The Pathogenesis By David S. Howell,

P

of Osteoarthritis

Asher I. Sapolsky.

Julio C. Pita, and J. Frederick Woessner

RIMARY

OSTEOARTHRITIS, also labeled osreoarthrosis and degenerdisease, is an affliction of peripheral and central articulations, characterized by degeneration of cartilage, subchondral bone thickening, eburnation, remodeling of bone, and formation of marginal spurs as well as subarticular bone cysts. Concurrently, there are variable joint effusions, a low-grade synovial inflammation, and a gradual development of joint instability, particularly in weight-bearing joints. Clinical expression of the disease is manifested by pain more than stiffness, with severest dysfunction resulting from involvement of back, hips, and knees. The disease is self-limited with morbid but not fatal consequences. A heritable primary form involving Heberden’s nodes and multiple joints at menopause has been reported.‘,” Inflammatory erosive forms have been described.“-” If there are known direct causes, the term secondary osteoarthritis is employed with several categories (Table 1). One group evolves from common inflammatory disorders such as rheumatoid arthritis. Endocrine or metabolic diseases and physically engendered disorders comprise other groups. One of growing importance is the presence of developmental abnormalities with biomechanical dysfunction (Table 1). A smaller number of secondary forms relate to connective tissue disorders such as Morquio’s syndrome. Other recent reviews are recommended for detailed coverage of etiology and pathologic features?; recent research,“.‘“.‘” general overview,‘4 chemical and physical properties of cartilage,“) animal models of the disease,x mechanical factors,!’ relationship to inflammatory arthritisfib and osteoarthritis of the back.“’ In this report current concepts concerning the pathogenic pathways involved in degeneration of cartilage are discussed. ative

joint

BIOLOGIC

CHARACTERISTICS

OF ARTICULAR

The principal role of this type of cartilage terial for the ends of the bone at diarthrodial

From Arthritis

the Arthritis

Section

of the Veteran5

Division and Department

is to provide a suitable covering majoints, which tends to be in the order

Administrarion

of Biochemistry,

CARTILAGE

Hospital,

University

the Department

of MiamiSchool of

oJ Medicine.

Medicine,

Miami,

Fla. Supported

by Grants AM-08662. AM-05038, and AM-16940from the National Institutes ofHealth, Foundation Center Grant, and Career Development and Research supportfunds. United States Veterans Administration Hospital, Miami. Fla. David S. Howell, M.D.: Professor of Medicine, Medical Investigator, VA Hospital, University of Miami School of Medicine, Miami, Fla. Asher I. Sapolsky, Ph.D.: Research Assistant Professor. Department of Biochemistry. University of Miami School of Medicine. Julio C. Pita, Ph.D.: Research Associate Professor, Department of Medicine, Research Chemist, VA Hospital, University of Miami Schoo! of Medicine.J. Frederick Woessner, Ph.D.: Professor of Biochemistry, Associate Professor of the Arthritis

Medicine, Reprint

University of MiamiSchool of Medicine. requests should be addressed to: Dr. David S. Howell,

MiamiSrhoolof

Medicine, P.O. Box 520875.

‘CTI976 b.v Grune

& Stratton,

Biscayne

Professor

of Medicine. Universit

I‘ of

Anne-r. Miami, Fla. 33152.

Inc.

Seminars in Arthritis and Rheumatism.

Vol. 5, No 4 (May),

1976

365

366

HOWELL

Table 1. Classification

of Osteoarthritides

Based on Nature

of the Primary

ET AL.

Disease

Primary Idiopathic Generalized-Kallgren

and Moore

Inflammatory-Crain

and Ehrlich

Secondary Inflammatory RA and variants Septic and tuberculosis Physical Factors Posttraumatic,

acute, chronic

Charcot

arthropathy

Endocrine

Influence

Diabetes mellitus Acromegaly Sex hormone Latrogenic Metabolic

aberrations

hyparadrenocorticism

(local and general)

Gout Hemochromatosis Ochronosis Chondrocalcinosis Paget’s disease Developmental Morquio’s Congenital

or Abiotrophic

Defects

(with variable

levels of heritability)

syndrome hip dysplasia

Legg-Perthas

disease

Slipped

capital femoral

Altered

femoral

epiphysis

head, femoral

neck relationships,

etc.

Miscellaneous Hemarthroses Avascular

associated with blood dyscrasias

necrosis

of 2-4 mm thick. Articular cartilage consists of a relatively small number of chondrocytes which are dispersed within an abundant extracellular matrix. These cells synthesize new matrix constituents and regulate degradation. Following growth and maturation, throughout the remaining life of the animal or man, a remarkably constant number of cells reside in each square centimeter of carin adulthood cell division is minimal, but can occur in response to injury tilage;15” or disease. Many data suggest that the amount of matrix formed is influenced by within the tissue local biomechanical requirements of the tissues. lo Microstresses resulting from normal joint function have been shown to stimulate increasing cartilage thickness. Thus, if the stimuli are reduced or absent, as during immobilization, the volume of matrix synthesized by chondrocytes diminishes.‘O According to one view, adult articular cartilage is essentially avascular and is nourished largely from the synoviai fluid. ‘v*OHowever, data exist to indicate a functional number of capillaries extend through the calcified cartilage zones.53 Each chondrocyte is protected by a thin layer of multiple proteins, hyaluronate, and interwoven collagen forming a capsule which may have some protective role for the cell stresses. Most of the interstitial matrix between the chondrocytes as

PATHOGENESIS

367

OF OSTEOARTHRITIS

well as in the capsules is composed of two important substances: (1) collagen, a fibrous protein which contributes to the structure and shape of the cartilage; and (2) proteoglycans and glycoproteins which form the “stuffing material” between the fibers. Collagen fibers imbed deeply into the bony matrix and extend upward forming functional, if not actual arcades. The collagen fibers of the top or tangential zone of cartilage are parallel to the cartilage surface, forming a “protecgreatly to the mechanical strength of the tive armor coat,“‘O thereby contributing surface against abrasive forces during joint motion. On the other hand, as one passes from the transitional to the radial zone many of the collagen fibers progressively assume a direction perpendicular to the cartilage surface, and after penetrating a layer of calcified cartilage they become anchored in subchondral bone. In experiments where the proteoglycan stuffing material was degraded enzymatically but collagen left intact, the cartilage was shown to retain its normal shape; however, the elastic properties were lost.‘” In other studies, resistance of articular cartilage to deformation was correlated principally with glycosaminoglycans used as an index of proteoglycan content.” The joint cartilage and capsule together with subchondral bone function to dissipate the energy of weight-bearing, and the elastic properties of cartilage together with lubricated surfaces resist frictional forces which would quickly destroy exposed tendon or bone.” Thus the special properties exhibited by cartilage are compressibility, elasticity, and self-lubrication,‘x due to the combined presence of collagen fibers, densely concentrated proteoglycans, and glycoprotein. The proteoglycans have enormous water-binding properties. These remarkable compounds under pressure release, and then on removal of pressure, regain their domains of water.lg Most theories on the development of osteoarthritis involve a loss of proteoglycans (see below). It is convenient to think of osteoarthritis in terms of (1) etiologic factors, and (2) a resultant more-or-less common pathway for proteoglycan loss and cartilage breakdown. This perspective has developed not only from biochemical evidence but also from a strikingly uniform morphological sequence of events which attends the various primary, secondary, and experimental osteoarthritides. PATHOLOGIC

EVENTS IN OSTEOARTHRlTlS

On direct observation, the glistening appearance of normal articular cartiiage disappears and is replaced by yellowish or brownish discolored spots seen occasionally before age 20.7 By age 40, articular cartilage of most persons reveals such spots, which usually are not part of the progressive ulceration of osteoarthritis.’ Also, the discoloration per se should probably be viewed with less concern regarding surface integrity than the presence of granularity and a velvety texture. Later, there is disruption of the surface with flaking and pitting. Erosion and ulceration of a few selected sites, as studied by Byers et al.*” (see below), progress so that an area becomes denuded of cartilage. In the advanced disease, eburnated, i.e., polished thickened subchondral bone is exposed to the joint space. Concomitant with even early osteoarthritis, there is remodeling of subchondral bone, thickening, and marginal new bone formation in the shape of lips or spurs. These spurs or osteophytes are accompanied by subchondral bony sclerosis and cyst formation. In the advanced stages of disease, the remodeling of bone is

368

HOWELL

ET AL.

considerable, with gross overall deformity including subluxation, instability, appearance of “joint mice” or loose bodies within the articular space, and a lowgrade proliferative synovitis, often with villous changes.7 At the beginning, examination with the light microscope shows surface irregularities and loss of staining of the matrix for proteoglycans as seen with alcian bluezO or safranin 0 stains, and unmasking of collagen fibersFa Fissures, usually vertical, are seen to progress finally to the depth of the cartilage. With aging there is alteration of surface matrix material, most dramatically observed by scanning electron microscopy.‘5b,21 Chondrocytes proliferate in their lacunae giving clones-in “brood capsules.” This finding is considered by some investigators to help distinguish the old degenerating cartilage from new fibrocartilage which may have grown in during remodeling of the bone from the joint margins.** It has been recently shown that over age 60 an increased number of capillaries invade the tidemark from subchondral bony marrow and cause calcification and new bone formation to develop in the radial zone of the osteoarthritic cartilage.z3 Reduplication of the tidemark may occur as this process advances. 23Similar capillary invasions occur at joint margins.7 The subchondral bony trabeculae become thickened, and microfractures of trabeculae are seen, thought by some to be an etiologic factor in osteophytic formation.“X In the advanced lesions, bone-on-bone contact appears, as well as fibrocartilage islands, either outgrowths through the cleft from a subchondral marrow vascularization site or, much more often, new ingrowths from the margins of the joints. The subchondral bone cysts often have a small opening communicating to the surface of the joint. It has been speculated that very high intra-articular pressures (at least in the hip) may initiate pseudo-cyst formation.’ Mesenchymal cells within the cyst, however, may synthesize mucoid contents and thereby may engender cyst enlargement. Focal aseptic necrosis of the femoral head may be seen in some osteoarthritic hips, accompanied often by microfractures with or without loss of circulation marrow and trabecular regions. Islands of lymphocytes may be seen in the hyperplastic synovial membranes and a thin web of synovial tissue and pseudopannus may form across parts of the articular surface. However, as already mentioned, there is no true pannus as seen in rheumatoid arthritis, and, except in erosive or rapidly progressive primary osteoarthritis, usually no dense collections of lymphocytes or plasma cells with marginal erosion of the cartilage are found. Nor are the subchondral marrow spaces filled with lymphocytes and plasma cells as often noted in rheumatoid arthritis. At the electron microscopic level, osteoarthritic cartilage cells present a wide variety of appearances. Some cells, particularly in the superficial zones, are in varying stages of lysis and disintegration. In the deeper zones or in the brood capsules, chondrocytes reveal highly developed Golgi, well-developed endoplasmic reticulum, and vesicle formation indicative of a high rate of synthesis.24 In some histologic areas, collagen fibers appear grossly normal, although in many areas there is evidence of accentuated collagen banding and much thickening of some of the fibers.24 Evidence of new matrix synthesis is seen in the halo zone around some of the cartilage cells and there are deep areas of clear-cut matrix degradation. In the deep radial zone, stains for alkaline phosphatase are often strongly positive.” Matrix vesicles, some containing electron dense particles suggestive of minerals,

PATHOGENESIS

OF

369

OSTEOARTHRITIS

PROTEASE ATTACK ON PROTEIN CORE

o AND b = LINK PROTEIN HYALURONIC HA BINDING

ACID IHA: SITE

‘CHONDROITIN SULFATE CHAINS

Fig. gregate

1.

Diagram

molecule

of showing

proteoglycan a current

agview

of its structure.

are found, especially tilage calcificatior,.‘5c

in histologic

BIOCHEMICAL

sites of capillary

invasion

and adjacent

EVENTS IN THE FINAL COMMON

new car-

PATHWAY

Throughout life, cartilage maintains a remarkable isolation from the rest of the body in terms of exposure to exogenous agents and endogenous chemical assault. This chemical isolation is in large part due to the proteoglycans which, being macromolecules with their strong negative charges and size, severely limit diffusion. Proteoglycans comprise about 10% of the dry weight of adult articular cartilage and because of their importance in understanding osteoarthritis one must digress briefly to describe proteoglycan structure. This subject has been studied intensively in several laboratories, which has resulted in major advances discussed in detail elsewhere.~“-~“,“.5-“7 Electron micrographs of the proteoglycan molecules, spread out in monolayers on a cytochrome C solution, have the startling appearance of a cluster of Christmas trees.” The “trunk” of each “tree” is thought to be composed of a hyaluronate molecule with each branch composed of the core protein of proteoglycan subunits. Symmetrically arranged secondary “branches” correspond to multiple linear glycosaminoglycans which are attached to each core protein. The cluster comprises a proteoglycan aggregate first discovered and defined by Hascall and Sajdera. 26.27By this hypothesis, the subunits are attached at intervals along a linear cartilage hyaluronate molecule,2x probably stabilized at each linkage site by at least two glycoproteins, a and bzg (Fig. 1). Each subunit molecule of proteoglycan consists of core proteins of molecular weight (MW) of about 200,000 Daltons.* Linear glycosaminoglycans (GAG) of 1 l,OOO-36,000 MW are attached to subunit core protein. The chemical nature of the GAG--core protein links has been characterized, and the protein core-hyaluronate linkage region is under intensive investigation. Among the exciting features of the proteoglycan molecules are their gargan-

*Because of their polydisperse can be given.

nature,

no exact value for molecular

size of subunits

or aggregates

370

HOWELL

ET AL.

tuan size and their physical properties, particularly their high level of sulfation and dense number of negative charges per unit volume.‘9 The repellant action of adjacent negative changes keeps their branches extended, encompassing water and contained solutes. These properties make proteoglycans ideal stuffing material for the interstices between cartilage collagen fibers. As already mentioned, proteoglycans are also largely responsible for reduced diffusion of all but select small molecules through the cartilage matrix. lsd Plasma proteins, except perhaps small amounts of albumin, are totally excluded. However, normal nutrition seems to require delivery in the adult of nutrients primarily, if not only, through the synovial fluid,‘“’ and low-molecular-weight compounds, amino acid, glucose, and other nutrients rapidly diffuse (within minutes) to the cartilage cells. Although variation in motion (cyclic loading) should not make much difference in the flux of nutrients to chondrocytes once inside the cartilage, delivery of nutrients from synovial fluid to the cartilage surface could be profoundly affected by immobility, as will be discussed below.‘5d Recent evidence has been accrued for possible failure of steps in proteoglycan synthesis in respect to 3sS sodium sulfate incorporation into proteoglycans,3” as well as altered degradation in human osteoarthritic cartilages. Studies of proteoglycan molecular size have indicated considerable variability, probably depending on the tissue sample. A proportion of proteoglycan of osteoarthritic cartilage was found much more readily extracted than normal by brief agitation of the tissue in iso-osmotic neutral salt, suggesting a reduced level of aggregation. y3 When proteoglycan was extracted on a microscale specifically within 1 mm from the border of an osteoarthritic ulceration, a sharp reduction in the sedimentation values was found.“’ In addition, there has been found to be a loss of the R-2 fraction considered to be a macroaggregate. Polysaccharide chain length of proteoglycans was first shown to be reduced in osteoarthritis by Bollet and Nance.32 Whether these changes represent failure of synthesis or accelerated degradation remains unknown. Mankin et al. extracted osteoarthritic cartilage for proteoglycans and isolated chondroitin-4 and -6 sulfate as well as keratan sulfate.30 In control hip cartilages they found that about 90% of the GAG was comprised of an equal mixture chondroitin-6 sulfate and keratan sulfate. There was a significant rise of chondroitin-4 sulfate content in the osteoarthritic tissues. It was hypothesized that this finding might reflect an inadequate repair response of these tissues to osteoarthritic degradation. Also, they found a high positive correlation between rates of synthesis of DNA and polysaccharide and the severity of the osteoarthritic processes measured by Mankin’s histochemical grading system.L”f~30This positive correlation was observed until an advanced grade of severity of osteoarthritis was obtained, at which point reparative synthetic processes in the cartilage seem to falter and subsequent decline in synthetic rates ensued. Because in the human osteoarthritic hip it is difficult to distinguish the original osteoarthritic cartilage from the largely osteophytic or fibrocartilage repair, despite careful histologic control, it has been necessary to reexamine continually the extent to which biochemical events are localized in remnants of old cartilage as opposed to the abundant osteophytic cartilage. Thus, it is reassuring that in OSteoarthritic model systems in dogs33 and rabbits,34.35 in which structural knee

PATHOGENESIS

371

OF OSTEOARTHRITIS

alterations lead to secondary cartilage degeneration, there is also evidence of accelerated protein synthesis in the tissues immediately surrounding the osteoarthritic lesions studied before fibrocartilage could have formed. However, in respect to glycosaminoglycans, Hjertquist and Lemperg in their data on human osteoarthritic articular knee cartilage did not find noticeably more chondroitin-4 sulfate in osteoarthritic than control samples, but did find interesting changes with aging. 95 Another facet of the biochemical response to osteoarthritic lesions studied recently has been the genetic peptide map of co11agen.36*37 Osteoarthritic tissue collagen was extracted and degraded to peptides analyzed by chromatographic and electrophoretic techniques. The genetic peptide hallmark of bone and skin collagen is type I, whereas in cartilage the collagen normally is principally composed of the genetic peptide type II. One laboratory group found that osteoarthritic hip lesions contained substantial amounts of type I collagen, thus providing evidence of an inappropriate repair response,“‘j but these findings were not confirmed by Fukae et al., who found only type II collagen in similar tissues using similar methods.37 The latter authors found that the osteoarthritic collagen contained chromatographically different compounds from those of normal articular cartilage, which they attributed to variations in lysine hydroxylation or 37 Also, in a dog model of osteoarthritis, all type II glycosylation of hydroxylysine. collagen synthesis was found in the earliest stages of disease.33 In regard to the repair of osteoarthritic ulceration, there is little evidence to date that structural renewal of the arcade appearance of collagen fibers is reduplicated in any of the healing lesions .* Also, in experimental injuries of knee cartilage in rabbits, despite continuous passive exercise which promoted healing dramatically, the repair cartilage appears not to have the same mechanical strength as the original tissue.3R Despite difficulties of reattainment of the original tough cartilaginous structure, clinical and laboratory experience with fibrocartilage layers formed after osteotomy and tenotomy indicate that a functional bearing surface can be reformed under special well-defined conditions.“g The fact that this occurs clinically, however, gives continued hope for the view that with proper pharmacologic and/or physical stimulation degenerating osteoarthritic cartilages could regenerate in a controlled reproducible manner to provide an effective joint restoration. Therapeutically, this would be an ideal approach. A prototype of what might be accomplished is seen in acromegaly, a disease in which a much thickened layer of apparently normal articular cartilage occurs throughout the 200 joints of the body perfused by an excess of somatomedin resulting from the overproduction of growth hormone.“O Unfortunately, this disease is characterized by a form of degenerative arthritis,4” considered by some authorities to result from the mechanical stresses resulting from overthickened articulations. To be effective for osteoarthritis, any hormonal treatment would have to be regulated in its dosage so as to restore but not to overthicken the cartilages. Following previous studies from Daughaday’s group and others,l’ McConaghey *This arcade appearance is paradoxically detected in polarizing light microscopic scanning

electron

microscopic

preparations.

studies,

but not in

372

HOWELL

ET AL.

and Sledge showed that most of the active agent in vitro, viz. somatomedin, arose from livers of hypophysectomized rats perfused with tissue culture medium containing growth hormone.“2 Sledge42 also showed that totally hepatectomized hypophysectomized rats were unresponsive to growth hormone, both in terms of failure to incorporate thymidine 3H into their rib cartilage and failure to produce somatomedin in serum measured by Daughaday’s bioassay.41 Two cartilage-active polypeptide fractions which appear after treatment of liver slices with growth hormone weigh 8000-10,000 MW. 41,42 These low-molecular-weight fractions theoretically could permeate articular cartilage and cause the expected stimulation of protein synthesis and cell division. Another growth factor of great interest is the connective tissue activating peptide (CTAP) of Castor.6d,43 This lowmolecular-weight polypeptide isolated from synovial membrane is a strong stimulator of matrix synthesis by cartilage cells in vitro. Some activity of this type is also demonstrable with the serum insulin-like substances.6d*43 Cell proliferation alone can be induced employing the tissue culture technique of Corvol et al. by a contaminant of pituitary thyrotropic hormone and chorionic gonadotrophin.“4 Chondroitin sulfate per se, when injected into dog knees, stimulated marginal cartilage production and bony spurs.45 An enigmatic problem for use of growth stimulators will be to heal selectively the ulcerative osteoarthritic lesions without promoting the untoward ocurrence of marginal bony and cartilaginous overgrowth. MECHANISMS

OF CARTILAGE

DEGRADATION

Inasmuch as the half-life of collagen in human articular cartilage is considered to be too long for practical measurement, it is not surprising that most attempts have yielded no detectable collagenase in normal cartilage. Cartilage tissue cultures of osteoarthritic tissue have been found after several days to show sporadically a small amount of collagenase. 46 Major constituents believed to be degraded are the proteoglycans and glycoproteins. These comprise both protein and aminosugar components for dismemberment. Except for a promising recent study exhaustive efforts have failed to show evidence of a on embryonic cartilage,!‘” chondroitinase necessary to make the initial cleavages in the long chains of chondroitin sulfate to liberate sulfated oligosaccharides. Nevertheless, there is a complement of exo-B-n-D-hexosaminidases and exo-B-d-glucuronidases capable of oligosaccharide breakdown in chondrocytes.l”g Thus it remains enigmatic whether in adult tissues this process is accomplished in cartilage cells.1ig~4” When labeled chondroitin sulfate chains are injected in vivo they are largely broken down to monomers in the liver.“’ Thus far, it has been possible to demonstrate only protease degradation of proteoglycans in cartilage cells. Cathepsin D was isolated from various animal and human cartilages and its biochemical properties were characterized and indicated action only at very acid pHs. Other acid hydrolases have been found, one of these in human cartilage is designated cathepsin F. Cathepsin D was found two- to three-fold greater in activity in osteoarthritic than in normal cartilages.‘” It was found that the cathepsin D was localized to lysosomal fractions of osteoarthritic cartilage, as expected from animal studies of cartilage.4g Fluorescent-labeled antibodies to purified cathepsin D register principally in human osteoarthritic car-

PATHOGENESIS

OF OSTEOARTHRITIS

373

tilage within the chondrocytes and also outside the cells’ limiting membranes and in surrounding matrix.“” This work strongly supports a major role of this enzyme, at least in later steps of cartilage degradation. However, inasmuch as cathepsin D and most other lysosomal hydrolases, including probably cathepsin F, act at very acid levels, it is considered likely that most of the proteoglycan degradation due to them occurs around the cartilage cells rather than in the deep interstices of the matrix. Cathepsin D inhibitors, e.g., pepstatin, are ineffective in vivo. Nevertheless, the search continues for other potent inhibitors which could be effective. To account for proteoglycan degradation distant from cells, enzymes active at due to a roughly neutral pH,4X possibly a neutral protease, initiate degradation neutral pH there. In this regard, a metal-binding neutral protease in multiple forms from cartilage has been purified a thousandfold and is a potent proteoglycanase.“’ It is estimated that about 85% of the protease activity which was extractable from normal human patellar cartilage resulted from cathepsins D and other acid hydrolases, and about 15% or less resulted from neutral protease activity.lZ,“l Because no pannus invades cartilage and no lymphocytic or other cellular infiltrates appear in osteoarthritic cartilage, it is almost certain that the enzymes described above are generated by the chondrocytes per se, and that at least the initial stage of cartilage degeneration is endogenously rather than exogenously caused. In support of this view, there was about l/70 as much cathepsin D activity in osteoarthritic synovial fluid as in the adjacent cartilage.‘” The potential for cartilage destruction increases once an ulceration appears, permitting entry of synovial fluids. The synovial fluid is theoretically the repository of enzymes deleterious to matrix, such as hyaluronidase,‘2 entering from the systemic circulation. Also, in normal synovial lining membrane a new metal-binding neutral protease has been demonstrated in tissue culture, as well as cathepsin D and collagenase?:; The extent to which these enzymes leaking into the ulcer from synovial sources contributes to degradation remains unknown. Without such ulcerations, however, as mentioned above, the highly charged macromolecules of cartilage effectively prevent molecules of 50,000 MW or more from entering the cartilage.lSd Thus there are essentially no globulins, such as the potent enzyme a2-macroglobulin or a-l trypsin inhibitor, and only a small amount of albumin, but enzymes of low MW, such as the exogenous enzyme papain used to produce experimental arthritis,lAh readily diffuse into cartilage. Once degraded by proteases, the penetrability of cartilage greatly increases? Nevertheless, there is in normal cartilage a low-molecular-weight native trypsin inhibitor which might account, in part, for the capacity of cartilage to resist capillary invasion by tumors, etc.T’b The cationic protein lysozyme is abundantly present in cartilage, and there is growing evidence that it has some role in regulating the size of proteoglycan aggregates,"4c."' In any event, depletion of glycosaminoglycans is a cardinal feature of all forms of naturally occurring and experimental osteoarthritides, primary as well as secondary, probably as a result of enzymic action. The depletion is registered by reduction of hexosamine, hexuronate, and sulfate.32.‘x Interestingly, there is an increased water content in osteoarthritic lesions,‘“’ apparently due to disruption of collagen and exposure of water-binding configurations following fiber breakdown. Loss of proteoglycans also leaves the collagen network relatively un-

374

HOWELL

ET AL

supported, accounting in part for the deepening fissures, greater exposure of collagen, and final mechanical disruption and breakdown of collagen fiber fragments which find their way into the synovial fluid. CHANGES

IN SYNOVIAL

MEMBRANE

A low-grade synovitis appears to result from removal of cartilage breakdown products through the interstitium of the lining synovial membrane. Demonstration by Moskowitz et al. that chondroitin sulfate may activate Hageman factor in vitnYg indicates that the kinin pathway could be activated in osteoarthritis. This finding, if operative in vivo, could help to account for vascular and connective tissue hyperplasia of the lining membranes, as well as the low-grade infiltration of mononuclear leukocytes.5g If one extrapolates evidence from studies of cartilage in patients with polychondritis (Hughes et al.,88 and Herman and DennisGo), the strong possibility is raised that a delayed immune response to proteoglycan protein fractions could occur in osteoarthritis too,p6”but this demonstration has not yet been made. To the authors’ knowledge, no evidence of systemic immunologic involvement of the B cells in human diseases involving proteoglycan breakdown has yet been found, despite the presence of at least two antigenic determinants in the proteoglycan molecule.8g Other biologic events of uncertain relevance to pathogenicity that are part of the pathologic picture of osteoarthritis are the capillary ingrowths invading the calcified cartilage and tidemark, not only in the remodeling of bone on joint margins but also in remodeling under the ulcerated cartilage lesions.23 A recent study indicates output of alkaline phosphatase and pyrophosphate into synthetic Eagle’s medium by pieces of human osteoarthritic cartilage.61 This evidence, together with the high pyrophosphate found in the synovial fluid and the high alkaline phosphatase of basal cells found in the cartilage of patients with osteoarthritis, raises the question of whether an undetermined disturbance of mineral metabolism is also an integral part of the osteoarthritis picture and may relate it to chondrocalcinosis.‘j2 Putting together the pathologic and chemical events as described here, one finds a flow diagram which seems as applicable now as when it was elaborated upon by Bollet in 1967 (Fig. 2).‘* Although proof that all elements of this pathway function universally remains to be established, it is a useful model (Fig. 2). ETIOLOGIC

FACTORS

Genetics Multifactorial genetic patterns appear to be involved in some forms of osteoarthritis, for example, that form appearing with Heberden’s nodes, and certainly with disorders like ochronosis in which deposition of an abnormal metabolic pigment may provoke cartilage degeneration. By and large, at present little can be made of genetics as a contributing factor to osteoarthritis in man,ap’4 although in inbred mice’j3 and in dogsgl a heritable predisposition to osteoarthritis has been scrutinized. Obesity in mice had no positive influence’ on osteoarthritis production, but in man severe obesity causing separation of the thighs by adipose tissue with mechanical factors was postulated to cause genu valgum and consequently a

PATHOGENESIS

OF OSTEOARTHRITIS

375

PHYSICAL STRESSES f CHCNDROCYTE INJURY

\ I RELEASE OF DEGRADATIVE ENZYMES

1

CARTILAGE EROSION

J ENTRY OF SYNOVIAI. FLUID ENZYMES 1 LOSS OF ELASTICITY AND SELF-LUBRICATING PROPERTIES

/

~ii%:-..

MATRIX DEGRADATION PRODUCTS, PROTEOGLYCAN, ETC.

_3

LOCAL CHONDROCYTE STIMULATION

CHONDROCYTE PROLIFERATION LOCAL AND SYSTEMIC HORMONES

\ I CARRIED IN SYNOVIAL FLUID To LINING MEMBRANE Fig. 2.

A postulated

final

common

pathway

or cycle

of cartilage

degeneration

predisposition to osteoarthritis of the knees. fi4 However a more complex relationship of obesity to osteoarthritis probably exists, complicated by endocrineX,‘” and metabolic factors. Results of epidemiologic studies in relation to climate, as exemplified by the controversial lower incidence of the disease in far Northern latitudes, and in relation to race, e.g., the lower incidence of osteoarthritis of the hips in Chinese, are difficult to assess.14 Endocrine factors have been studied extensively in animals, but application of the results to humans is difficult to interpret. In general, androgenie steroids provide an acceleratory affect on osteoarthritis, whereas estrogens have an inhibitory action, as reviewed by Moskowitz.““x Another factor, joint lubrication, has undergone intensive study and views concerning its importance have shifted radically over the past 10 yr. Previously it was thought that joint stiffness resulted largely from failure of lubrication of articuiar surfaces due to failure of the principal contributor to synovial fluid viscosity, hyaluronic acid. Later studies have shown that hyaluronate is a poor lubricant in solution in in vitro models of cartilage-cartilage bearings and that digestion of synovial hyaluronic acid with hyaluronidase does not lessen synovial fluid lubrication.” In fact a hyaluronate-free glycoprotein probably makes an important contribution to lubrication within the joint.65 On the other hand, in periarticular soft tissues, where most of the resistance to joint motion occurs, hyaluronic acid seems to be an effective lubricant per se.g The important literature on joint lubrication has been reviewed elsewhere.g Trauma and Microtrauma Epidemiologic evidence strongly indicates the importance of wear-and-tear and microtrauma as reviewed by Lee et al. I4 Industrial or athletic joint functional

376

HOWELL

EXCESSIVE LCCAL INCONGRUENCE SECONDARY To JOINT OR BONE DISEASES

AGING LOSS OF SLIGHT NORMAL INCONGRUENCE

IMMOBILIZATION

’ / ’ I// IMPAIRED NUTRITION OF CHONDRCCYTES I

INJURY OF CHCNDRCCYTE

/

ET AL

DEVELOPMENTAL DEFECTS

A

,NO/

DISTRIBUTION OF PHYSICAL STRESSES*

%%ILITY

-

SURFACE FISSURES

+-.

\

\

\

ABNORMAL

FORCE ATTENUATION \

JOINT MOTION ABNORMALITIES SECONDARY M ORTHOPEDIC OR NEUROLOGICAL DISEASES

SUEICHONDRAL STIFFENING

MACRO

AND MICRO TRAUMA

t RELEASE OF DEGRADATIVE ENZYMES

W

CARTILAGE DESTRUCTION -

l

INCLUDES ABNORMAL INSTANT CENTER PATHS Fig. 3.

Hypothetical

effects of biomechanical

factors in promoting osteoarthritis

overload has been clearly demonstrated to be an occupational hazard (Fig. 3). A high incidence of osteoarthritis has been found in the elbows and knees of miners, shoulders and elbows of pneumatic drill operators, fingers of cotton pickers, spines, knees, and elbows of wrestlers, patellae and femoral articulations of cyclists, shoulders and elbows of baseball pitchers, ankles and feet of professional dancers, hands of boxers, and knees of football players.14 Workers were found to have more severe osteoarthritis in the dominant (right) hand than in the left hand.4 A relationship between major stress in joints and osteoarthritis of animals has also been observed. Conversely, partial immobilization as occurs following poliomyelitis or neurological defects has been shown to have a protective effect in regard to incidence of osteoarthritis.14 The feminine predominance of osteoarthritic involvement of distal interphalangeal joints has been considered in the past to be of genetic origin, but studies by Radin et al. indicate the possibility of higher stresses in the feminine grasp on these DIP joints. 66 Women with masculine occupations had a lower incidence of osteoarthrosis of the hand than housewives. 67 Ligamentous laxity may also predis-

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pose to osteoarthrosis, at least in the presence of sufficient microtrauma. Studies on the nature of these forces involved in occupations such as those listed above have found them to be indeed large. It has been estimated that during walking four to five times the body weight is passed through the knees or hips, and Sokoloff estimated ten times the body weight might be applied to certain surfaces within the knee during deep knee bending.’ Unusually high surface loads may increase the deformation of cartilage, rupture surface collagen fibers, and result in lateral extension causing horizontal clefts in the cartilage. 68 High constant loads with oscillation were well tolerated by articular cartilages in in vitro model systems studied by Radin and PauLeY However, repeated impact loading caused rapid deterioration (Fig. 3). Radin suggested that the thinness of cartilage excludes it as a major dissipator of energy, and that the main force of impact loading is attenuated by subchondral bone as well as by the joint capsule and muscular structures.” Overload is dissipated by fracturing of the trabeculae with consequent marginal joint remodeling and loss of elasticity of the subchondral bone. This stiffening and loss of capacity of the bone to absorb loading energies might expose the articular cartilage to such insults as to set off the final events of the common pathway!’ (Figs. 2 and 3). Evidence favoring this theory is increasing, but proof is not at hand. Certainly, osteoporosis of the femoral head, which would lead to greater compliance in the subchondral bone, is associated with a lower incidence of osteoarthritis of the hip.“’ Another form of physical stress, studied by Frankel et al., relates to the fact that joints most susceptible to osteoarthritis do not rotate like hinges but involve a certain amount of gliding. 7’ In these moving joints there is an instant center of rotation which normally is perpendicular to the point of impact. In the presence of abnormal motions or shocks, as from errors in gait (Fig. 3) the pathway of instant centers may no longer parallel the cartilage surface and may impinge into the cartilage, thereby setting up abnormal force patterns. Particularly with the use ofjoint replacements, various prostheses, and exercises, correction of abnormal instant-center pathways is an important new contribution to guiding therapy on a sound bioengineering basis. Developmental Defects Predisposing malfunctioning articulations occur when there is too great an incongruence between two opposing articulations, as in the shallow acetabulum of Legg-Perthes disease and congenital hip dysplasia, and in the alterations of slipped capital femoral epiphyses (Table 1). These comprise a small proportion of the total problem of osteoarthritis. However, over the past decade, studies have raised the possibility, although still controversial, that up to 80% of so-called primary osteoarthritis may, in fact, be a form secondary to developmental defects in the hip. Major studies by Murray and by Stahlberg and Harris support this view.‘“-‘” It was shown that a common finding of predictive value in those coming to hip surgery was a tilt of the femoral head on femoral neck, pistol grip deformity, and shallowness of the acetabulum. These factors were all roughly measurable by carefully taking x-rays of the hip and fitting some critical measurements into a formula.72~7y These intriguing observations are so important as to warrant considerable further study on a prospective basis, since in neither study were optimal controls possible. Studies done by Ory predict the probability of os-

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teoarthrosis of the knee based on mild genu valgus or varus deformities.‘” Ficat suggests that chondromalacia patellae probably develops because of undue lateral tensile forces.76 Swanson et al. have found a region at the zenith of the acetabulum which is often fibrocartilagenous, and in some patients this region exerts excessive pressure on the femoral head during weight bearing.77 All of these factors may be considered examples of overt or excessive joint incongruity. In each instance, abnormal stresses would develop at the point of incongruence, theoretically leading to cartilage degeneration. There is little argument that some cases of osteoarthritis are based on such a development. Joint Remodeling and Excessive Congruity On the other hand, Bullough et al. have advanced evidence that overcongruence is accompanied by the development of osteoarthritis.78 These investigators removed human femoral acetabular articulations at autopsy and remounted the joints in a way such that they could map the contact points of normal versus osteoarthritic patients. In the majority of the osteoarthritic patients, in contrast to normal, the weight bearing was not at the apex under physiologic loads but in a rim of the femoral head a centimeter or so back from the apex. In contrast to primary osteoarthritic cartilage, under the same pressure in their model systems, the apex of the femoral head contacted the acetabulum.7x Histologic studies showed evidence of remodeling of the bone as postulated by Johnson to occur as a normal function of aging. 7g Such remodeling accelerated in the sixth decade premonitory to development of osteoarthritis. 78In the knee, similar measurements of contact indicated that the vault or cone of untouched cartilage on each femoral condyle developed due to the carrying of the weight on a rim, composed of the tibia1 plateau on one side and the meniscus on the other side. Joint remodeling or loss of meniscal function caused loss of this normal incongruity with weight bearing on the apices as a function of the time and bony remodeling. Examples of such increased congruity in the temporo-mandibular joint and most other joints in which osteoarthritis occurs have been observed. 8o Bullough et al. point to studies concerning loss of nutrition in the absence of joint motion, but their emphasis is that even with joint motion, a small amount of incongruity is needed to give proper physical stimulus for normal chondrocyte function and for distribution of synovial nutrients.78 As with too much incongruence, the proportion of osteoarthritics in which too little incongruence is a critical factor remains unknown. It should be further noted in respect to nutrition that dependence of chondrocytes on intermittent compression for distribution of small molecular nutrients of the cartilage is contested by Maroudas.lsd Thus, whether modest or moderate exercise is essential for joint nutrition or whether repeated heavy impact loading may have a deleterious effect requires more study on nutrition. Lack of nutrition has been postulated to be responsible for the frequent finding of surface ulcerations and histologic cell loss found in certain parts of hip articular cartilage which fail to receive adequate intermittent compression. In fact, total immobilization of a limb was shown by Enneking and Horowitz and others to result in cartilage destruction and fibrous or bony ankylosissl as well as increased stiffening of collagen in joint capsules.82

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OF OSTEOARTHRITIS

Aging

Only minor effects of morphological and biochemical aging of cartilage cells or matrix on production of osteoarthritis have yet been uncovered.7 There are important hints of histologic changes in the surface of the cartilage and alterations of collagen cross-linking not readily detected, partly due to the insolubility of aged collagen. Certainly, the depressing effect of age on the capacity of articular cartilage to withstand fatigue testing raises the possibility of as yet uncategorized of human articular subtle chemical changes in cartilage. 83 Characterization proteoglycans and collagen using new tissue culture methods may eventually uncover such changes.84 Certain histologic studies of Vignon et al. show deep cartilage cellular degeneration, which the writer thinks could be interpreted as a primary tissue failure rather than a response to surface physiologic factors.X.5 Also, biochemical and histochemical studies demonstrated a significant increase in extracellular lipids with advancing age. g4 Remodeling as a function of aging as described by Johnson could have profound effects with respect to joint congruence and attrition of cells attendant on loss of nourishment.7g Working on these, perhaps, rather constant factors are variable factors such as physical and genetic makeup, body weight, and occupation, and the length of time that these factors have been operating. Byers et al. have attempted to correlate these factors in a computer program wherein some sort of predictive relationship might be quantitated.“” Of particular interest is the question as to which factors cause pathologic osteoarthritic progressive lesions versus those which seem not to progress.X6*X7In the studies of Silberberg and Silberberg in mice, senescent and osteoarthritic changes in cartilage were accelerated by a prolonged use of a high fat diet.Y2 Also, we are probably on the verge of a new era of study of regulators of cartilage cell metabolism in osteoarthritis. This era involves research on intra- and extracellular receptors sites for PTH, the HO-cholecalciferols, somatomedin, CTAP, sex and adrenal steroids, etc. and investigation of the role of other regulators now sought in cartilage, such as prostaglandins of the E and F series, superoxide production, cyclic AMP and cyclic GMP mediation pathways with their special phospho-di-esterases, etc. Another current question in what regulatory pathways are involved when chondrocytes synthesize matrix, proliferate during injury, and develop phagocytic functions with aging. Hopefully, through perpetuation of such clinical, epidemiologic, cell biologic, and biochemical research as that reviewed here, many complexities of osteoarthritis will be clarified over the next decade and thereby enable more effective therapy. ACKNOWLEDGMENT The authors are indebted to Dr. Leon Sokoloff, Dr. Roland Moskowitz, Dr. Lent Johnson, Dr. Peter Butlough, Dr. Henry Mankin, and Dr. Eric Radin for helpful comments during the preparation of this review. However, the views expressed here are not necessarily identical to those of the above investigators.

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S-E, Hjertquist S-O: bovine articular carand distribution in to age. Calcif Tissue