystals are quite soluble in neutral buffered 4% formaldehyde, the routine histologic fixative. If tissue confirmation of gout is required, fixation in 95% alcohol should be employed (5).
The term endemic osteoarthritis encompasses special types of noninflammatory deforming joint disease occurring frequently in certain geographically confined areas (5). Although these disorders have certain features in common with generalized OA, they differ from the latter in affecting younger individuals and in producing stunted growth. Although evidence of pathogenesis is accumulating in several different countries, speculation continues on the cause of these disorders. Three types currently receiving attention are discussed here.
Kashin-Beck Disease
Kashin-Beck disease, formerly known as endemic osteoarthrosis deformans, affects at least 2 million individuals in northern China, North Korea, Siberia (224), and Tibet (225). The changes first appear during childhood and develop with variable severity in different affected individuals. The early changes consist of a zonal necrosis of the articular and epiphyseal chondrocytes (5). Profound deformity is the result in many affected individuals (226,227). Several theories as to the cause of the disorder have emerged. The most evidence favors the soil and water in the region being deficient in selenium and iodine (228), and the combination of these two factors results in the disorder. Although earlier studies failed to demonstrate inhibitory effects of selenium deficiency on short-term chondrocyte monolayer cultures (5), intact selenium-deficient mice develop a Kashin-Beck-type osteoarthropathy when supplemented with dietary fulvic acid, a product of mold growth (229). Interestingly, mycotoxins, particularly those of Fusarium species, have long been suspected as having some role in the disorder (230). Fulvic acid, a complex contaminant of water derived from decay of moldy soil, inhibits processing of type II procollagen in chicken articular cartilage (231). Related mold-derived compounds known as the humic acid solvent extraction fraction induce oxidative stress in cultured rabbit articular chondrocytes (232). Thus, a synergism between selenium deficiency and mold toxins may be the basis of the disorder. However, the exact pathogenesis of this regionally devastating disorder remains obscure (233).
Mseleni Disease and Handigodu Disease
Mseleni disease, common in northern Zululand, has been described more recently than Kashin-Beck disease. The disorder is polyarticular and noninflammatory, and the hip is particularly susceptible. In surgically resected femoral heads, eburnation was absent. The joint surface was instead covered by a combination of regenerated and degenerated cartilage (5). Some investigators have proposed that the disorder is heterogeneous, in part being hereditary spondyloepiphyseal dysplasia (5). With regard to spondyloepiphyseal dysplasia, localized occurrences of a dwarfing variant have been described (234), and some studies have suggested mutation in the type II collagen gene (235). Patients with Mseleni joint disease are also more likely to show histologic evidence of osteopenia, osteomalacia, and osteoclast failure, but abnormalities in calcium metabolism have not been identified (5). Generalized OA of the usual sort seen in predominantly European populations occurs less frequently in black Africans (236). As with Kashin-Beck disease, the definitive pathogenesis is as of yet unclear.
Handigodu disease is another form of proliferative OA seen in a geographically confined region of South India. The disorder is polyarticular, affects both genders, and can lead to severe deformity. Many similarities to Mseleni osteoarthropathy exist. However, at least some cases of Handigodu disease demonstrate an autosomal-dominant pattern of inheritance (237). Some cases may be related to borreliosis (238).

Joint disease following recurrent hemarthroses in the hemophilias has many features in common with OA (239). Like ordinary OA, erosion of articular cartilage occurs early, accompanied by eburnation of bone and marginal osteophyte formation. Unlike the subchondral pseudocysts of OA, those in hemophilic arthropathy are filled with hemorrhagic material. The synovium usually contains such immense quantities of hemosiderin that it appears reddish brown grossly, but only minute quantities can be detected in articular chondrocytes (5). How the iron reaches the chondrocytes is unknown because excessive iron is not detectable in the matrix (5). In advanced lesions, the destruction of the joint is more profound than that seen in OA, with disintegration and fibrous ankylosis being the end result. Although hemophilic arthropathy may affect any combination of joints, the larger peripheral joints are particularly prone to severe involvement, especially the knee and elbow joints.
The pathogenesis of the cartilage destruction is not completely understood, although it is somehow related to recurrent articular hemorrhage. Two general hypotheses are entertained. One is that chondrolytic enzymes are released from hemosiderin-laden synovial macrophages (240). A second is that cartilage damage is due to toxic products of hemoglobin degradation such as free radicals created by ionic iron from degraded hemoglobin. In experimental models, blood injections alter proteoglycan synthesis (241).
A number of types of multiple epiphyseal dysplasia have been described (242). In these rare conditions, epiphyseal growth and maturation of variable portions of the axial and appendicular skeleton are defective. Some are known to be associated with abnormalities of the type II procollagen gene (202,203,204,205,206,207,208), as described previously. Many affected persons die in infancy (242), but precocious OA develops with great frequency in those who survive childhood. In many instances, the OA has supervened in joints where the contiguous bone is markedly deformed. In some instances, the anatomic changes are indistinguishable from those of common OA; in others, eburnation is absent, and the articular surface is covered by a shaggy reparative cartilage (5). The femoral heads of such patients are small and flattened. Similar changes are seen on the surface of femoral heads removed from children with spastic cerebral palsy, although many of these children are afflicted with hip dislocations as well (159). OA has been reported in patients with a rare form of heritable osteochondrosis of the digits known as the nail-patella syndrome (hereditary osteoonychodysplasia, Turner-Kieser syndrome, iliac horn syndrome). Heritable causes of joint laxity such as osteogenesis imperfecta (243), Ehlers-Danlos syndrome (244), and Larsen syndrome (245) are also associated with precocious OA.
OA commonly follows developmental dysplasia of the hip (congenital hip dysplasia) in humans, possibly caused by elevated pressure resulting from the distribution of forces over the reduced contact area of the dysplastic femoral head (246). The disorder is relatively common, occurring in about 1.1 to 1.5 per 1,000 live births (247,248), and is more frequent in females. The disorder is usually clinically manifest at birth, with hip dislocation detectable by clinical examination. The existence of unrecognized forme fruste variants causing localized hip OA in a greater number of individuals in adult life is controversial (5). The hereditary contribution to the prevalence of this condition is also the subject of debate. Its frequency is increased in conditions with oligohydramnios (5), pointing toward an acquired defect in utero. As such, the disorder is definitely more common in offspring of diabetic mothers (249,250). Other studies suggest a hereditary component in some cases (251,252). In dogs, however, the evidence supports a strong genetic contribution (253). Certain breeds, such as German shepherds, commonly develop it, whereas others, such as American greyhounds, do not. Shepherd dogs are also prone to dysplasia and secondary OA of the elbow. The condition is of considerable economic importance in work dogs of other types as well.
Malum Coxae Senilis
Several childhood hip abnormalities lead to premature osteoarthritic degeneration in adult life. Such disorders include developmental dysplasia of the hip (congenital hip dysplasia) (246), Legg-Calvé-Perthes disease (254), slipped capital femoral epiphysis (255), and congenital coxa vara (256). At times, there is such a clear history that a pathogenetic sequence seems certain. In other patients, however, no precursor state is evident. These patients are sometimes considered to have a forme fruste of congenital hip dysplasia (5). This retrospective view may be questioned because subluxation has been documented only as a late manifestation of the joint deformity. Earlier views that subclinical hip dysplasia is frequently responsible for isolated OA of the hip have not been substantiated (257,258).
Legg-Calvé-Perthes disease results from necrosis of the growth center of the femoral head in childhood. The disorder may be primary or a complication of surgical intervention in congenital hip dysplasia (259,260). A severe secondary OA characterized by a flattened femoral head with bilateral beaklike osteophytes results. Because synovitis is a feature of early stages in the disorder (261), increased intraarticular pressure has been implicated. Hypercoagulability due to inherited factor V (Leiden) mutations is also associated with the disorder (262) and may influence severity (263). Slipped capital femoral epiphysis occurs in older boys of endomorphic habitus and results from a fracture through the physeal growth plate. Complete or total detachment is characterized by secondary osteonecrosis

and severe precocious OA (255). Between 25% and 40% of cases are bilateral (264). The disorder is also associated with acromegaly and conditions treated with synthetic growth hormone (265), such as renal failure. Studies of archived human skeletons suggested that 8% were involved by slipped capital femoral epiphyses and that the condition was associated with severe OA (266). Thus, the condition is not uncommon as a cause of adult OA.
Chondromalacia Patellae
The term chondromalacia patellae is used loosely to describe a clinically distinctive, posttraumatic softening of the articular cartilage of the patella in young persons. The anatomic lesions resemble those of early OA, although subtle differences have been described by some authors (33, 34). Changes involve the cartilage and the subchondral bone (5). Softening, swelling, and increased water content of cartilage have all been reported in the early stages of chondromalacia. In a minority of patients, a significant inflammatory component may be present secondary to irritation of synovium from detachment of cartilage fragments (detritic synovitis). Some studies have suggested that many cases of chondromalacia patellae do not progress to OA of the type seen in older individuals (35). Some evidence favors hypermobility of the knee joint as an evocative factor (267).
Neuropathic Arthropathies
Neuropathic arthropathies comprise articular degenerations with varying morphologies according to the duration and type of the underlying sensory defects (268) (see Chapter 93). Collectively, these are called Charcot joints owing to their description by J. M. Charcot in 1868. The changes resemble those of severe OA but are more profoundly destructive. Extensive detritic synovitis is characteristic and is frequently accompanied by secondary osteochondromatosis. The pathogenesis of these lesions is complex, with damaged neurovascular reflexes, sensory denervation, and metabolic factors all having advocates. In the diabetic foot, the most frequent site of Charcot joints in the United States (269), the landmarks of the tarsal bones are often obliterated by fusion (5), indicating extensive remodeling. Some authors have proposed that subtle sensory deprivation contributes to the acceleration of some cases of idiopathic OA (270). The clinical and pathologic similarity between Charcot joints and severe examples of CPPD crystal arthropathy has also been noted.
Associated Osteonecrosis
OA as a late sequela of previous bone infarction (osteonecrosis) has been the subject of a large body of literature. The epiphyseal ends of the bones are involved primarily in osteonecrosis because they receive a discrete arterial supply distinct from that to the remainder of the bone (5). The femoral and humeral heads are the most frequent sites of osteonecrosis (5). Articular cartilage derives nutrition from synovial fluid, so that infarction is limited to the subchondral bone and marrow, which fracture and collapse, leading to loss of the normal congruency of the joint surface. Proliferative remodeling leads to osteophyte formation, although the osteophytes are often not as pronounced as in primary OA. As the disorder progresses, the articular cartilage may slough, leading to exposure of bone and further remodeling. Osteonecrosis principally begins in only one articular member of a joint, but in later stages, secondary degeneration involves the mating articular surfaces (271). Although overt OA may ensue, eburnation is usually not a conspicuous feature. Ordinary OA of the hip may be associated with areas in which the osteocytes of underlying subchondral bone (Fig. 108.4) are necrotic (9, 90). The preponderance of evidence, however, suggests that such necrosis is a secondary event (9) that may contribute to rapid progression of deformity (8, 93). Primary osteonecrosis is associated with a number of conditions that enhance thrombosis of the osseous microcirculation (263,272). The possible role, if any, of hypercoagulability and venous occlusive disease observed in some cases of OA (92) secondary to osteonecrosis has not been established.
A special form of osteonecrosis of the medial femoral condyle develops in elderly persons (5) and leads to gonarthrosis. The sudden onset of symptoms (pain) may have been precipitated by a segmental fracture with depression of the articular cortex. Others have associated the disorder with medial meniscus tears (5) and with meniscectomy (273). OA has been described as a late consequence of meniscal disease as well. Thus, when segmental infarction occurs in OA of the knee (5), it probably is a secondary phenomenon, as in the hip.
The persistent erosion of articular cartilage in OA has long aroused interest in the limited ability of this tissue to grow (5). By all measures, the metabolic activity of hyaline cartilage is low. Experimentally induced gaps in articular cartilage show little tendency to repair if they do not penetrate into the vascularized bone marrow, leading to a common view that failure of cartilage repair is responsible for the irreversible development of OA (5).
Such dogma warrants serious reconsideration. Chondrocytes are capable of brisk mitotic and metabolic activities in vitro (5). Their release from surrounding matrix by enzymes provides a stimulus to cell division in vivo, as illustrated by proliferating cell clones near areas of matrix fibrillation (Fig. 108.2). Thymidine incorporation (46) and biosynthetic activities of chondrocytes (36, 76) are increased in OA. Although their rate of repair is low, it may be significant over the extended periods required for the development of OA. Cartilage defects may be reconstituted

by autologous chondrocyte transplants, further indicating a capacity for repair (29) under the right conditions.
The more obvious mechanism of cartilage repair lies in the proliferation and differentiation from pluripotential cells in the subchondral bone marrow. The fibrocartilaginous covering of osteophytes illustrates repair by this mechanism (77). Foci of hyaline and fibrocartilage also develop in the fibroosseous granulation tissue forming beneath metallic joint prostheses (5). Wedge osteotomies designed to redistribute forces in hips with OA have resulted in radiologic widening of the joint space and, in a few instances, in fibrocartilaginous recovering of joint surfaces. Thus, despite evidence of both increased apoptosis (55,56,58,59,60,61) and somatic mutations (47) in chondrocytes in OA, there is ample evidence of proliferation and repair in vivo.
The clinical and experimental pathology of OA suggests certain concepts about pathogenesis of the disease. These should be viewed as subject to modification as our knowledge of the molecular events underlying the morphologic lesions is enhanced.
Primary versus Secondary Osteoarthritis
OA frequently develops in joints with clearcut preexisting structural abnormalities. These cases are classified as secondary OA. In primary OA, no trauma or other predisposition can be identified, and intrinsic alterations of the articular tissues, or response to normal cumulative stresses, are presumed to be responsible. Differences in the conformation of OA joints in ochronotic or postinflammatory arthropathies suggest that intrinsic cartilage damage is also responsible for concentric (nonhypertrophic) OA, whereas mechanical overloading is responsible for the much more common varieties in which overt joint remodeling is conspicuous. In the hip joint, the patterns of cartilage loss and osteophyte development have been proposed as representative of the original causal abnormalities (5). Use of surgically resected femoral heads to support such causal explanations is quite difficult, owing to the advanced nature of the changes in such specimens. One school of thought proposes that a preexisting structural basis for OA of the hip can be identified in most cases (5). The entire issue is controversial because others report a much lower percentage of preexisting conditions (257,258,266,274) and recognize primary OA of the hip as the dominant entity (275). There is also evidence that generalized OA is common in individuals requiring hip surgery for localized disease (276). Similar frequency of polyarticular disease is found in patients who present with OA of the knee (195). Because the possibility exists that a genetic predisposition to generalized OA (197,198) might predispose to secondary OA (129), the entire issue is far from resolved.
Origin in Bone or in Cartilage
If the earliest events in the progression to OA occur in articular cartilage (6,7,17,18,36,37,55,56,57,58,59,60,61), then the bone remodeling results from the loss of energy-absorbing function of the cartilage. The osteophytes in primary OA can thus be viewed as an attempt to redistribute the increased transmitted forces over a greater surface area. If the primary alteration is in the subchondral bone (16,19,20,21,22,23,24,25,26,27,28) or in the basal layer of calcified cartilage (14,15,18), then the cartilage changes represent a failure of cartilage repair to compensate for the remodeling, including that of calcified cartilage (14, 15). Evidence that bony changes underlie the deterioration of cartilage includes the following: (a) articular cartilage has little measurable impact-absorbing function; (b) microfractures and subchondral trabecular sclerosis precede measurable changes in the cartilage; and (c) cartilage is mechanically more susceptible to impact loading that produces deformation of subchondral bone than to shearing stresses. Osteophytes, the most conspicuous features of established OA of the hip, develop very early, concomitant with the first radiologic evidence of joint space narrowing (5). Similar early remodeling changes are present in experimental OA in rabbits (11) and dogs (12, 151). The pathogenesis of OA likely involves an interaction between intrinsic deranged cartilage metabolism and extrinsic potentiating mechanical factors. Their relative contribution may vary in different joints and in different forms of OA.
Systemic Contributions to Osteoarthritis
Several systemic factors have been previously considered in relation to OA, including age, metabolic and genetic influences, obesity, and exercise. A salient feature of OA is a strong association with advancing age (5). This may suggest either that a series of cumulative insults is required to produce disease or that time-dependent molecular alterations engendered by genetic defects occur independently of environmental insults. Some degree of deterioration of the articular surface occurs linearly with increasing age, but the rate is greater in some joints than others (275). The changes in surgically resected osteoarthritic hip and knee specimens are far outside the normal distribution of changes seen in natural aging, suggesting that other local or systemic factors are necessary for progressive OA to occur (274,275).
Metabolic Factors
The increased prevalence of OA in patients with several different types of metabolic disease (e.g., ochronosis and acromegaly) has suggested that systemic factors are important in some variants of OA. Likewise, CPPD deposition disease with secondary OA is common in hemochromatosis (277) and hyperparathyroidism (97) and may eventuate in a

pattern of secondary OA. The contribution of the most common of all metabolic disorders, diabetes mellitus (278), to OA is more difficult to demonstrate (279). Some authors have associated hyperglycemia on clinical and epidemiologic grounds with symptomatic OA (280), but others have not (281). Diabetes is associated with several other joint disorders, including neuropathic arthropathy (269), ankylosing hyperostosis (180), and other manifestations of the DISH syndrome as well as the syndrome of fibrositis with limited joint mobility (278). The contribution of maternal diabetes mellitus to congenital hip dysplasia has been discussed elsewhere (249,250) and is probably due primarily to in utero positional abnormalities. It is more difficult to demonstrate molecular and biochemical pathology directly linking diabetes to primary OA. The relationship is complicated by the association of obesity with both type II diabetes mellitus and OA (282).
Other systemic factors may influence OA as well. Important sex differences in human OA exist, and multiple joint involvement is far more frequent in women (194,195). In men, OA of hips, wrist, and spine (283) is more frequent.
Although both osteoporosis and OA are diseases that appear in older individuals, they do not frequently coexist. The age-corrected incidence of OA is decreased in individuals with osteoporosis (28,167,284). Conversely, the existence of OA may retard the development of osteoporosis (169,170,285). Increased tissue concentrations of insulin-like growth factors I and II (286) and osteocalcin (254) in bone (287) and cartilage (288) have been identified in association with OA. Production of osteonectin (84) and osteopontin (85) by chondrocytes in osteoarthritic joints has also been identified. This raises the possibility that local factors may be the mechanism of increased bone density in some cases of OA. The subject is complex because of differences in methodology used to assess patient status with respect to OA. The inverse relationship between OA and osteoporosis in some cases may be related to the greater plasticity of osteoporotic bone. However, the local and distant effect of substances produced in response to OA may be factors in creating greater bone mass.
Genetic Factors
Genetic factors contributing to OA in humans (194,195,196,197,198,199,200,201) and other species may have systemic, metabolic, or, as in the dysplasias, local effects. Data regarding inheritance of Heberden’s nodes have been interpreted as reflecting involvement of a single gene, which is dominant in females and recessive in males (5). In other studies, mendelian recessive inheritance for OA in hand and knee joints with a multifactorial additional component has been advanced (200). Increased frequency of certain HLA antigens in patients with generalized OA suggests a genetic component (196,197), as does association with estrogen gene polymorphisms (198) and chromosomal 2q abnormalities (199). Likewise, vitamin D receptor gene polymorphism (289) has been associated with early OA of the knee. Some have found specific genotypes of the cartilage matrix protein genes significantly associated with polyarticular OA in men (290). Likewise, twin studies have shown an increased likelihood of OA in identical as opposed to fraternal twins, leading to the conclusion that the genetic influence on hand and knee involvement ranges up to 65% (291).
The contribution of inherited abnormalities in type II collagens to the overall incidence of primary OA remains uncertain. Because of the number of exons in the gene (208), large-scale screening of patients with generalized OA is conceptually difficult. However, the available evidence does not indicate genetic linkage of generalized OA of the usual sort to the loci encoding type II collagen (211). Genetic linkage of a multiple epiphyseal dysplasia phenotype to a specific defect of the a2 chain of type IX collagen has been demonstrated (292), but a role in common varieties of OA for so-called minor collagen constituents of cartilage is problematic.
Obesity is accepted as a definite contributory factor to the development of OA. It seems self-evident that excessive weight imposes a mechanical burden on the joints undergoing impulse loading, but several studies indicate that the situation is not so simple. In mice, obesity itself does not have an important effect on OA (5). However, epidemiologic data support an association of human OA of the knee with obesity (275,276,293), especially in women. The association with OA of the hip is weaker, perhaps owing to confounding variables such as the local factors discussed previously (274,282). Heberden nodes are apparently not associated with obesity (5), although OA of the hand and wrist is more common in obese patients (294). The caveat that patients with OA are likely to exercise less and thus become obese is worthy of consideration (5). This may be one factor in the observation that survival is reduced in women with increasing prevalence of full-body radiographically defined OA (295). Spondylosis is also more common in obese persons than in those of normal weight (5). Because joints involved in such studies are often not weight bearing, constitutional effects of obesity may be as important as biomechanical considerations. One plausible explanation is the increase in generalized bone density (171) seen in obese as opposed to nonobese individuals.
Ligamentous Laxity
OA is associated with a variety of postural abnormalities of joints with laxity of the ligamentous structures (242). Severe joint hypermobility occurring in states such as Marfan and Ehlers-Danlos syndromes is associated with OA (242, 244). Joint degeneration in patients with osteogenesis imperfecta

is due not only to structural abnormality of underlying bone but also to ligamentous laxity (242). Some other states, such as the Larsen syndrome, combine multiple congenital joint dislocations and epiphyseal dysplasias (242, 245). Other studies have implicated an increased frequency of OA, especially of the knee and shoulder, occurring with idiopathic joint hypermobility (5). In particular, chondromalacia patellae is associated with hypermobility of the knee in young, active individuals (267).
Mechanical Factors in Osteoarthritis
Mechanical factors have been proposed to evoke OA in specific joints. Elbow OA of foundry workers using long tongs to lift hot metals and “coal miner’s back” are two such examples. Vibratory trauma has been implicated in the cause of OA of the hands and feet in some studies, but not others (283). OA of the knee was more common in a study in individuals whose occupations involved heavy labor (283). OA of the hip has been correlated with heavy physical workload in women (274) and men (296). Heavy use of the hands is linked with interphalangeal OA (189) as well.
In numerous studies, the occurrence of OA in runners was not increased over control populations (283). Other types of athletic activity may be more influential. Retired soccer players, for example, had more OA of the hips than age- and weight-matched control group athletes in one study, but not in another (5). However, competitive sports have been considered a significant risk factor for OA of the knee (283). The possibility that repetitive trauma induces OA more commonly in genetically predisposed susceptible individuals cannot be excluded (130). Single injuries probably do not cause OA unless they are severe enough to disorganize the joint surface or its major stabilizing structures (Fig. 108.6).
Direct evidence for the mechanical abrasion of cartilage from the joint surface is provided by the shards of cartilage found in the synovial fluid and synovium in OA (117). In ochronosis, such joint detritus is a dominant feature of the disease and incites significant immune and inflammatory response in the synovium (218). The actual mechanical basis of the abrasion injuries in common OA is less obvious, but their presence is undeniable for direct morphologic (117) and indirect biochemical (118) evidence.
One cause of increased cartilage abrasion could be decreased or disordered joint lubrication (5). The articular cartilage of animal joints oscillated in vitro in the absence of synovial fluid undergoes rapid frictional destruction. Instillation of testicular hyaluronidase also leads to in vitro scoring of joint surfaces. Although the depolymerization of synovial mucin could account for the friction, it is possible that the hyaluronidase may also have acted directly on the cartilage matrix. The subject of joint lubrication has attracted much interest in recent years. Hyaluronidase abolishes the viscosity of synovial fluid but not its lubricating ability (5). Under conditions reproducing the joint loading occurring during walking, the friction on human femoral heads increased after hyaluronidase digestion of synovial fluid (5). These studies reflect the different characteristics of boundary and fluid film lubrication processes operating in joint function (297).
The volume, hyaluronate content, and relative viscosity of synovial fluid are usually normal in OA, although other studies have shown diminished polymerization of synovial mucin and a reduction of the hyaluronate content (5). The contradictory data arise in part because truly normal synovial fluids are not readily obtained for comparison. In the absence of joint disease, the amount of synovial fluid within joints is small, and many joints aspirated have low-grade synovitis (5). The synovial fluid also contains a lubricating glycoprotein called lubricin (297,298) and a surface-active phospholipid produced by synovial cells (299). The latter is bound to the surface of cartilage, probably transported to that site by the former. Some studies have indicated that lubricin may function in lubrication as a carrier for the phospholipid (300). In other studies, phospholipase digestion failed to abolish the lubricating ability of synovial fluid (301). Studies of femoral heads and knees removed for severe OA showed decreased surface-active phospholipid recoverable from the surface of worn as opposed to unworn areas (302). Whether this is a primary or secondary phenomenon is unclear. In a synthetic bearing test system, no deficiency in the boundary-lubricating ability of synovial fluid was found in OA in previous studies (5).
The forces applied over the hip, knee, and ankle joints are characterized by being intermittent and are often several multiples of the body weight (303), even in simple, apparently nonstressful movements such as walking on level ground. The resistance to wear under such conditions is a complex function involving lubrication, the elastic properties of the articular cartilage, and the deformation of the underlying bone (discussed in detail in Chapters 7 and 8). The elastic properties of cartilage, as measured by either stiffness or recovery from deformation, are not altered by aging unless fibrillation is also present (5).
The stiffness of the underlying bone has been increasingly considered as a factor in the development of OA (19,20,21), and the decreased stiffness of osteoporotic bone may explain why OA is less common in osteoporotic patients (28,284,285). However, some evidence from studies of comparative pathology of OA suggests that deficiency of mineralized bone may adversely affect cartilage (5). Such deficiency of mechanical support may contribute to the arthropathy seen in hyperparathyroidism (97). Conversely, osteopetrosis, a rare condition characterized by markedly increased stiffness of bone, favors the development of premature OA (5). The cause-and-effect relationship, however, is still unclear because fractures with deformity also characterize this disorder.
Paget disease (osteitis deformans) produces significant bone abnormalities that may extend into the subchondral osteoarticular junction and produce irregularities at the

joint surface (see Chapter 123). The hip is frequently the site of mixed patterns of Paget disease and OA (304), and protrusio acetabuli develops in approximately 25% of such patients, a far higher frequency than in OA without Paget disease (5).
Understanding the pathogenesis of OA requires reconciliation of apparently divergent biomechanical and biochemical concepts about the initial events in its evolution. The nature of the lesions and numerous lines of experimental work seem to reaffirm an interdependence between mechanical wear-and-tear processes and an altered metabolic state of articular tissues (5). The pathologic findings in OA do not establish that the disease is an inevitable concomitant of aging (283) or that the lesions, once developed, have no biologic potential for repair. Furthermore, secondary variants of OA develop commonly in association with a number of systemic or localized conditions. In some cases, such as ochronosis, hemophilia, and osteonecrosis, specific pathology gives evidence of a preexisting disease state. In others, such information is lacking. In secondary OA following long-standing RA of the hip, the stigmata of previous inflammatory insult to the cartilage and subchondral bone may be minimally, if at all, evident. Such scenarios serve to confound attempts to distinguish between primary and secondary OA on pathologic grounds in many cases. In other cases, coexistence of OA and other states, such as chondrocalcinosis, makes establishment of causality difficult. This phenomenon contributes to continuing disputes on the contributions of systemic factors to localized OA, especially of the hip joint. Inasmuch as OA is a pathologic final common pathway for a number of predisposing disease conditions, a relative degree of uncertainty about the primacy of local versus systemic factors will persist pending availability and application of more discriminatory molecular pathologic techniques to augment traditional pathologic methodology.
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