in S eminars zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGF Arthritis VOL. III, and Rheumatism NO. 3 The Etiology zyxwvutsrqponmlkj SPRIlVG and Pathogenesis A Review 1974 of Osteoarthrosis: Peter Lee, Patrick J. Rooney, Roger D. Sturrock, Alistair C. Kennedy, and W. Carson Dick zyxwvutsrqponmlkjihgfedcbaZYX STEOARTHROSIS, also known as osteoarthritis and degenerative joint disease, is defined in pathological terms as a disease of central and peripheral diarthrodial joints comprising: attrition and lysis of cartilage, subchondral bone sclerosis (often termed eburnation when marked), remodeling of bone ends with marginal osteophyte formation, and juxta-articular bone cysts. There is often accompanying synovitis and joint effusion. The radiological features reflect these pathological changes with loss of joint space, subchondral bone sclerosis and cyst formation, and osteophytosis. Clinically the disease is characterized by pain and dysfunction of afflicted joints, which are often the seat of bony swelling and deformity. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONM 0 Primary and Secondary Osteoarthrosis The adjective primary is used when no etiological factors when any such factors are apparent, the term secondary is osteoarthrosis may prove to be a heterogeneous collection and some secondary causes may well be merely localizing that these terms should be used with caution. can be determined; employed. Primary of different entities, factors, suggesting Epidemiology Evidence of osteoarthrosis has been found in the dinosaur’04 and in ancient human skeletal remains.‘04,205 Osteoarthrosis occurs in all mammalian species, including those that swim in the sea, in birdqzS4 and in all races of man. Epidemiological studies in England have shown that over 80% of people over the age of 55 have radiological evidence of osteoarthrosis.“’ That these figures are not excessive is suggested by the finding of similar prevalence rates in other studies. The 1960-1962 United States Health Examination Survey showed radiological From the Centre _for Rheumatic Diseases and University Deparrmenr of M edicine. Glasgow Roy al Infirmary, Glasgow . Scotland. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDC P. Lee, M.B., M.R.A.C.P.; M.R.C.P.; A. C. Kennedy, P. J. Rooney, M.B., Ch.B., M.R.C.P.; M.B., Ch.B., M.R.C.P.; W. C. Dick, Rheumatic Diseases, University Deparrmenr of M edicine, Glasgow R. D. Sturrock, M.B., Ch.B, M.D.. M.R.C.P.; C’entre for Roy al Infirmary. Glasgow . Scotland. s> I974 by Grune & Stratton, Inc. Seminor s in Arfhritis and Rheumof ism, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDC Vol. 3, No. 3 (Spring), 1974 189 190 LEE ET A L. evidence of osteoarthrosis in the hands or feet of over 40 million Americans, which represents 37% of the target population,” and these changes were associated with symptoms in 5 million persons.60 In all epidemiological studies, the prevalence of osteoarthrosis rises markedly with advancing years, but it is worth noting that radiological evidence of the disease was present in one survey in 10% of persons between the ages of 15 and 24.‘43 Clinically, however, overt disease is rare in young subjects, and its occurrence should stimulate a search for precipitating factors or other disease. The evidence supports a uniformly high prevalence across geographic and ethnic barriers, with certain fascinating but yet unexplained exceptions such as the reduced prevalence of osteoarthrosis in the hips of Chinese.“’ However, prevalence rates are difficult to compare because of variations in diagnostic criteria, joints, and age groups studied. In ;eneral, males and females are approximately equally affected, with males beLg rather more commonly afflicted under the age of 45 and females more commonly affected over that age. ‘28,90Females are much more commonly afflicted in the case of severe disease,‘43 primary generalized osteoarthrosis,‘2’,‘30 Heberden’s nodes,‘29.263and erosive osteoarthritis.*” The prevalence of osteoarthrosis is increased in certain joints that are subjected to excessive use, and the list of such associations is both long and fascinating (Table 1); however, some of the associations remain contentious and should be interpreted with caution. In a similar manner, the prevalence of osteoarthrosis is increased in several local and systemic congenital and acquired diseases (Table 2). One of the interesting features in population studies of osteoarthrosis is that there is often a variable discrepancy between the presence and severity of the disease radiologically and the clinical features. In one survey, only 25% of miners with radiological features of osteoarthrosis of the knee had symptoms in that joint,‘26 but in another there was a correlation between radiological evidence of osteoarthrosis of the hip and clinical symptoms.‘** Thus epidemiological studies may give misleadingly high prevalence rates of the disease, if based on radiological evidence. Osteoarthrosis is a common cause of disability in western countries and conTa b le 1. O ste o a rthro sir in Va rio us Jo ints Asso c ia te d Jo ints Invo lve d Elb o ws a nd kne e s Ankle s, fe e t, a nd kne e s a nd Sho ulde rs fe e t a nd b a lle t e lb o ws Po te lla - fe m o ra l Fing e rs Ankle s a nd Spine s, kne e s, kne e s 8, e lb o ws Fing e rs Sho ulde rs Hips so c c e r (c o llie rs)‘“) 33.260,262 pla ye rs Am e ric a n fo o tb a ll 113 b o xe rs Ha nds Ankle s Spe c ific O c c upa tio ns O c c upa tio n m ine rs Kne e s With e lb o ws 33.52 b a se b a ll pitc he rs3’ 10 c yc lists 284 c ric ke t b o wle rs la c ro sse wre stle rs c o tto n a nd da nc e rs pla ye rs223 pla ye rs2” I44 pic ke rs pne um a tic - drill fa rm e rr’ 141 o pe ra to rs”’ 191 O STEO A RTHRO SIS Ta b le 2. C o ng e nita l C o ng e nita l a nd Ac q uire d Dise a se s Pre dispo sing to Sub se q ue nt O ste o a rthro sir a nd / o r Ac q uire d He re dita ry Syste m ic Lo c a l tra um a c o ng e nita l hip dyspla sia a va sc ula r infla m m a to ry ne c ro sis a rthritis, rhe um a to id Mo rq uio ’s syndro m e na il- pa te lla r fa m ilia l syndro m e c ho ndro dyspla sia he re dita ry o ste o - Le g g - Pe rthe s slippe d se ptic fe m o ra l a nd Pa g e t’s a rthritis g o ut dise a se e piphysis tub e rc ula r a rthritis hype rc o rtic ism , o c ro m e g a ly dise a se o nyc ho dysplo sia Ka shin- Be c k he m o philia ne uro pa thic diso rde rs: dise a se c ho ndro c a lc ino sis he m o c hro m a to sis Wilso n’s dise a se a lka pto nurio ta b le s do rso lis dia b e tic ne uro pa thy m e ning o m ye lo c e le syring o m ye lia pe riphe ra l ne rve Se c tio n tributes significantly to the socioeconomic impact of rheumatic diseases. Osteoarthrosis, together with disk degeneration, is the most frequent cause of rheumatic symptoms and is the major rheumatic disease causing loss of time from work in men.‘42*2g4Considering that a recent estimate of the annual loss of productivity through rheumatism in the United Kingdom was 2190 million,7 the number of days lost from work being over 35 million in 1967,235 osteoarthrosis itself must represent a considerable economic loss to the community. Mechanism of Pain in Osteoarthrosis Pain is the dominant complaint in this disorder, and yet its origin and pathogenesis remain uncertain. It probably does not arise in degenerating cartilage, which is devoid of nerve endings, although nerve endings are present in the joint capsule, related ligaments and muscles, and subchondral bone. Kellgren’24 considered that much of the pain is the result of minor trauma to the thickened contracted capsule when the joint is forced beyond its restricted range of movement; however, the occurrence of pain at rest and nocturnal pain are less easily explained on this basis. Myelinated nerves have been seen accompanying subchondral bone blood vessels,“’ and it may be that interruption of these nerves accounts for the relief of pain following osteotomy.27g On the other hand, abnormalities of venous drainage with vascular congestion have been described in the femoral head, and it has been suggested that the pain mechanism in this context is primarily vascular in nature-a kind of femoral head “migraine”.2’2 Recently the possibility of a prostaglandin-mediated pain mechanism has been raised by the observation that prostaglandins may sensitize tissue to pain,76*77 and this would provide a rationale for the use of prostaglandinsynthetase-blocking anti-inflammatory and analgesic drugs. Confirmation of this fresh line of investigation is presently awaited. A synovitis may occur in osteoarthrosis, although this is not generally a con- 192 LEE ET AL stant feature of the disease. Acute pain may result from a traumatic synnvitis, or this could possibly be secondary to a foreign-body reaction to flakes of debrided cartilage.“’ The development of Heberden’s nodes may rarely be heralded by the rapid onset of redness, swelling, pain, and tenderness, with the symptoms being particularly prominent following prolonged activity. zyxwvutsrqponmlkjihg Normal Joint Lubrication The precise lubricating mechanism operative in diarthrodial joints remains conjectural. MacConnaill’@’ proposed a simple hydrodynamic concept in which the articular surfaces are separated by a thick wedged-shaped film of synovial fluid that is generated as a result of movement and encouraged by the normal surface incongruities. However, this principle is not considered to be suited to the slowly reciprocating motion under heavy loads found in human joints, and it did not receive support from subsequent experimental results.42~27’ Later, Charnley42,43 suggested that the cartilage itself may be more important than the lubricant and that the cartilage surfaces are separated by a monomolecular film of lubricant. This phenomenon is termed boundary lubrication and functions on the principle that the thin layer of molecules slide over opposing surfaces more readily than they are sheared off the surface to which they are attached. While the boundary phenomenon is efficient under low loads, the system fails when the intra-articular pressure rises sufficiently for the lubricant to be sheared off the surface of the articular cartilage.2’8 McCutchen ‘6’*‘62proposed the concept of “weeping” lubrication. This is dependent upon a porous deformable structure capable of expelling fluid when that fluid was expressed compressed. McCutchen and Lewis ‘@ demonstrated from cartilage when compressed and concluded that this phenomenon had a major role in joint lubrication. Dintenfass59 proposed the elastohydrodynamic theory to account for the elastic or thixotropic properties of synovial fluid, experimentally for while Linn I48 suggested that the very low values obtained sheer deformation ruled out a major hydrodynamic element. phenomenon, a concept that deDowson et al.62 proposed the squeeze-film pends on a flow of water out of joint fluid into cartilage as the opposing surfaces come together and generate pressure in the lubricant. The passage of hyaluronic acid from synovial fluid into cartilage is restricted by its large molecular size, and the pore size of articular cartilage will only permit the passage of of water out of the synovial water and small solutes.‘62~‘73~203Th e movement fluid would therefore tend to produce a concentrated gel of hyaluronic acid. Dowson et al.62 have demonstrated that the viscosity of a squeeze film is several times greater than that of normal synovial fluid. Walker et al.288 then proposed the concept of boosted lubrication to supplement the squeeze-film principle. This is dependent upon the electron-microscopic findings that the articular cartilage surface is not smooth, but undulating and rough.83”57,289 Upon loading of the joint, lakes of synovial fluid are trapped within these surface pits and become concentrated with increasing pressure. However, the significance of these synovial-fluid pools is at present uncertain, and Radin and Pau1218 have suggested that they may in fact be artifactual. Clearly, the weeping lubrication concept of McCutchen E’ is in conflict with 193 O STEO A RTHRO SIS the squeeze-film principle of Dowson et a1.,62 and at the present time it is not clear which system operates preferentially in animal joints. Present evidence indicates that the low coefficient of friction in joints is attributable to a combination of boundary lubrication, which is operative under low loads, and a form of fluid lubrication under high loading. softRadin and Paulzi8 widened their concept to include the nonarticulating tissue system, claiming that the functional resistance to motion caused by soft tissue greatly exceeds restriction of cartilage-on-cartilage movements. The soft-tissue system depends upon the thixotropic synovial fluid, which keeps soft-tissue surfaces apart during movement. Both the protein and the polysaccharide moieties of synovial fluid, particularly the former, would now appear to be operative in accounting for its lubricating properties.‘63*222 On the other hand, the cartilage-on-cartilage system in their concept is not dependent upon hyaluronic acid, but upon a synovial fluid glycoprotein acting in the cartilage system by a cartilage boundary effect. Synovial Fluid in Osteoarthrosis There is no general agreement on the rheological synovial-fluid findings in osteoarthrosis, and there is no satisfactory evidence to suggest that impairment of the lubricating properties of synovial fluid plays an important role in the pathogenesis of this disease. The viscosity of synovial fluid is usually normal in osteoarthrosis, but on occasion may be increased.75~z27 Ropes and Bauer227 also reported a normal hyaluronic acid content, but more recently several workers have produced evidence of diminished polymerization of synovial mucin, as well as a reduction in hyaluronic acid concentration.‘7,20*‘32,26’ Cartilage-on-cartilage lubrication is not dependent upon hyaluronic acid, since digestion of the latter with hyaluronidase does not decrease its lubricating properties of synovial efficiency in this system.‘49 However, loss of lubricating fluid following proteolytic digestion may well be due to destruction of the glycoprotein fraction on which cartilage-on-cartilage lubrication is dependent.’ Ionic Environmental Factors There is a high, fixed negative charge due to the anionic polysaccharides of cartilage matrix that imposes restrictions on molecular movement from fluid to cartilage. Even substances of low molecular weight are unable to enter zyxwvutsrqponml passively if they are negatively charged, and the uptake of the sulfate anion is probably an active process.39 On the other hand, cationic dyes or neutrally charged glucose will readily enter cartilage. Cartilage elasticity is preserved on isotonic sodium chloride, but is lost if divalent cations are substituted, possibly due to collapse of the polysaccharide chain as the anionic matrix becomes neutralized.39 The influence of the ionic environment upon the development of osteoarthrosis warrants further investigation. PATHOLOGY OF OSTEOARTHROSIS The sequence of events in the development of osteoarthrosis has not, as yet, been defined, but early changes in osteoarthrosis appear to occur in the artic- 194 LEE ET Al. ular cartilage, which loses its normal resiliencez5’ and undergoes softening, probably as a consequence of changes in the cartilagenous matrix. Despite the implications of weightbearing on the etiology of osteoarthrosis, these early cartilage changes have also been seen in the nonpressure areas of the femoral head9’ and on the noncontact areas of the radial head in the elbow.89 Direct inspection of these areas reveals a loss of the normal glistening, smooth pearly surface and transformation to a velvet texture with yellow discoloration. The surface of the articular cartilage becomes fissured and irregular, with crevices extending deeply (as far as the base of the calcified zone) and running parallel to the plane of the collagen fibers.‘-’ The appearances of these lesions under electron microscopy suggests that they are the result of buckling and invagination of the superficial zone, rather than cleavage of the articular cartilage.2N Histologically, there is early swelling of the matrix, increased affinity for hematoxylin stain,16 and, correspondingly, a loss of metachromasia”’ in the involved areas. These zones also have a reduced affinity for alcian blue.256 Under electron microscopy, the collagen fibers of the superficial layer appear to be of smaller diameter and less well organized than in the corresponding area of age-matched normal cartilage. *XIAlthough there is a reduction in number of surface chondrocytes, clumping of cells around the cartilagenous fissures occurs. Mitotic figures are also seen, indicating proliferation of these cells, and are consistent with attempted repair of the damaged tissues. The surviving superficial chondrocytes are larger, have well-developed rough endoplasmic reticulum and Golgi apparatus, and are surrounded by a small pericellular halo of fibrils. 2’3,290These appearances are consistent with those of metabolically active cells and possibly indicate synthesis and secretion of collagen or mucopolysaccharide or both. With progression of osteoarthrosis, the numbers of degenerating cells increase, and there is an absence of the filamentous halo.180~‘8’~290 The extent to which these events may perpetuate the osteoarthrosic process is not certain, but erosive osteoarthritis*” may simply represent the extreme end of a spectrum of pathological events. With cartilage destruction, the underlying subchondral bone becomes progressively sclerosed (eburnated), with vascular proliferation and dense calcification and ossification. The underlying bone marrow becomes fibrotic and may be progressively replaced in this region by sclerotic bone.97 Recent evidence suggests that there may be biochemical changes in subchondral bone at an early stage in the evolution of the disease; this will be discussed further below. Cysts may be seen within the subchondral bone and may be due to fractures of the trabecullae as a result of altered forces within the bone ends,“7,269 or to extrusion of synovial fluid under pressure through minute defects in the disthat these cysts eased cartilage. 13*The latter would explain the observation communicate with the joint cavity and may expand as a result of pressure transmitted to them during movement.40*“s Osteophyte formation is usually considered to be a late manifestation of osteoarthrosis, although it may be seen radiologically in the absence of any other evidence of degenerative joint disease. These occur typically at the joint margin, or at the point of ligamentous or capsular attachment, and are most 195 O STEO A RTHRO SIS prominent at sites not subject to mechanical pressure, such as on the acetabular rim or margin of the femoral head. Histologically, an osteophyte consists of an excrescence of cancellous bone, often with a covering of hyaline cartilage,255 and is formed by enchondral ossification. They appear to expand in the direction of least constraint. Trueta2” suggested that osteophytes were due to the proliferation of blood vessels into areas of degenerating cartilage. Swanson and Freeman,269 however, postulated that changes in stress distribution in bone accompanying loss of cartilage cause small subchondral bone fractures near the articular margin, thus precipitating vascular invasion and subsequent osteophyte formation. Danielson,56 in a study of hip joints, showed a dissociation between osteophytosis and osteoarthrosis and indeed demonstrated that osteophytosis did not presage the later development of osteoarthrosis in the knee but rather was associated with a tendency of osteoarthrosis to undergo regression. Marshall and 01ssen,‘76 in dog experiments, showed that osteophytes formed and proliferated while the articular cartilage remained normal. These investigators considered that instability was the major factor in determining this phenomenon. On the other hand, Kellgren, Lawrence, and Bier’29 have demonstrated that the incidence of multiple-joint osteoarthrosis is statistically increased in patients with Heberden’s nodes. The underlying basis of these pathological events remains entirely obscure. Heberden’s nodes require special consideration. Most are associated with the typical pathological features of osteoarthrosis, but rarely osteophyte formation may be associated with hypertrophy of the articular cartilage.46 Cystic formation can occur within Heberden’s nodes, and the cystic fluid has been identified as hyaluronic acid.‘14 Clinically, at present there are two recognizable types of Heberden’s nodes: the traumatic or acquired and the genetically influenced.263 BIO C HEMIC AL ABNO RMALITIES O F ARTIC ULAR C ARTILAG E IN O STEO ARTHRO SIS The main histochemical and chemical alteration of articular cartilage in osteoarthrosis is a relative diminution of concentration of the matrix components, particularly glycosaminoglycans (polysaccharides). Although osteoarthrosic erosion of articular cartilage necessarily requires a disruption of collagen fibers, neither the concentration nor the solubility of the latter has been found to be significantly altered in fibrillated cartilage.26”89 It is possible that the basic lesion in the ground substance leaves the collagen bundles unsupported so that the latter may subsequently fracture under mechanical stress.‘% The depletion of glycosaminoglycans occurs particularly in the more superficial layers with softening of the cartilage, but extends deeper with progression of the disease. The reduced components include hexosamine, sulfate, chondroitin sulfate,26~‘0’~‘77and in advanced lesions, keratin sulfate.27 The earliest change is said to be a reduction in chondroitin sulfate concentration. There is also a reduction in the length of the polysaccharide chains of chondroitin sulfate.27 In a study of glycosaminoglycan content over the surface area of hip joints, 196 LEE ET AL. Maroudas, Evans, and Almeida’75 demonstrated a topical variation that closely correlated with areas of local fibrillation. Such a finding suggests a focal characteristic of degenerative changes in osteoarthrosis rather than a generalized degradative process within the joint. Such variations are not present in normal joints, and there is no age variation. This work is complementary to the earlier findings of Ballet and Nance,” who found increased polysaccharide synthesis when measured by “S and 14C acetate incorporation into chondroitin sulfate in abnormal cartilage as compared to that from normal sites in the same joint. The metabolism of mucopolysaccharides is probably a continuous process of synthesis and breakdown, and in adult rabbit articular cartilage there seems to be a half-life of about 8 days. ‘69Adult cartilage retains this ability to synthesize mucopolysaccharide rapidly. 5’,‘69In osteoarthrosis it appears that the chondrocyte responds to a reduction in matrix mucopolysaccharide content by increased synthesis, as is indicated by an increase in 35S incorporation. This suggests that there is a sensitive cellular mechanism present for the surveillance and homeostatic control of the matrix. There is experimental evidence that the proteinpolysaccharide complexes reformed during cartilage repair may not be entirely normal structurally,‘g4 and if in addition there is loss of functional efficiency, this may go some way toward explaining the frequently progressive course of degenerative joint disease. The demonstration of antigenicity to elements of cartilage88*‘08 may also be of interest in the present context, but whether this will prove to be of any significance in the pathogenesis of osteoarthrosis remains to be established. REG ENERATIO N AND REPAIR O F ARTIC ULAR C ARTILAG E The proliferation and clustering of chondrocytes adjacent to fissures in degenerate cartilage may be interpreted as an attempt at healing. These cells show an increased uptake of radio-sulfate, and despite the overall reduction in mucopolysaccharide content of cartilage matrix, its rate of synthesis is markedly increased.50 The assessment of cartilage regeneration is extremely difficult since the rate of repair is relatively slow, as measured clinically. In addition to the histological and biochemical evidence, a number of clinical observations support the concept of cartilage regeneration. It is known that the osteophytes of degenerative joint disease consist in part of well-differentiated articular cartilage, and, similarly, intra-articular loose bodies commonly have a concentric layer of hyaline cartilage surrounding a nidus of necrotic bone. Growth of articular cartilage is a well-recognized phenomenon in and regeneration of articular cartilage has been observed acromega1y,‘25 beneath the prosthesis following cup arthroplasties of the hip.282 There have been reported several observations of recovery of the radiological joint space in degenerative hip disease following osteotomy,‘196s2w but one could question the validity of such radiological observations. More recently, there have been several reports of spontaneous recovery of the joint space in osteoarthrosis of the hip.56,20g*234 Perry, Smith, and Whiteside209 observed that where recovery occurred, osteophytes were prominent. It is postulated that these may be important in the stabilization of the joint, thus allowing healing to proceed. In the case reported by Storey and Landells, at postmortem the femoral head was found to be covered with fibrous cartilage. 197 O STEO A RTHRO SIS Against this evidence of articular cartilage regeneration in osteoarthrosis is the infrequency of recovery in osteoarthrosic femoral heads,‘83 highlighting the limitations of natural recovery. This is supported by the observation by regeneration of lost tissue following Meachim’79 that there is no significant superficial experimental sacrifice of rabbit articular cartilage, despite the proliferation and clustering of chondrocytes. In addition, the regenerative cartilage is abnormal and is usually fibrocartilagenous rather than hyaline.ls3 EFFEC T O F DRUG S A number of drugs have been tried in attempts to delay the progression of osteoarthrosis. Epsilon-aminocaproic acid is a plasmin inhibitor and also inhibits the degradative action of cathepsins on cartilage.5 Rumalon, an extract of calf cartilage, has previously been reported from in vitro experiments to stimulate chondroitin sulfate synthesis by both normal and osteoarthritic cartilagez2 and to be clinically useful in treating osteoarthrosis.285 However, in more recent studies Rumalon failed to increase radiosulfate incorporation by articular chondrocytes in monolayer culture.1663167 In a controlled trial, early administration of aspirin in recurrent lateral dislocation of the patella prevented the subsequent development of chondromalacia,47 thus confirming previous observations in rabbits. 86*25’This protective action of aspirin is thought to be on the basis of degradative enzyme inhibition, in particular of the lysosomal protease cathepsin,2s’ which, it is suggested, allows the reparative process to keep pace with the rate of destruction. The relevance of these observations to the treatment of osteoarthrosis must at present remain doubtful, and until the etiology of this disease is clarified, its management remains essentially symptomatic. AG E AND O STEO ARTHRO SIS The increasing prevalence of osteoarthrosis in the elderly has stimulated the wear-and-tear theory, which suggests that the disease may develop because of the diminished capacity of aging articular cartilage to resist mechanical stress, but the role of aging in the development of osteoarthrosis remains contentious. There is sufficient evidence to state that progressive changes in the physical and biochemical properties of cartilage OCCUJ with advancing age from the second decade onward.9*189,‘95 The se changes are predominantly seen in nonarticular cartilage such as costal cartilage where there is marked reduction in the relative proportion of collagen protein, a change in amino acid composition, and a considerable decrease in relative amounts of hydroxyproline, proline, glycine, and hydroxylysine during the second to fourth decades.‘89 Concurrently, during the third decade, changes occur in the mucopolysaccharide fraction with decreased chondroitin sulfate and increased kerato sulfate concentrations,93,‘34.178 as well as a reduction in water content.“’ There is a reduction in the ratio of the light to the heavy fractions of protein polysaccharide.‘36 Interestingly, there is fess agreement regarding changes in articular cartilage with age,6,‘00 and such biochemical age changes as have been found in costal cartilage appear to be virtually absent or much less marked in articular cartiHistological changes have been noted in articular cartilage with lage. 27~‘8’~‘87~‘89~255 198 LEE ET At. advancing years, and Barnett, Cochrane, and Palfrey” demonstrated submicroscopic fissures and surface irregularities in aged articular rabbit cartilage. Radiosulfate (35S) incorporation by chondrocytes is decreased in costal cartilage with increasing age, but chondrocyte clusters in aging articular cartilage show enhanced uptake that is even higher in osteoarthrosic clusters.50*‘0g~180 These studies indicate that chondrocytes do not lose their ability to synthesize chondroitin sulfate with advancing age. There is ample evidence to suggest that the increased “S incorporation is due to increased chondrocyte activity rather than to increased cellularity. Despite the increasing numbers of degenerating cells with progression of osteoarthrosis,‘sO~‘s’ the rate of DNA synthesis is increased.‘6ss’70 In addition, ultrastructural changes, such as more extensively developed rough endoplasmic reticulum and Golgi apparatus and an increase in numbers of centrioles observed in viable cells, have been correlated with increased metabolic activity.2’3v290 VASC ULAR INFLUENC ES It is noteworthy that closing of the subchondral osseous plate occurs at a time similar to that recorded for early evidence of degenerative changes. At this time the subchondral vascular supply to cartilage is regressing, and it has been suggested that therein may lie the seeds for the later development of osteoarthrosis.230 Against this is the fact that the earliest changes are seen on the superficial layers of the cartilage, and not in the depths, as this hypothesis might suggest. Although Cheyne14’ concluded from injection studies in cadavers that there is a reduced vascularity of the femoral head in the elderly, this was not conSchajowicz, and Truetag demonstrated an firmed by later work.97*28’ Harrison, increased proximal femoral blood flow in osteoarthrosis. Abnormal venous drainage has also been demonstrated in osteoarthrosis of the hip,‘*6,2’2 but the significance of these findings remains far from clear. No etiological relationship has been demonstrated between generalized but the possibility of abnormalities of atherosclerosis and osteoarthrosis,49 the microvasculature has not been excluded. Elevated intra-articular temperatureslo7 and radioisotopic abnormalities57~ss suggest increased microvascular flow, although these may be merely reflecting an accompanying synovitis. LO C A L PREDISPO SING Avascular C AUSES zyxwvutsrqponmlkjihgfedcbaZYX Necrosis Avascular necrosis, from whichever of its possible causes (Table 3) is frequently followed by osteoarthrosis. Indeed, Trueta279 has suggested that many instances of primary osteoarthrosis are related to avascular necrosis, and it would be impossible to exclude this hypothesis on a clinical or even a radiological basis. Congenital or Developmental Abnormalities of Joint Architecture From 20 to 50% of cases of osteoarthrosis of the hip have been attributed in different surveys to congenital hip dysplasia, Legg-Perthes disease, and slipped femoral epiphyses.‘*‘52s’99 IYY O STEO A RTHRO SIS Ta b le 3. 1. Po st- tra um a tic 2. Idio po thic 2M’295 3. C o rtic o ste ro id 4. C a isso n C a use s o f Ase ptic Ne c ro sis (usua lly fra c ture o r sub luxa tio n) the ro py79’98 dise a se ’97 5. Syste m ic 6. Rhe um a to id lup us 7. Sc le ro de rm a 292 a. Pa nc re a titi? ’ 9. Alc o ho lism 95 10. Sic kle 11. G o uc he r’s e rythe m o to sus63 a rthritis3’ c e ll o ne m io 232’233 dise a se , he m o philia , a rte ria l e m b o liza tio n”8 zyxwvutsrqponmlkjihgfedcba Congenital hip dysplasia is a condition in which there is underdevelopment of the acetabulum and is associated with either subluxation or frank dislocation of the femoral head. Late recognition or inadequate corrective measures invariably lead to early and progressive development of osteoarthrosis of the hip in later life. It is likely that the poor anatomical relationship of the acetabulum and femoral head in this situation leads to excessive stress on the articular cartilage. Evidence from twin studies suggests that there is a genetic predisposition to this disorder38z”’ and that multiple genes with incomplete penetrance are involved. Females are more often involved than males. Environmental factors and racial differences appear to be important in the expression of the disorder in the genetically susceptible individual. The condition appears in oversized pups allowed to run free rather than in those confined to cages.226 Congenital subluxation is more frequent following breech delivery224 and is relatively uncommon in the Chinese, whose infants are carried in slings on mothers’ backs with the hip in flexion and abduction.‘02 In Legg- - Perthes disease there is avascular necrosis, either partial or complete, of the proximal capital femoral epiphyses. The peak incidence occurs in the group 4 to 8 yr of age, predominantly in boys, and distortion of the softened femoral head in the healing phase appears to be the major factor in the subsequent development of osteoarthrosis. Slipped capital femoral epiphy ses generally occurs in overweight children in the group 9 to 15 yr of age. The underlying cause is unknown, but again if the resultant deformity is not promptly corrected then the subsequent development of osteoarthrosis in early adult life is almost inevitable. An extremely low incidence of osteoarthrosis of the hip has been reported in the Hong Kong Chinese population.‘02 This may be correlated with the relative paucity of such predisposing conditions as avascular necrosis, congenital hip dysplasia, LegggPerthes disease, and slipped femoral epiphyses in these people, as well as differences in racial characteristics. The Chinese are said to have different sitting and walking patterns as compared to their western counterparts, and they may possibly subject their hips to less stress.*19 Charcot.joints (neuropathic arthropathies) in tabes dorsalis, diabetes mellitus, and syringomyelia can be regarded as severe forms of osteoarthrosis that are due to repeated trauma and loss of the protective proprioceptive mech- 200 LEE ET AL. anisms. The earlier concept of bone reflex activity69 has not been supported SYSTEMIC Inflammatory atrophy from in experimental PREDISPO SING abnormal studies. neurovascular ABNO RMALITIES zyxwvutsrqponmlkjihgfedcba Arthritis It is well recognized that inflammatory disease of diarthrodial joints may predispose to the subsequent development of osteoarthrosis, particularly in the nonspecific inflammatory disorders such as rheumatoid arthritis. Indeed, in later years the secondary osteoarthrosic process may become so dominant as to obscure the features of the underlying inflammatory disease. Interestingly, when considering septic arthritis, if specific therapy is instituted early and complete resolution is achieved before articular cartilage damage occurs, osteoarthrosis is most unlikely to supervene. On the other hand, delayed diagnosis or inadequate therapy may lead to destruction of articular cartilage, bony erosions, and the subsequent development of osteoarthrosis.229 Both septic and tuberculous arthritis are major predisposing causes of osteoarthrosis, especially in underdeveloped areas such as Central Africa and Asia. Hemophilia Osteoarthrosis is a common complication of hemophilia. The joints most frequently involved are the elbows and knees,2T’92 and the pathological process is characterized by repeated hemorrhages into synovium and into subchondral bone.“’ Pannus formation and cartilage degeneration follow, and there is a remodeling of the bone ends, often with joint enlargement. A notable radiological feature particularly involving the tibia is severe subchondral bone destruction with cystic formation.‘92 Whereas arthropathy is extremely common in patients with less than 1% of the normal content of antihemophiliac globulin, it is unusual in hemophilia with an excess of 3%.* The prolonged presence of blood and its products in the joints seems to be an important factor in the pathogenesis of this disease.*” Both the incidence and severity of the arthropathy increase rapidly following puberty, despite the fact that the hemorrhagic incidents tend to decrease at this age.* It is not known whether there is any relationship between hemophiliac arthropathy and the fibrin-induced arthritis of Dumonde and GlynnM although similar pathogenetic mechanisms may be operative. It seems likely that joint damage prior to maturation is particularly important in the later development of osteoarthrosis. Hemochromatosis and W ilson’s Disease One form of arthropathy that may complicate hemochromatosis is osteoarthrosis, and this may appear de novo or in association with calcium pyrophosphate dihydrate (CPPD) crystal deposition (pseudo gout) and chondrocalcinosis.66.94*23’ The relevance of iron in the pathogenesis of this form of osteoarthrosis is not clear, but it is interesting in this context that a similar form of arthritis has also been described in secondary hemosiderosis66 and in Hemosiderin deposits have been obrabbits following iron administration.32 served in the articular cartilage of hemochromatosis.236 Osteoarthrosis may also 201 O STEO A RTHRO SIS supervene in the later stages of Wilson’s disease (hepatolenticular degeneration). 74,78,22X zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Alkaptonuria A prototype metabolic disorder that is associated with osteoarthrosis is alkaptonuria (ochronosis). It is not understood precisely how the metabolic defect induces articular cartilage degradation, but the later development of ochronosis is invariably associated with osteoarthrosis. Sokoloff255 has suggested that perhaps a colorless and as yet unrecognized metabolite may be involved in the pathogenesis of generalized osteoarthrosis, but to date no evidence has been advanced to support this hypothesis. Spondyloepiphyseal Dy splasia Spondyloepiphyseal dysplasia (Morquio’s syndrome) is a rare autosomal recessive disorder of mucopolysaccharide metabolism in which large quantities of kerato sulfate are excreted in the urine. In addition to gross skeletal deformities, there is epiphyseal dysplasia and fragmentation of articular cartilage.16’ A further rare familial disorder associated with the early development of osteoarthrosis in multiple joints is spondyloepiphyseal dysplasia tarda, which has been described in two families by Moldawer et al. I90 This disorder has similar features to those of Morquio’s syndrome, but as yet the underlying metabolic abnormality is not known. Cry stal Deposition Disease In gout, hyperuricaemia may be associated on and in the articular cartilage. In addition changes, osteoarthrosis may be a complication CPPD Cry stal Deposition Disease (Pseudo with deposition of urate crystals to the typical erosive and cystic of this disease. Gout) This disease entity is characterized by chondrocalcinosis and the intraarticular presence of calcium pyrophosphate dihydrate (CPPD) crystals.15’ Definite criteria have been proposed for its diagnosis.ls8 The acute gout-like arthritis is the known manifestation of CPPD crystal deposition disease, but only constitutes 307, of cases. A number of patients may demonstrate features of the disease without symptoms. As many as 6Oy; of cases have a progressive, chronic arthritis involving the larger joints that is indistinguishable from osteoarthrosis.‘S8 Histologically, the crystals are deposited in both degenerate and normal cartilage.15* At present it is not possible to say whether the crystal deposition is the primary event or a consequence of the degenerative changes; however, Zitman and Sitaj296 showed in their studies that the calcification process clearly preceded the degenerative changes. Lathyrism Lathyrism is a disease produced in young growing animals that have been fed with Lathyrus odoratus. These animals develop disorganized epiphyses. osteoporosis, and osteochondritis. 8,‘33The responsible moiety is @(N-y-L-glutamyl) aminoproprionitryl,‘84 which interferes with normal collagen formation. 202 LEE ET AL. The collagen produced is and remains soluble, and although proline incorporation and hydroxylation is normal,‘s3 a cross-linking failure seems likely. Divalent cations may be involved in this disease.8,‘33 zyxwvutsrqponmlkjihgfedcbaZYXWV Nutritional Factors Interest in the possible influence of nutritional factor? has been focused by the recognition of osteoarthrosis in Kashin-Beck disease.255 This is a disorder of growing children and is endemic in certain areas of Siberia, Mongolia, and North Korea. The disorder has been attributed to ingestion of grain contaminated with the fungus Fusaria sporotrichielfa,‘98 but others consider the disease due to a mineral defect of grain grown in endemic areas.44 It is manifest by fusiform swellings of joints, and in addition to growth defects, those children suffering from it develop florid osteoarthrosis later in life. To date, no other nutritional factor has been clearly implicated in the pathogenesis of osteoarthrosis. Obesity The relationship between obesity and osteoarthrosis is by no means clear; it has caused considerable debate and much divided opinion. Although from population surveys there appears to be a clear association between obesity and severe osteoarthrosis of the weightbearing joints, hips, and knees,‘2ss’43 nonweightbearing joints such as the distal interphalangeal and acromioclavicular joints are also severely involved in the obese.238,2““,245 Radiological surveys have revealed no excess of osteoarthrosis in the knees and hips56 or in the hands and feet7’ of obese subjects. In females under the age of 64, obesity was found to favor osteoarthrosis of the hands, but not the feet.263 Stecher263 found no correlation between obesity and the occurrence of Heberden’s nodes, but this view is disputed by the findings of others.12’ Sokoloff et al.?s7 in mice studies, found no correlation between the arthritis score and body weight of these animals. Interestingly, these workers were able to separate the genetic control of obesity and osteoarthrosis in breeding experiments.257 In a series of well-controlled animal experiments, Silberberg et a1.24’m243*246 have studied the influence of dietary lipids on the development of osteoarthrosis. A lard-enriched diet had a major influence on the severity and age of onset of the disease. However, Sokoloff et a1.258.259were unable to demonstrate any deleterious effect of dietary supplements with vegetable and unsaturated fats. Eskimos, who subsist largely on a fat diet, do not show a greater prevalence of osteoarthrosis.” fat and corn oil More recently, several workers 85,‘85have injected autologous into rabbit joints. The lipid is absorbed and incorporated into chondrocytes. Greater numbers of necrotic chondrocytes were noted in injected joints, and early fibrillation changes were occasionally noted. The relevance of these observations to human osteoarthrosis remains entirely conjectural, but a complex interrelationship between osteoarthrosis, obesity, fat metabolism, and diabetes is currently being proposed. 203 O STEO A RTHRO SIS Diabetes M ellitus and Related Endocrine Disorders of osteoarthrosis has been reported in patients with of anti-insulin serum to mice produced glycosuria, hyperglycemia, and histological evidence of enhanced degenerative changes in articular cartilage.237 Phosphorylated glucose intermediates are precursors of both the galactosamine and glucuronic acid moieties of glycosaminoglycan, the incorporation of which is under hormonal control. Therefore, impaired glucose utilization would be expected to decrease the formation of polysaccharides, which is in accord with the biochemical abnormalities recorded in this disease. Also, it would seem that hormonal imbalance, particularly involving cortisol or growth hormone, might be expected to affect glycosaminoglycan metabolism. In acromegaly , the articular cartilage is not only thickened with active proliferation of cartilage cells,” but there is also accelerated degeneration.‘25~286 Accelerated degenerative joint disease has also been noted in mice following experimental induction of a state of growth hormone excess.248,249 However, one could also argue that the accompanying osteoarthritic changes are due to abnormal physical stress as a result of altered joint contours rather than any disturbance in glucose handling.‘25 In a detailed morphological study of three cases, Bluestone et a1.18 noted increased new-bone formation, with active remodeling in addition to specific ulceration of cartilage at weightbearing sites. Sex hormones have also been implicated in the development of degenerative joint disease. Androgens were found to accentuate, and estrogen to retard, the subsequent onset of osteoarthrosis if administered during the period of groWth.2~,2“5-24’ However, orchiectomy was not observed to influence the course of degenerative joint disease in mice.253 The apparent protective action of estrogen is rather surprising since it has been shown to impair the production of mucopolysaccharide2’4 and also to reduce the superficial chondrocyte count.2“” On the other hand, there is increased cytoplasmic glycogen deposition and increased thickness of the collagen fibrils.240 The paradoxical observation that oophorectomizing these animals results in an ainelioration of their joint disease is yet to be explained, although this procedure will reduce the production of androgens as well as estrogens.239 The production of chondroitin sulfate in articular cartilage is known to be impaired following adrenal corticosteroid therapy.*’ Both starvation and administration of large doses of cortisone acetate in rabbits resulted in a marked reduction in the rates of protein and polysaccharide synthesis in articular cartilage, with the changes being more marked in the cortisone-treated group.“’ Such factors may be at least partially responsible for the development of Charcot-like changes following repeated intra-articular injections4s265 or prolonged oral corticosteroid therapy.‘96 Systemic or topical corticosteroid therapy in large doses has also been associated with aseptic necrosis, especially involving but not confined to the 98,268 and degenerative joint disease. 36 It has been demonstrated in rabbits hip, that excessive corticosteroid administration can result in fatty changes in the liver and systemic fat embolization, with the latter producing aseptic necrosis when involving interosseous sites.80 An increased incidence diabetes mellitus.245*287 Administration zyxwvutsrqp 204 LEE ET AL. G ENETIC FAC TO RS IN O STEO ARTHRO SIS The influence of genetic mechanisms upon the development of osteoarthrosis has been a tantilizing problem for many years. Kellgren et al.lz9 have demonstrated familial aggregation with a probable genetic basis, and Stecher263 suggested that a single autosomal dominant gene with reduced prevalence in males was operative in the development of Heberden’s node formation. The statistical basis of the later report has been questioned,129*‘93 and it is certainly true that no evidence has been advanced to show that the occurrence of osteoarthrosis can be predicted on a genetic basis. These factors militate against the acceptance of a major genetic influence in this disease, but by no means preclude minor and possibly polygenic influences. Incontrovertible evidence of genetic influences upon osteoarthrosis is provided by the osteoarthrosis that complicates some uncommon local or systemic chondrodysplasia,34*‘23 the genetically determined diseases, such as familial nail-patella syndrome (hereditary osteo-onychodysplasia),65 and alkaptonuria.1373201 Genetic factors can influence the later development of osteoarthrosis in several ways, including abnormalities in the development and preservation of articular surface congruity, biochemical defects in ground substance or collagen synthesis by cartilage cells, or any biochemical defect that might lead to abnormality in cartilage milieu or abnormality in the turnover and distribution of lysosomal or other degradative enzymes. This list may well be incomplete and osteoarthrosis itself could easily be a collection of different diseases. Thus it may be unreasonable to expect osteoarthrosis to be a single genetic defect. Even in an inherited form of the disease in an inbred colony of mice257 the pathogenesis remains unclear, and the situation may well be analogous to the study of the gouty trait. DESTRUC TIVE ENZYMES The relevance of intracellular enzymes to destructive changes of joints is a burgeoning area of research endeavor. For convenience, intracellular enzymes may be considered on the basis of the subcellular fraction with which they are associated. For example, enzymes such as acid phosphatase, nucleosidase, and acid proteases are associated on subcellular fractionation with lysosomes, the enzymes glutamic oxalic transaminase and alkaline phosphatase with the mitochondria, and myeloperoxidase with peroxisome.‘46 It should be emphasized that these associations are derived from mechanical and biochemical manipulations of whole cells, and in many instances there is little other indication of their derivation. Further, it should be noted that available techniques in this field are restricted, monitoring systems are often imprecise, and the possibility of experimental artifacts is ever present. Finally, the in vitro findings should be interpreted with caution, especially when relating to the in vivo situation. The rapid destruction of cartilage observed in suppurative arthritis has been simulated in vitro by incubating cartilage in purulent material or with a media such destruction of cartilage containing leucocytes from it. 5s~‘05~2”However, requires the digestion of collagen fibers, and there is evidence that such changes in septic arthritis cannot be accounted for by enzymatic activity alone.55 zyxwvutsrqp O STEO A RTHRO SIS 205 The protein-polysaccharide of ground substance can be degraded in a number of ways: depolymerization of the polysaccharides, removal of the sulfate, degradation of the protein, or separation of the polysaccharide from the protein.256 Several enzyme systems that have been identified in both cartilage and synovial fluid are capable of causing such changes. Articular cartilage is generally regarded as impermeable to protein. The intact proteoglycan molecule is entrapped within the collagen network, but once degraded by enzymes it can readily diffuse out of the cartilagenous tissue.2y,35.‘56The impermeability of cartilage to protein also protects the collagen in cartilage from the action of collagenolytic enzymes such as bacterial collagenase in vitro. Incubation of articular cartilage in collagenase was found only to produce collagen degeneration in the peripheral zones.‘94 Maroudas’74 has suggested that enzymes of high molecular weight could not be operative in the pathogenesis of cartilage destruction, since they would be excluded by the ground-substance molecular sieve. However, that some proteases can penetrate even normal cartilage is demonstrated by the intravenous injection of papain into rabbits, producing cartilage lysis.273 There is collapse of the ears owing to underlying cartilage destruction, and chondroitin sulfate diffuses readily out of cartilage into blood and urine. Histologically, there is loss of metachromasia, fibrillation, and cartilage disruption. A similar acute lysis syndrome occurs rarely in man in a disease known as relapsing polychondritis.‘08 In addition to widespread collapse of nonarticular cartilage, damage to articular cartilage and subsequent development of osteoarthrosis has been reported.208 The immunological demonstration of anti-cartilage antibodies and of lymphocyte sensitization to cartilage components”’ may be the result of, rather than the cause of, the disease. Collagenase, a neutral protease capable of degrading undenatured collagen, has been found in a number of tissues. It is present in synovium,24 especially in rheumatoid arthritis.14’ Whereas collagenase alone was unable to degrade whole articular cartilage, cartilage that had been pretreated with cathepsin became highly permeable on subsequent exposure to collagenase, suggesting synergism between two enzymes.‘54 However, the role of collagenases in the pathogenesis of osteoarthrosis is presently not known. It has been postulated that abnormal physical stress may rupture lysosomes within chondrocytes, activating proteolytic enzymes.24 Migration of lysosomes to the cell surface, with subsequent discharge of their contents into the extracellular environment, could induce proteinpolysaccharide degradation. Although it is not known whether physical stress is capable of initiating such a process, there is evidence to suggest that cells are capable of influencing changes in the surrounding cartilagenous matrix. Bollet2’ demonstrated that the material surrounding chondrocytes, close to the articular surface of osteoarthritic cartilage, was of lower molecular weight than the corresponding material in deeper layers. Weiss and Mirow290 demonstrated increased numbers of lysosomal-like structures in cells of osteoarthritic articular cartilage. Cartilage contains one or more enzymes capable of splitting the proteins polysaccharide molecule of matrix.5,48,276,293Its biological behavior and pH optimum suggest that it may be lysosomal in origin, probably a cathepsin. Massive doses of vitamin A administered to rabbits produce a papain-like action on 206 LEE ET Al. articular cartilage,“’ and it is believed that this is due to the release of cathepsins from the lysosomes in the chondrocytes. A number of hydrolases (including P-acetylglucosaminase, P-glucuronidase) having the capacity to split matrix polysaccharide are present in normal synovial fluid?’ but the levels of these are not demonstrably elevated in osteoarthrosis. A large number of synovial fluid glycolytic enzymes have been studied, but only aldolase has been found in increased concentrations in osteoarthrosis and with more markedly elevated levels in the inflammatory joint conditions.9’*29’ Synovial fluid levels of pepsin, cathepsin, and trypsin are all increased in relationship to serum levels in osteoarthrosis.283 Elevated levels of hyaluronidase have been reported in the synovium and synovial fluid of osteoarthritic joints.25 However, the enzyme has not been found to be present in chondrocytes or leukocytes, and, again, the levels in osteoarthrosis are much lower than are found in the inflammatory arthrides. On the other hand, the polysaccharide chains of chondroitin sulfate have been found to be reduced in length in osteoarthrosis,22*27 and this has been attributed to hyaluronidase activity. In addition, immunofluorescent studies indicate a resemblance of osteoarthritic cartilage (particularly that adjacent to the articular surface) to cartilage that has been treated with hyaluronidase.” Despite the absence of hyaluronidase from chondrocytes, local factors may be of importance in potentiating the activity of this enzyme once penetration into cartilage has been achieved. It has been demonstrated in vitro that hyaluronidase is more active in the degradation of cartilage polysaccharide in a lactate environment and is impaired following inhibition of lactate synthesis by 24 Glycolysis of articular cartilage is predominantly anaerobic3’ chondrocytes. and the high local concentration of lactic acid could therefore be sufficient to influence the pH and degradative action of such acidophilic enzymes as hyaluronidase and cathepsin. Plasminogen is present in synovial fluid in low concentrations, and activators are found in most tissues. Its activated form plasmin shows optimal activity at a neutral pH and in vitro has been shown capable of degrading cartilage protein-polysaccharide moieties. 135Increased levels of fibrinogen degradation products in synovial fluid of osteoarthritic joints have been demonstrated, and its activators in indicating active fibrinolysis, I4 but the role of plasminogen this disease remains to be fully elucidated. It is particularly noteworthy that biochemical abnormalities similar to those described in osteoarthrosis have also been seen in degenerative disk disease, an area that is not bathed by synovial fluid. PHYSIC AL FAC TO RS It is generally accepted that the normal and regular use of a joint does not predispose to osteoarthrosis, and heavy use of well-aligned joints apparently rarely induces cartilage breakdown.23 Freunda2 has suggested that there is an optimum cartilage load above and below which the frequency of joint disease increases. This concept is supported by the reduced incidence of osteoarthrosis in partially immobilized limbs, such as following poliomyelitis,” by the protective effects of other neurological defects on its development,53 and by the find- O STEO A RTHRO SIS 207 immobilization resulted in ings of Enneking and Horowitz72 that complete articular cartilage destruction and even fibrous or boney ankylosis of the joint. Similar histological changes have been observed in experimental animals following prolonged joint immobilization.73,92,272 A mechanism has been proposed that possibly could account for these clinical observations, namely the dependence of cartilage nutrition on intermittent compression in a sponge-like action.‘03~“2~‘50 It was found in the adult that nutritional diffusion was from synovial fluid only, whereas in immature cartilage this occurred from subchondral bone as well. Increased compression with continued exercise and motion leads to an increase in cartilage fluid content and thickening of cartilage with cellular proliferation and mitotic figures.54~“2~278 In contrast, experimental cessation of all joint movement results in cartilage degeneration, apparently from the deprivation of nutrition.72 The findings of a low sulfate content in cartilage of poliomyelitis patients6’ and the rapid cartilage atrophy and reduction in sulfate content following denervation of animal limbs3 however, are at variance with the above concept. first appears Although several workers 89,97have noted that early osteoarthrosis in nonweightbearing joints (elbows) and in nonweightbearing areas of the hip, the degenerative changes in these areas may be the consequence of underutilization. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Extrinsic Forces Clearly, the load on cartilage is distributed across the area of contact and is dependent upon the thickness, deformability, and character of the cartilage itself. Loadbearing and intrinsic forces have long been discussed in the etiology of osteoarthrosis. It is only recently that the influence of extra-articular extrinsic forces on cartilage loading has been recognized. These consist of the forces produced by the surrounding muscles and are difficult to measure, but Bonde-Petersen” has estimated a figure of 1964 kg fcm in the quadriceps of healthy subjects, rising to 2215 with isometric contractions. Similar figures have been found by other workers.‘47 Much of the force across a joint is attributable to muscle contraction22’.225 and not to weightbearing; therefore the upper-limb joints could conceivably be subjected to forces of the same magnitude per unit area as their lower-limb counterparts. Abnormal muscle pull, such as occurs with muscle spasms developing secondarily to articular disease, can undoubtedly generate a greater and more sustained compression of joint surfaces while the patient is in bed than occurs during normal walking.266 The female predominance of osteoarthrosic involvement of the distal interphalangeal joints has previously been attributed to genetic factors,263 but recent evidence suggests that the feminine grasp subjects these joints to higher stresses than are experienced by men. 2’5 Women indulging in masculine occupations have a lower incidence of osteoarthrosis of the hand, and this entity is uncommon in the male, except following trauma.” It has been suggested that ligamentous laxity predisposes to osteoarthrosis,13’ this also having been observed in experimental animal m o de ls.202 However, this phenomenon was not confirmed by Glyn et a1.87 in their findings on poliomyelitis victims, despite the fact that joints in a paralyzed limb are 208 LEE ET AL. subject to greater trauma protective muscle control. Intrinsic than normal because of the absence or deficiency of Forces It has been calculated that forces of up to four times and 5.8 times body weight are encountered in the kneeig’ and hip joints2” respectively, when walking. Sokoloff 256has suggested values of up to 10 times body weight in the knee joint during deep knee bending on the basis of several different methods of estimation. These forces have to be absorbed and transmitted by the joint structures. It seems likely that the influence of external stresses are small compared to the internal stress, but they may act as localizing factors. There have been several reports of osteoarthrosic change following repeated impact loading. 70,“o,‘55 In their studies using bovine joints, Radin and Pau12” found no significant wear of the articular cartilage despite prolonged oscillation under high constant loading. However, repeated impact loading caused rapid cartilage wear, with an early and marked rise in coefficient of friction and exposure of subchondral bone within 192 hr. In addition, these workers were able to induce severe degenerative joint changes in adult animals following application of similar forces.22’x252It has been suggested 2’6 that the thinness of cartilage precludes the structure as a major energy absorber and that the main force of impact is absorbed by subchondral bone and soft tissues. Microfractures have been demonstrated in the subchondral bones of joints subjected to repeated impulse loading,22’ and it has been further postulated that healing of these microfractures leads to bone remodeling, with resultant stiffening and reduced ability to absorb stresses, thereby exposing the articular cartilage to greater insult.2’g*220 Swanson and Freeman26g suggested that unusually high loads may increase the load deformation of cartilage sufficiently to rupture the surface collagen fibers with surface fibrillation. Disruption of the surface layers would then result in lateral extension of stresses and could possibly account for horizontal clefts that have been observed in human osteoarthrosic cartilage and mucopolysaccharide-depleted articular cartilage in hamsters.‘82 Remodeling Bone remodeling is probably a continuous and normal event”6”‘7 produced in response to normal stresses, and it is conceivable that it is the control of this remodeling process that is abnormal in osteoarthrosis. Recently it has been suggested that remodeling is dependent upon the influence of local electrical potentials’3g or piezoelectricity.‘5 Justus and Luft12’ have suggested in a similar manner that bone remodeling is a mechanicalchemical effect in which an initial mechanical stress later leads to a chemical reaction. In the piezoelectricity theory, a charge is generated by the separation of the centers of neutrality of positive and negative charges in a crystal lattice during movement. These charges are not only thought to influence remodeling but are also considered to have a significant role in the healing of fractures and structural maintenance.‘3g%264 Trueta,280 Swanson and Freeman,26g and Marmor’72 have suggested that a 209 O STEO A RTHRO SIS major factor in pathogenesis of osteoarthrosis is altered remodeling due to uneven distribution of pressure within the joint. Supporting these contentions is the fact that degenerative changes appear to be earliest in that part of the joint bearing the brunt of the normal pressure.‘6,99 In particular, 0ryZo4 demonstrated increased osteoarthrosis on the side of increased pressure in varus and valgus deformities of the knee, while Ekholm68 demonstrated increased osteoarthrosis on the side of the knee joint exposed to the greatest pressure, the fibular side. The findings of Harrison et a1.97 and Goodfellow and Bullough89 that osteoarthrosis appears early in nonweightbearing joints and in nonweightbearing areas ofjoints does not contradict this concept, since the changes seen in these areas are considered to be due to disuse. 89 The present evidence strongly favors mechanical stress (in some form and by some as yet undetermined mechanism) as having a major role in the pathogenesis of osteoarthrosis. zyxwvutsrqponmlkjihgfedcbaZY Instant Center Pathway From tine studies of moving joints, Frankel, Burnstein, and Brooks” have proposed a concept termed the instant center pathway. The instant center is the point of rotation at any given time. These authors suggest that an abnormal instant center tends toward the development of degenerative joint disease precipitated by trauma and that one started a biophysical and biochemical train of events leading to all the changes seen in osteoarthrosis. Bollet23 has proposed a self-perpetuating cycle consisting of trauma or abnormal physical stress, activation of proteolytic enzymes, increase rate of degradation of matrix components, decreased concentration of matrix components, altered physical characteristics, and erosion of articular cartilage in the development of osteoarthrosis. It has become universally recognized that osteoarthrosis is much imore complex than can be accounted for by a simple process of wear and tear. The various hypotheses put forward incriminate various aspects of normal joint function, but the underlying cause remains unknown. Perpetuation of joint damage may depend upon a chain of events, as suggested by various authors.23.2’9 It is our hope that the contents of this review will stimulate interest in this fascinating disease, which has a particularly refreshing feature, namely minimal immunological involvement in its pathogenesis. REFERENC ES I. 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