Osteoarthritis: A Review of the Cell Biology Involved and

Evidence for Reversibility. Management Rationally Related

to Known Genesis and Pathophysiology
By John H. Bland and Sheldon M. Cooper

C
LINICIANS regard osteoarthritis (OA) as ease, is inappropriate if words are to describe the
a common (indeed universal), slowly pro- process.
gressive disorder that occurs in mid- to late life. It OA is commonly regarded as an inevitable
mainly affects weight-bearing joints and periph- consequence of aging, a wear and tear manifesta-
eral and axial articulations, and it is clinically tion, or as a result of some abnormal joint
characterized by pain, deformity, limitation of mechanics. The past decade has experienced an
motion, and inexorably progressive disability. explosion of knowledge about the structural,
Reversal or even arrest of the process is rarely biochemical, and metabolic characteristics of
considered. The histologic changes are focal, normal and osteoarthritic connectivie tissue
erosive lesions of the surface of hyaline cartilage; structures. New formulations of the etiology and
mitosis and formation of chondrocyte clones with pathogenesis of OA have been proposed. When
an increase in DNA-RNA turnover; and synthe- management and therapy can be closely related
sis of type II collagen and proteoglycan. The to the etiology and the pathogenetic steps are
subchondral bone osteoblasts are activated to identified in a disease process, arrest or reversal
produce increased and thickened subchondral becomes possible. We are near that point in
bone; the entire end of the bone is extensively understanding OA. The stakes are high because
remodeled, marginal osteophytes develop, and this disorder is universal in humans. OA is a
subarticular bone cysts occur. multifactorial process; perhaps not a disease, but
All tissues in and around the joint experience an ancient paleozoic mechanism of repair of
hypertrophy: motion is limited. Loss of congruity dense tissues developing in vertebrate animals.
of the cartilage surface results in increased The goals of this review are: (1) to review past
mechanical instability. Variable joint effusions and current definitions of OA and consider his-
and synovial inflammation follow as joint insta- torical concepts, phylogenesis, and paleobiology.
bility develops, especially in the weight-bearing (2) Identify certain myths and misconceptions.
joints. The patient experiences more pain than (3) Review the normal structure and function of
stiffness: the worst clinical dysfunction involves the tissue components involved in OA. (4)
the back, neck, hips, knees, and thumbs. Since Review the pathophysiology involved, emphasiz-
the cell biology involved is excessively synthetic, ing that all mechanisms result in the same
the most popular name, degenerative joint dis- sequence of events, a final common pathway:
outline common etiologic and pathogenetic
From the Rheumatology and Clinical Immunology Unit,
mechanisms. (5) Review present lines of evi-
Department of Medicine, University of Vermont College of dence for actual or potential reversibility. (6)
Medicine, Burlington. Outline a program of management related to the
John H. Bland, MD: Professor of Medicine, Rheumatolo- stage of development fitted to the cell biology
gy; and Sheldon M. Cooper, MD: Associate Professor of
involved.
Medicine, Director, Rheumatology and Clinical Immunol-
ogy Unit. University of Vermont College of Medicine, Bur-
lington. EPIDEMIOLOGY: PREVALENCE, INCIDENCE,
Supported in part by grants from the Given Foundation, AND IMPORTANCE
Visiting Scientist (NIH), Commonwealth Foundation, Ver-
mont Chapter of the Arthritis Foundation, and a grant from OA has the highest morbidity of all illnesses of
Blake and Sheila Lawrence. mankind. It is demonstrable in a 35% incidence
Address reprint requests to John H. Bland, MD, Rheuma- in the knees as early as age 30, becoming almost
tology and Clinical Immunology Unit, University of Ver-
universal with increasing age (ie, >50 years).’ At
mont College of Medicine, Department of Medicine, Given
Medical Building, Room D-301, Burlington, VT 05405.
least 85% of persons 70 to 79 years of age have
0 I984 by Grune & Stratton, Inc. diagnosable OA.* The compromise of joint func-
0049-0172/84/1402-0002$5.00/0 tion is common and the quality of life is dimin-

106 Seminars in Arthritrs and Rheumatism, Vol 14, No 2 (NovemberI, 1984

OA REVIEW
ished; an estimated 180,000 people in the US are
bed to wheel chair invalids because of OA-with
an extensive morbidity in the population, often
unidentified or regarded as a problem to which
there is no solution.’ Population studies do not
identify the prevalence of clinically significant
OA because at a given time the lesions may not
be associated with pain or disability.4
Although the greatest prevalence is among the
elderly, OA causes more absenteeism than any
joint disease in the age groups gainfully
employed in industry as well as in the armed
forces.5,6 A 10% incidence of radiologic OA was
shown in the 15 to 24-year-old age groups.’
Heine, in 1962, in a series of 1,000 autopsies
showed an increase in OA by his criteria begin-
ning at age 15 and including patients over 80’
(Fig 1). In one survey, 80% of a population
sample over age 55 had OA. Although asymp-
tomatic, the disease is known to be present at the
cell and tissue level and is in development
decades earlier.8 Radiologic OA in the hands and
feet of >40 million Americans was reported
(33% of the target population) but symptoms or
disability occurred in only 5 million people.9~‘0
OA prevalence in a population is not influenced
by geographic area, ethnic group, or climate.
Men and women are equally affected, men with a
greater prevalence before age 45 and women
with a higher prevalence after age 45.8,9 Severe
20
0
0 20 40 60 80
Fig 1. Note the striking increase in OA in multiple
joints indentified by a pathologist. appearing as early es 15
years of age and becoming nearly universal beyond age 60.’
Spondylosis is underestimated.
107
disease more commonly affects women than men
(22% v 19%) and patients with primary general-
ized OA.‘,”
OA occurs more in weight bearing and exces-
sively used joints. There are large descrepancies
between the radiologic incidence of OA and
clinical complaints, one survey showing clinical
complaints in only 25% of a group of miners all of
whom had definite, sometimes extensive, radio-
logic evidence of OA in their knees.‘* However,
when OA involves the hips there is a clear
correlation between radiologic changes and clini-
cal complaints and disability. In Western coun-
tries OA is an extremely common cause of
disability: it is the most frequent cause of
rheumatic symptoms and results in the most loss
of time from work.‘3m’s The disease has an enor-
mous socioeconomic impact and a great dollar
loss to the world.
NOMENCLATURE
Though Tarnopolsky’6 collected 54 names for
OA only four will be considered here: osteoar-
thritis, osteoarthrosis, degenerative joint disease,
and hypertrophic arthritis. No one name is satis-
factory. Osteoarthrosis, popular in Great Britain
and Europe, implies by its suffix “osis” an
increase, or a general overproduction. This is
appropriate since all elements in and about the
joint increase. Also implied in this term is that
the disease is not primarily inflammatory. While
this is partially true, by the time the lesions result
in clinical symptoms and signs, there is always an
inflammatory component. Degenerative joint
disease, the most widely used term in the US, is
unsuitable if the name is to describe the disease.
Degenerative means a deterioration and implies
a running down or catabolic process, which is not
suitably descriptive. Hypertrophic arthritis, now
out of style, was used in the late 19th and early
20th century to imply hypertrophy of joint tis-
sues, in contrast to atrophic arthritis (rheuma-
toid arthritis [RA]). OA seems the best of a poor
lot since the disease does involve the bones and
joints and has associated inflammation at least
by the time it is clinically significant. This name
is generally attributed to J.K. Spender, an
English physician of the late 19th century.
It is clinically useful to call the disease pri-
mary OA when the etiology is not known or if the
mechanism is genetic. Secondary OA is used to
108
designate all situations in which an initiating
factor is known or strongly presumed. New clas-
sifications are arising as more initiating factors
are recognized. It appears now that whatever the
initiating factor, the cellular and pathophysio-
logic events constitute a final common pathway,
as though a triggering stimulus trips a series that
proceeds on to the gross anatomic changes of
advanced OA (unless the mechanism is stopped,
interrupted, or even occasionally reversed).
OA IN HUMAN HISTORY
All primates develop OA, and some historians
have thought that the semierect posture of the
Neanderthaloid man was due to OA of their
spines rather than their simian derivation.‘7m’9
Sokoloff notes that OA was first recognized as a
discrete entity within the memory of many cur-
rent rheumatologists and pathologists. From the
time of Hippocrates (460 to 377 BC), all forms of
chronic arthritis were regarded as multiple clini-
cal reflections of gout until 1889 when Spender
coined the term OA. Even then it was not specifi-
cally used until the younger Garrod did so in
1907. In the late 18th and early 19th centuries
there were scattered clinical and pathologic de-
scriptions of what is now regarded as OA.2”m25
In 1877 Weichselbaum accurately described
severe lesions in end-stage 0A.2h In 1907 to 1910
the clinical and pathologic separation of RA and
OA occurred simultaneously in America and
Europe.27.28 The current and most widely used
term, degenerative joint disease, was coined and
used by Bennett et al at the Massachusetts
General Hospital in 1942.29 From their studies
they concluded that OA originates as a degenera-
tion of hyaline cartilage and is basically
inherent senescence of that tissue, not necessarily
confined to the joints. Little progress was made
in OA from 1942 until the post World War II
renaissance in medical research since 1950. The
next 30 years are the years that shook rheumato-
logy.
PHYLOGENETICS AND PALEOBIOLOGY OF OA
An important phylogenetic fact is that OA
occurs in most mammals surviving the evolution-
ary process and was present in prehistoric mam-
mals. OA has been seen in all Phyla of verte-
brates having bony skeletons and is well repre-
BLAND AND COOPER
sented among ancient and modern animals:
amphibia, reptiles, birds, and mammals. No evi-
dence of OA has been identified in animals with
cartilaginous skeletons, eg, Squalus acanthias,
the dogfish shark. We can speculate that OA
arrived with the phylogenetic appearance of
bone.
Survey of ancient and modern literature sug-
gests that the paleophysiology and pathology of
OA closely resembles the characteristics found in
humans and modern animals. Such observations
are of more than academic interest since chon-
drocyte, synoviocyte, and osteocyte evolution
involved development of distinctive enzyme sys-
tems, endocrine regulatory mechanisms. cell-
cycle characteristics, and synthetic and degrada-
tive capabilities. Thus, a reasonable etiologic and
pathogenetic theory is that OA may have its
origin in an ancient process that has been
retained in modern species and can be identified
and studied.
Moodie described OA lesions in fossil reptiles
in the Mesozoic period from 60 to 185 million
years ago.30 The famous cave bears of Bonn had
spinal osteophytes described by Virchow in 1895,
and Kaiser, quoting Virchow, described other
skeletal abnormalities in the bears.” Diplodocus
longus, a giant sauropod dinosaur had osteophy-
tosis of caudal vertebrae.32 Fox in an outstanding
survey of spinal osteophytosis and OA in captive
and wild mammals reported that the major
lesions were in principle weight-bearing joints
and the larger the mammal the more the OA.”
Still, bulky megasomes, 13 rhinoceroses and 16
camels had no OA. Carnivora had most joint
disease in the forelegs and in artiodactyls (rumi-
nants, ungulates) the hind limbs were mainly
an
affected. Ankylosis of vertebral osteophytes, rare
in humans, is common in quadripeds. The signifi-
cance of these findings? Fox studied 173 rodents
and found no OA, but the Silberbergs first
showed that it did occur in small laboratory
animals, notably mice, rarely, if ever in rats.“’ It
does occur in several strains of mice, in Syrian
hamsters, guinea pigs and Praomy natalensis, the
African multimammate mouse.35
The majority of German shepherd dogs have
OA of the hips, apparently related to a flattened
acetabulum and dorsal subluxation. All patho-
logic changes seen in human OA are present
except for pseudocysts. OA is common in horses
OA REVIEW 109

with histologic changes indistinguishable from Table 2. OA v Aging

humans. The greatest modern economic losses OA Awg

occur in the multibillion dollar thoroughbred Highly anabolic and syn- Normal metabolism
horse-racing industry where carpal OA appears thetic process

early and is severe.37 The hip joint is rarely Enzymatic destruction of Normal enzymatic

hard tissue remodeling

involved in horses. Sokoloff3* reported primary
Remodeling all tissues about Cartilage changes only
OA in birds dying in zoologic gardens.
joint, articular and periar-
Two phylogenetic observations are intriguing: titular
animals that hang upside down do not get OA Chondrocyte mitosis No mitosis

(sloths and bats); animals that spend their entire Intense increased synthesis Normal rates synthesis, col-

collagen and proteoglycan lagen and proteoglycan

lives in water (whales, seals, dolphins, and por-
Increased water content No change
poises) do get OA. The latter observation is
cartilage
contrary to the “wear and tear” theory since Fibrillation, focal and pro- Fibrillation non progressive,
these mammals are constantly supported by gressive at weight bear- non-werght bearing sites

water. If the mechanisms underlying OA in ing sites

Eburnation. ivory-like No eburnation
vertebrates are similar or identical, interpreta-
Osteophytes occur with Osteophytes only with ex-
tion of these observations might cast some light
other changes cessive use
on etiology and pathogenesis. No increased collagen X link Increased collagen X link

Inflammation No inflammation

No pigment-cartilage Pigment-cartilage
MYTHS AND MISCONCEPTIONS OF OA

Table 1 lists common myths and misconcep-

Wear and Tear
tions in OA.
In the strictest sense, OA is not a wear and
tear phenomenon. The mammalian joint, if ini-
Aging
tially normal and not subjected to grossly exces-
Though OA is a disease of increasing preva- sive load, cannot be worn out. The lubrication is
lence with advancing years, a cause and effect so efficient that there is almost no shear force.
relationship should not be assumed; in fact, the Wear cannot occur unless there are shearing
concept of aging is an elusive one. One idea is forces operative between two surfaces. The coef-
that aging is, in effect, a disease caused by the ficient of friction is about that of ice on ice, or
cumulative acquisition of injuries to tissues, ulti- fivefold lower than the lowest coefficient of fric-
mately leading to loss of structure and later tion devised by lubrication engineers with ball
function. Another theory is that aging is a geneti- bearings and oil.4’45 The joint is an efficient
cally determined process in which all living mate- piece of machinery. Thus, to describe OA as a
rials, at varying rates, deteriorate with time. A consequence of wear and tear or aging is
third idea is that aging is some combination of inappropriate.
both mechanisms. Let us consider the conse-
quences of aging and OA separately. Table 2 lists The Chondrocyte, an Effete Cell
age changes compared to those of OA. While The chondrocyte is anything but effete, since it
aging implies atrophy and wearing out, OA is metabolically active and responds to mechani-
changes are anabolic and synthetic3’ Of interest, cal, endocrine, biochemical, and microenviron-
progeria, a set of rare clinical syndromes charac- mental stimuli with increased rates of synthesis
terized by rapidly developing premature senility of proteoglycans, type II collagen, and degrada-
has not been associated with OA.40 tive enzymes.46-49 Chondrocytes do not normally
divide but with appropriate stimuli such as a
Table 1. Myths and Misconceptions in OA change in the microenvironment the cells divide
OA is a consequence of chronologic age forming brood clusters: clones.
OA is secondary to wear and tear
Dogma: cartilage cannot heal and repair itself
OA Is Inexorably Progressive
Chondrocytes are effete cells that cannot replicate or change The course of OA occasionally remits sponta-
rates of synthesis and degradiation of cartilage macromolecules
neously.50 Pauwels” showed that by precise oper-
110 BLAND AND COOPER

ative planning, OA of the hip could be arrested Table 3. Sites of Water Binding in Cartilage

and reversed. Macquet5* could predictably G&S

reverse OA of the knee by surgically changing, Proteoglycans

Collagen
the biomechanical factors. There is a firm body
Surface layering
of evidence in clinical and experimental OA
Protein of proteoglycan
research that the process can often be arrested Collagen
and occasionally reversed.“3 The fully detailed H bond to anions

evidence is presented later. H bond to cations

Hydrophobic bonding to protein

Cartilage Cannot Heal Itself Holes m collagen

Intracellular water
Though poorly responsive to trauma, there is Metabolic water

hard evidence that healing of cartilage lesions

can and does occur.54m63The new cartilage may
be a mix of fibrocartilage and hyaline cartilage.
The distal end of the bone has increased turnover
and even the uninvolved contralateral bone has
increased metabolism.64 With burgeoning knowl-
edge of hyaline cartilage physiology and cell
biology, how to arrest and reverse the process
becomes more apparent.65mh7
CURRENT CONCEPTS OF NORMAL
PHYSIOLOGY OF ARTICULAR TISSUE
Physiology here is defined as characteristic
or promoting normal healthy structure and func-
tion of joint tissues. Strangely and interesting
intraarticular temperatures range from 90.3 “F
to 94.5 “F. Little new data or speculation about
clinical application has appeared since Horvath
and Hollander observed this 30 years ago.68@
Hyaline Cartilage
This remarkable tissue is avascular, aneural,
alymphatic, and caps the ends of bones at joints.
It is hypocellular with only 5% of the volume
occupied by cells. Cartilage is 75% to 80% water
by weight, the water being mainly bound in the
highly aggregated, hydrophilic proteoglycans.
Water, the major constituent of cartilage, is vital
to nutrition, permitting entry of nutrient solutes
and exit of waste materials between itself and
synovial fluid. Table 3 lists possible sites of water
binding in hyaline cartilage. Hyaline cartilage is
like a water-filled sponge, but tons of force are
required to sqeeze water out. DePuky showed
that we are all 0.75 inch shorter at night than in
the morning, reflecting the aggregate compres-
sion of all hyaline cartilage.” With night rest the
cartilage rehydrates, delivering the solute mate-
rial to the chondrocyte for its metabolic process;
during the day we normally compress all carti-
lage, delivering waste materials to the joint space
for pickup by synovial vessel plexuses.7’m73
The surface of cartilage is almost frictionless,
especially at high shear rates. Joint lubrication
under high load conditions is due to a film of
fluid squeezed out of the cartilage interstitial
fluid (weeping lubrication). Under low load con-
ditions, boundary lubrication from synovial fluid
is most important. Cartilage is a deformable,
of weeping bearing having a serviceable anaerobic
as well as aerobic metabolism. The matrix com-
prises a collagenous framework (fibrillary
matrix) within which is entrapped proteoglycan.
Though the tensile strength of the collagen is
that of steel wire, it cannot support compressive
load since it would fold or crumple. It is the
hydrostatic pressure of water bound to proteogly-
can, retained and restrained by the collagen
meshwork, that gives cartilage its resilience and
load-bearing properties. Chondrocytes are ami-
totic unless some change occurs in their microen-
vironment. These cells conduct their own internal
remodeling system, synthesizing the collagen and
proteoglycan of cartilage as well as the enzymes
necessary for breakdown and turnover. In fact,
recent research suggests amyloid secretion by
chondrocytes;74 presence of amianthoid (asbes-
tos-like collagen fiber) in cartilage, and foci of
apatite crystals in OA cartilage.75 Chondrocytes
normally have the longest cell cycle in the body.
Proteoglycan and Type It Collagen
Figure 2 is a schematic representation of
aggregated proteoglycan. Many metabolic stud-
ies using radioisotopic substrates confirm that
chondrocytes synthesize the component macro-
OA REVIEW 111

Synovium
The synovial membrane is essential to the
normal function of a diarthrodial joint. All
nutrients and wastes exchanged between blood
and joint tissues pass through the synovium.
Blood-borne nutrients must pass through the
synovium before entry into cartilage; likewise
waste products must pass through synovium to
the circulation. Synovial cells synthesize and
Fig 2. The backbone of the proteoglycan molecule is export protein and proteoglycan; in abnormal
long chain, random-coil hyaluronic acid with alternating
monomers of glucouronic acid and glucosamine. The side
states they produce large amounts of prostaglan-
chains, in three dimensional array, are in the shape of dins and degradative enzymes, notably collagen-
test-tube brushes: the short one keratosulfate and the long ase. These cells produce “messenger molecules”
one chondroitin sulfate attached to the protein core. The
gylcosaminoglycan side chain attaches to hyaluronic acid by
that can regulate chondrocyte, and possibly
the link protein. osteoblast and fibroblast, metabolism.
The innermost layer of synovial cells has many
molecules of proteoglycans and collagen, processes enmeshed in a loose matrix of collagen
assemble them intracellularly, and export them fibrils, supported by nearby loose connective
rapidly to the extracellular space.66X67A half life tissue with an extensive network of capillaries
of as little as eight days has been shown for small and lymphatics. It is so well supplied with capil-
portions of proteog1ycans.76 Glycosaminoglycan laries that the term glomeruloid has been
refers to the long-chain carbohydrate polymers applied. Deeper strata contain larger blood ves-
of repeating disaccharide units, glucosamine or sels and a well-developed lymphatic system. The
galactosamine, and glucuronic acid and the pro- synovial tissue becomes ever denser as it blends
tein core. These units attach via link protein to with the capsule, there being no distinct ana-
hyaluronic acid that aggregates to high molecu- tomic boundary between the two. The most fre-
lar weights (100 x 106) extracellularly. quent living cell is called type A with numerous,
Collagen type II and proteoglycan interact by large vacuoles, mitochondria, intracellular fi-
an unknown mechanism, probably chemical brils, filopodia, a very active pinocytotic capil-
bonding, that gives the whole cartilage its lary, and a prominent golgi apparatus, clearly
remarkable properties. The turnover of collagen designed for phagocytosis. The less common type
is normally slow, if it turns over at all. The B cell has an abundant rough endoplasmic retic-
turnover rate does increase in OA at an esti- ulum, characteristic of a synthetic cell. There are
mated half life of 50 to 300 days.” crossover cells with characteristics of both. Fen-
estrated capillaries are seen near the synovial
Enzymes surface, similar to those in the renal glomeruli,
Many enzymes have been identified in artic- choroid plexus, intestinal villi, and some endo-
ular cartilage. Cathepsin D, Bl, and F, with acid crine and exocrine glands; all suggesting an
pH optima, are regarded as the major proteogly- adaptation to rapid exchange of water and
can-degrading enzymes, acting either intracellu- solutes. It is sensitive, highly reactive tissue.
larly or near the cell surface. Neutral proteases
and aryl sulfatases are also present. Immunore- Lubrication
active collagenase has been detected in articular Soft tissues are lubricated mainly by hyal-
cartilage, but collagenase activity has not been uranic acid that serves very well. It also provides
demonstrated, presumably due to the presence of partial lubrication in joints themselves because
an inhibitor. Hyaluronidase is present in syno- of its property of thixotropy, the faster the rate of
vium and in synovial fluid, but not articular shear, the lower the viscosity of hyaluronic acid.
cartilage. Lysozyme is present in articular carti- Recently one of two proteins called lubricin
lage in large amounts and may regulate the size necessary to normal joint lubrication has been
of proteoglycan aggregates. studied by Swarm.” Joint lubrication is normal
112
after surface treatment with hyaluronidase, but
with protease application the normal lubrication
is lost. It has been postulated that failure of
synthesis or export of lubricin may explain the
cartilage failure in 0A.78 Cartilage fails because
the normal material is subjected to abnormal
loads or defective cartilage is subjected to physio-
logic loads.79
Bone
Cartilage is resistant to shear forces due to its
superior lubrication but is susceptible to repeti-
tive impulsive loading; it is superior to bone in
absorbing impact shock, but there is not enough
of it to matter. Most of the impact force is
absorbed by bone and the neuromuscular appa-
ratus. In walking, jumping, and running, force is
transmitted to the large bulbous bone ends that
are strong, brittle, and less deformable but still
plastic. Bone is not as good as cartilage for the
purpose, but there is so much of it that it can do
the job. It has been argued that microfractures
in subchondral bone heal with callus, causing
stiffening and loss of compliance with more
microfractures and more stiffening, ultimately
damaging the overlying hyaline cartilage. Bone
hypertrophies with use and over use. The large
osteophytes of OA and the extensive remodeling
of the whole end of the bone are both contribu-
tors to clinical OA.
Changes in arterial and venous blood flow
have long been thought to play some role in OA,
eg, microvascular necroses of subchondral
bone.79 Isotope scanning methods show aug-
mented uptake and increased flow at sites of OA.
This is more likely a consequence of increased
metabolism of cartilage and bone cells involved
in the OA process instead of a primary disorder.
Rapidly forming osteophytes may be partially
attributed to increased blood flow.
Bursae
These structures have been given little atten-
tion in the study of OA though they are involved,
particularly in the overall hypertrophy and
hyperplasia of all intra- and extraarticular tis-
sues in the disease.
Bursae are closed sacs, lined with synovial
membrane, often found about and near joints.
They facilitate the gliding of one musculoskeletal
structure on another, eg, skin or tendon over
BLAND AND COOPER
bone. Bywaters listed 156 known bursae in the
body.80 They are classified as subcutaneous or
deep, the latter being situated beneath the deep
fascia. KeyR’ described and classified three types
of bursa: areolar, fibrous, and adipose according
to their density and histologic characteristics.
Tendon sheaths are a specific variety of deep
bursae.
Bursae appear early in intrauterine life at the
same time as joints. Motion, pressure, and fric-
tion play a major role in their development, as is
so with joints. So-called adventitious bursae
(newly developed) may occur at any time over
pressure points or bony prominences such as
hallux valgus or exostoses or osteophytes of OA.
This ability to produce synovial structures at any
time and where needed is an expression of the
pluripotentiality of connective tissue cells. Bur-
sae around joints may develop or have communi-
cating channels into the joint space, eg, iliopsoas
bursa with the hip joint and subacromial bursa
with the shoulder. In OA, existing normal bursae
frequently enlarge or new bursae may develop
about the deformed joint with its large osteo-
phytes and altered biomechanics. Such bursae
may be the source of symptoms and need
recognition.
Tendons and Ligaments
The function of tendons is the transmission of
muscle tension to the mobile part. Tendons have
enormous tensile strength, resistance to compres-
sion, flexibility, and near perfect elasticity. These
properties relate to the highly organized longitu-
dinal arrangement of the collagen structure, sim-
ilar to ligaments and dense fascia. Tendons
develop early in intrauterine life first appearing
as a condensation of mesenchymal cells, followed
by collagen deposition. Development of cavita-
tion between flexor tendons and their sheaths
occur by the second month of gestation. Tendons
appear, even in the absence of muscle, but with-
out muscle the tendon rudiments atrophy
quickly. Thus muscle may not be necessary to
differentiation but is necessary for sustained
development. Motion is essential for develop-
ment of tendons and even more important for
maintenance of their structure and function, an
important clinical issue in 0A.82
Adult tendon is 50% to 70% water but the dry
weight is about 75% type 1 collagen, with 2%’
OA REVIEW 113

elastin, both fibrous proteins being embedded in result in a characteristic end-point, which we
a proteoglycan water matrix.83 The fibers are have operationally and clinically defined as OA.
surrounded by epitenon and permeated by endo- The precise sequence of the changes and their
tenon, a delicate connective tissue framework relationship to one another is subject to debate.
carrying blood vessels, lymphatics, and nerves. We must emphasize that the course may arrest
Tendons are attached to bone in a four-layer at any point, may continue on to gross joint
arrangement: tendon (also ligament), fibrocarti- destruction, or may reverse. It is logical that if
lage, mineralized fibrocartilage, and bone. The reversal is to occur, the earlier therapy is begun,
fibers penetrate the outer bone lamellae. Vascu- the greater the chance for reversal.
larization for tendons occur at bone attachments, The most prominent early (though not neces-
muscle attachments, and intermediate vessels; sarily the first) change is seen in the articular
however, tendons often have hypovascular areas, cartilage that demonstrates a decrease in both
eg, biceps and supraspinatus tendons. Tendons proteoglycan content and state of aggregation
are richly innervated by nerves from attached and an increase in water content. There is also a
muscle as well as from regional cutaneous and decrease in chondroitin sulfate chain length and
deeper nerve. Synovial tendon sheaths promote a change in glycosaminoglycan composition. At
tendon gliding and contribute a nutritional role. the cellular level, the chondrocyte, a normally
They are especially prominent in flexor tendons amitotic cell, divides to form clones (“brood
of the fingers and about the wrist. clusters”) of cells. The chondrocyte also
Tendons have near perfect elasticity. They do increases its synthesis of proteoglycan and type
atrophy with decrease or loss of mechanical II collagen, two- to fourfold over normal, in an
stimulation, losing both elasticity and tensile apparent attempt to reverse the matrix depletion.
strength. For reasons not well understood, ten- There is augmented DNA-RNA turnover and
dons, capsules and ligaments about or crossing increased enzyme synthesis. The increased chon-
joints with OA, enlarge and hypertrophy. There drocyte synthesis of matrix elements continues as
are no data to suggest any change in physical the disease progresses, until a stage is reached
properties. It seems these tissues, by some sort of where tissue changes are advanced and synthesis
intercellular message to fibroblasts, participate falls. At the tissue level the cartilage surface
in the general anabolic, synthetic process that loses its smooth texture, becomes fibrillated, and
characterizes OA. Tendons are not metabolically develops clefts and crevices, at first tangential to
inert structures but are subject to a variety of the surface and later vertical, extending down to
pathologic processes, including OA. and through the subchondral bone.84 There is loss
Ligaments and capsules are similar to tendons of congruity of joint surfaces (Fig 3).
and behave pathologically and metabolically the Coincident, preceding, or following the
same. Ligaments are fibrous bands holding bones changes in articular cartilage, the subchondral
together. They are necessary to maintain the bone undergoes a proliferative change. The bony
stability of joints and are required to control proliferation occurs primarly at the joint margins
posture. They do not transmit muscle action and floor of the cartilage lesions. The prolifera-
directly. Ligaments may be mainly collagenous, tion appears to be an attempt to increase the area
eg, cruciate ligaments of the knee; or primarily available for load-bearing, but it has the undesir-
elastic, eg, ligamenta flava of the spine, ligamen- able effect of decreasing compliance and increas-
tous muscles. They may be anatomically clas- ing the stiffness of the subchondral bone. The
sified as intraarticular, extraarticular, and more brittle subchondral bone is more prone to
vertebral. develop microfractures, which result in new cal-
lus formation and more microfractures. Osteo-
PATHOPHYSIOLOGY OF OA phytes develop, and subluxations and joint insta-
This summary of the molecular and tissue bility follow (Fig 4).
cellular events in OA represents a current formu- Synovial proliferation and active synovitis
lation of the pathophysiology. It is important to appear. Synovial cells at the periphery become
recognize that regardless of the initiating or metaplastic, and in some instances produce
primary event, the joint undergoes changes that osteophytes, a mix of bone covered with hyaline-
 114 BLAND AND COOPER

Fig 5. Bilateral OA of the hips with overall increase in

bone volume. Note the striking increase in the density of
the subchondral bone. both in the acetabulum and the
femoral head; asymmetrical narrowing of the joint Space
Isuperolateral): extensive osteophytosis and pseudocysts.

Joint fluid is pushed through the crevices in

subchondral bone at microfracture sites, the
marrow reacts to the presence of joint fluid and
characteristic pseudocysts develop.
The clinical correlates are pain and restricted
motion. The inflammatory components result in
Fig 3. Chondrocyte clones or brood clusters. The ami- heat, redness, and swelling and may be exagger-
totic cell has become mitotic and increased its metabolic ated in a rapidly developing process. Joint
turnover. Note the shredding or fibrillation on superficial
destruction is the end point. Table 4 lists the
layers of cartilage. Reprinted with permission.&
pathophysiologic features.
like and fibrocartilage. All local elements in and It is obvious that in OA, synthetic and degrad-
about the joint hypertrophy, including capsule, ative forces are operating in tandem. Unchecked,
ligaments, tendons, muscles, and bones (Fig 5). the process proceeds on to an imbalance of these
There is extensive remodelling of the entire bone forces and joint destruction. The keys to arrest-
ends and connective tissues about them (Fig 6). ing or reversing the process are ( I ) the usual slow
rate of progression and (2) the evidence that the
tissues involved are capable of repair. In fact,

Fig 4. The fibrillation on superficial layers of cartilage

has progressed to vertical clefts that ultimately extend to
the subchondral bone. Cloning increases as does macromo-
lecular Synthesis. Reprinted with p8rmiSSiOnof W. Kelly. E. Fig 6. 58V8re synovitis of advanced OA with marked
Harris, S. Ruddy, et al feds): Textbook of Rheumatology.- cellular infiltration end extensive synovial proliferation.
OA REVIEW 115

Table 4. Four Steps in Pathophysiology of OA broaden the contact area. The osteophytes con-
1. Microenvironment of chondrocytes changes; chondrocytes tain new cancellous bone and are covered with
mitose, produce clones that increase rates of all export prod- hyaline and/or fibrocartilage. This new material
ucts, proteoglycans, collagen, and enzymes. seems to arise from synovial metaplastic cells at
2. Subchondral bone osteoblasts increase rates of synthesis;
the periphery of the joint, near the bone-
density of subchondral bone increases: stiffness increases;

microfractures follow.
cartilage interface. It is probable that the early
3. Osteophytes form at periphery of joint (metaplastic synovial metabolic changes in the cartilage, mitosis,
cells), active inflammatory process, synovitis. increased DNA-RNA turnover and collagen and
4. Pseudocysts form in trabecular bone below subchondral proteoglycan synthesis are reversible if the stress
bone; increased volume and density all articular and periar-
in the cartilage is reduced to normal load (Fig
titular structures, capsules. tendons, ligaments, bones.
7).
The pathologic changes in OA are most con-
much of the pathophysiology is the result of this spicuous in cartilage, focusing most investiga-
vigorous, though inadequate attempt to repair. tors’ attention on this tissue as the primary site in
Our goal is to ablate, arrest, or reverse the the pathogenetic sequence. Changes in the carti-
metabolic cascade responsible for joint destruc- lage matrix, either in the proteoglycan or collag-
tion without adversely compromising other cellu- en, could lead to changes in the microevironment
lar functions. of the chondrocyte, triggering the process. In
early experimental OA there is an increase in the
PATHOGENETIC THEORIES OF OA
water content of cartilage, associated with
The past two decades has seen great advances increased extractability and swelling of proteo-
in knowledge of the cell biology of the tissue glycans. Increased water content may result
involved in OA allowing a more rational from a loss of restraint within the collagen net-
approach to its etiology and pathogenesis. The work. There is a decrease in proteoglycan
causes or factors that influence the development aggregation and a change of composition in
of OA are multiple. In some cases the operative glycosaminoglycans. There is subsequent loss of
factors may be apparent, in others they may be proteoglycan from hyaline cartilage, and a loss of
obscure. The relationship and sequence of the stiffness and elasticity of the tissue. The chondro-
various pathologic changes are poorly under- cyte suffers increased mechanical stress, carti-
stood. In this section we review the most widely lage permeability increases, self-lubrication is
held theories about the pathogenesis of OA and impaired, and fibrillation of cartilage is found.
the factors influencing its development. While this sequence of events is attractive, the
Radin et al have proposed that the primary significance and cause of the initial biochemical
event in OA occurs in the subchondral bone.79 changes are not resolved. Additionally, these
Either excessive repetitive impulsive loading of experimental animal models represent secondary
normal subchondral bone or defective subchon- OA and their relationship to human disease must
dral bone subjected to physiologic load results in be established.
microfractures with callus formation, preceeding The following factors are known to influence
any change in cartilage or surface or deep tissue. the development of OA. There is considerable
The microfracture heals and the bone is less evidence that endocrine forces may initiate or
compliant, a little stiffer. More microfractures accelerate the process. Change, from any cause,
follow with increasing stiffness and more callus; in the chondrocyte’s microenvironment may trig-
the subchondral bone increases in density, ger the process. Virtually all hormones act,
becoming sclerotic. Such bone cannot absorb directly or indirectly, on the connective tissue
shock as well and results in increased intraos- cells: fibroblast, osteoblast, and chondrocyte.85
seous venous pressure, a major contributor to The mature, amitotic chondrocyte is regulated
pain in OA. by growth hormone via somatomedin synthesized
With loss of normal shock absorption the in the liver.86 OA does occur in acromegaly.*’
collagen of hyaline cartilage sustains fatigue Insulin stimulates chondrocytes to increased
stress “fractures.” Osteophytes form at the incorporation of “S-sulfate reflecting an increase
periphery of the joint, presumably in an effort to in the synthesis and assembly of proteoglycans.
116 BLAND AND COOPER

Fig 7. (Top, /eft) shows severe ulceration of the medial femoral condyle, albeit with a mix of fibrocertilage and hyaline
cartilage remaining; top, right, increased density of subchondral bone in medial compartment and severe narrowing of joint
space; bottom, left, gross remodeling of all joint structures with marked varus deformity; and bottom, right, increased bone
volume, osteophytes and joint surface destruction, and collapse of the tibia1plateau.

Diabetic patients have a greater incidence and a therapeutic role for estrogen blockade.“,gJ
serverity of OA than non-diabetics, suggesting a Estrogen in high dose and oophorectomy sup-
relationship.88’89 Patients with hypothyroidism pressed immune synovitis in rabbits, a contra-
and myxedema have increased OA compared to diction that nonetheless suggests a role for
age- and sex-matched population samples and at estrogen mediation of inflammation.y5
least 25% of myxedema patients have calcium There is a genetic form of OA that is dominant
pyrophosphate dihydrate crystal deposition dis- in women and recessive in men. Affected individ-
ease with consequent secondary 0A85,9S92 (Fig uals have involvement with Heberden and Bou-
8). chard nodes plus the first carpometacarpal joint,
Estradiol receptors have been demonstrated in the cervical and lumbar spine, knees, and first
chondrocytes. Estradiol worsens and tamoxifen, metatasophalangeal joint”,96397 (Fig 9). This
an antiestrogen, improves experimental OA, form of OA is sometimes inflammatory and
decreasing erosive lesions in animals, suggesting erosive.98399Alkaptonuria, inherited as an autoso-
OA REVIEW 117

Fig 8. /_&, a femoral head removed at total hip replacement revealing osteophytes. a surface mix of hyaline and
fibrocartilage, and extensive ulceration. Right,an x-ray film illustrating remodeling, marked proliferation of subchondral bone,
molding, narrow joint space, and pseudocysts.

ma1 recessive trait, is due to deficiency of homo- Bones and joints remodel over time. The joints
gentisic acid oxidase that results in ochronosis of the feet and the temporomandibular joint
and one of the most severe types of OA seen. seem to get larger with advancing age as do the
These obvious hereditary forms of OA suggest nose and ears. This is not related to epiphyseal
that more subtle genetic factors may play a role growth but to interstitial bone growth. If there is
in the pathogenesis of the disease ie, triggering continuous remodeling of bone as well as carti-
metabolites that are not obtrusive and pigmented lage, it is conveivable that this could lead to 0‘4.
(homogentisic acid) and hence not recognized as Both progressive and regressive remodeling
pathogenetic. occurs, subchondral cysts are seen, and marginal
lipping are all a part and consequence of this
normal process in the absence of OA. Cartilage
shedding of miniscule fragments is constantly in
process reflecting cartilage remodeling. John-
son loo is the principle proponent of the remodel-
ing theory. Recently Vignon et al”’ presented
further evidence of cartilage remodeling and
hypertrophic repair in experimental OA.
A variety of chemical substances trigger the
cellular events in OA. Deposition of a number of
crystals, notably calcium pyrophosphate dihy-
drate, hydroxyapalite, a variety of calcium phos-
phates, and monosodium urate may be primary
or secondary events leading to OA.“’ These
crystals may be responsible for many of the
Fig 9. X-ray film of the knee of a patient with myxedeme
and calcium pyrophosphate dihydrate crystal deposition
inflammatory phenomena found in OA (Fig 10).
chondrocalcinosis. Note wafer-like deposition of calcium Electron-dense material coats crystals; this may
pyrophosphate dihydrate crystals in the hyaline cartilage and be protein, carboxyglutamic acid, glycosamino-
menisci of an asymptomatic knee, perhaps to become symp-
tomatic later with release of the crystals into the joint glycan, enzyme or enzyme-inhibitors, or some
space. unknown substance.‘03m’0s The growth of human
118 BLAND AND COOPER

operative in OA, especially late in the destructive

phases of the disease. Utsinger et aI”’ have
demonstrated an increase in Ia+ T lymphocytes
in both synovium and synovial fluid in erosive
OA, similar to what has been described in RA.
Mononuclear cells make up the predominant
synovial infiltrate in many cases of OA. The
subchondral intratrabecular marrow undergoes
vascularized transformation with lymphocyte
and plasma cell infiltration. Cartilage proteogly-
cans, collagen, and chondrocyte moieties all have
known immunogenicity.74.‘09.“o Lymphokines
have been detected in OA synovial fluid.“’
Cooke”’ has shown immune complexes deposited
in superficial layers of hyaline cartilage and
menisci in OA. Intervertebral disc material is
antigenic.“’ All of the above data support the
concept of immunologic mechanisms contribut-
ing to the pathogenesis of OA, possibly primari-
ly, certainly late in the course.
Though OA is commonly described as a nonin-
flammatory process, the greatest body of evi-
dence is to the contrary. Symptoms of inflamma-
tion are usually the presenting sign of OA. The
disease may have been present for months or
years, but when it becomes clinically apparent,
Fig 10. Roentgenogram of hands illustrating genetic
inflammation is identifiable by clinical and labo-
primary generalized OA with extensive DIP, PIP, and 1st
CMC joint involvement. There was clinically manifest ratory parameters. Examples are the flareups of
severe inflammation. heat, redness, swelling, and pain of the interphal-
angeal joints of the hands, hot and swollen knees
bone cells may also be stimulated by “human with chronic or acute synovial effusion, and the
skeletal growth factor.” It has a molecular mass pain at rest in hip OA. There is localized stiffness
of 83,000 daltons and is specific for osteocyte with immobilization in OA joints. Synovial fluid
stimulation. It may play a role in the etiology of shows increasing evidence of inflammation cor-
OA, osteoporosis, periodontal disease, and Paget relating with intensity of disease; with increased
disease.‘(” Uridine diphosphate, a proteoglycan cell counts, mostly mononuclear; elevated total
intermediate results in prolonged stimulation of protein and immunoglobulin concentrations; an
proteoglycan synthesis. Overall growth in carti- increase in synovial fluid complement; and
lage as well as bone is promoted by homocysteic increased levels of pyrophosphate.
acid and is responsible for the skeletal abnormal- The synovial membrane shows mild to moder-
ities in homocystinuria. Both compounds could ate proliferation of synovial lining cells and infil-
be involved in the pathogenesis of OA.‘“’ tration of mononuclear cells. Lysosomal hydro-
Since hyaline cartilage is avascular, aneural, lases are increased as are neutral proteases,
and alymphatic, it is in a sense, outside the body, again correlating with the grade of inflammation
and its molecular components may be antigenic. present. The magnitude of inflammatory synovi-
The immune system may not recognize antigenic tis varies widely from case to case.‘14 It has been
determinants of cartilage itself. The rheumatoid proposed that there are subsets of OA in which
synovial pannus appears to be following a inflammation is the initial event.“5
chemotactic gradient in cartilage and the same Some evidence suggests that the initial event
behavior occurs in severe erosive OA. There is in OA is an imbalance between leaking of
increasing evidence of immunologic mechanisms enzymes and the presence of enzyme inhibitor.
OA REVIEW
Proteolytic enzymes that normally leak from the
phagocytic (type A) synovial cells are neutral-
ized, in the healthy joint by inhibitors synthe-
sized by B type lining cells. Absence of the
inhibitor may trigger OA.‘16
Synovium can have a striking influence in the
structure of nearby hyaline cartilage. The carti-
lage is avascular and dependent on synovial
blood vessels and much less so on subchondral
bone for gas exchange and metabolic require-
ments. In organ culture synovium synthesizes
and releases a family of substances, sometimes
called catabolins that carry messages to chondro-
cytes to enzymatically degrade the cartilage
matrix in the neighboring microenvironment of
the cell, breaking down proteoglycan and releas-
ing collagen both of which may be antigenic.
Structural integrity of cartilage matrix is lost
and its physical properties altered. Thus, this
endogenous system operating between synovial
cells and chondrocytes could be the earliest step
in cartilage disintegration in OA, ie, the primary
disorder could be either within the synovial cell
or the chondrocyte.“’
EVIDENCE FOR REVERSIBILITY OF THE OA
PROCESS: DIRECT, INDIRECT, IN VIVO, IN
VITRO, CLINICAL, AND EXPERIMENTAL
The thesis developed is that the process or
sequence of events resulting in OA is subject to
arrest and sometimes reversal. Osteoarthritic
chondrocytes are metabolically active, producing
increased amounts of proteoglycan and type II
collagen.“* Hyaline and fibrocartilagenous heal-
ing of joint surface lesions seems dependent at
least on motion and hydrostatic pressure, ie,
equal pressure from all directions.“9,‘20 Data
collected from the earliest lesions of clinical and
experimental OA to the most advanced disease
suggest that the cellular and tissue response is
purposeful and is aimed at repair of the anatomic
defects.‘*’ The critical issue is whether chondro-
cyte function can be restored to normal at an
early stage in OA. This section reports evidence
supporting the concept of slowing down, arrest-
ing, or reversing OA.
Spontaneous Remission
Perry et also in studying the natural history of
OA of the hip over a ten-year period reported
marked clinical improvement and radiologic
119
recovery of the joint space in 14 of 31 hips. All
had pseudocystic changes suggesting that the
arthritis was advanced. The joint space recovery
seemed to depend on development of upper and
lower pole osteophytes. The cysts disappeared.
The hips, though still restricted in motion, were
stabilized, pain was gone or much diminished,
and analgesic intake ceased. The remaining hips
progressed on to increasing disability and joint
destruction.
These results suggest arrest and at least par-
tial reversal of OA for poorly understood reasons.
One could speculate that the osteophytes in some
way stabilized the joint and turned off the
sequence that leads to progressive joint destruc-
tion. The authors purposely applied no therapy
and regarded their results as reflecting the natu-
ral course of the disease. Eight similar cases were
reported in 1964,54 two in 1968,‘** and one in
1971.12’ Harrison et a1’24 observed healing and
thought that as a consequence of the destructive
process, fibrous marrow might reach the surface
of the bone and differentiate into fibrocartilage.
Such fibrocartilage tufts usually remain discrete,
but sometimes become confluent, resurfacing the
bone. Johnson (personal communication, August
1982, Kingston, Ontario) believes that chondro-
cytes producing fibrocartilage, can on continuing
use and mechanical stimulation, differentiate
into chondrocytes that synthesize the proper
macromolecular mix that is hyaline articular
cartilage. Jacobs’*’ reported one such case.
This degree of healing in OA while uncom-
mon, occurs in a setting of unaided natural
forces. Yet it does occur! It behooves us to
determine the mechanism of repair, in the hope
of being able to induce healing. One can also
question why this type of repair is so infrequent?
Perhaps it occurs in early OA more often than is
recognized. Osteophytes buttress and otherwise
stabilize the joint; synovial osteocartilaginous
‘large bodies’ limit range of motion and prevent
body weight from compressing the head into the
acetabulum. When the femoral head is stable
(but with some mobility) the OA joint can pro-
duce and maintain a bearing surface elastic
enough to function for many years, albeit with-
out the almost frictionless characteristic of the
original hyaline cartilage. If it is not painful such
a joint may be serviceable and preferable to total
hip joint replacement.
 BLAND AND COOPER

Hip Joint Healing in Chronic Juvenile Arthritis joint adhesions and pannus formation was seen
Bernstein et a1’26showed reversibility of severe and further cartilage degeneration followed.
secondary OA in six children with juvenile Another group was allowed to run free. Bone
chronic polyarthritis. Both clinical and radio- healed a little faster and the cartilage defects
logic improvement, impressive and striking in all were filled with fibrous tissue with imperfect
cases, occurred six months to five years after a healing. A third group subjected to continuous
program of antiinflammatory agents and vigor- passive motion to the joint (begun postopera-
ous physical therapy, with emphasis on con- tively as animals were coming out of anesthesia)
tinuing ambulation. No specific medication demonstrated healing via regeneration of true
could be credited. Disease activity was well con- hyaline cartilage, chondrogenesis. Healing oc-
trolled. Possibly a child’s greater potential for curred in over 50% of the defects in four weeks.
bone (and other connective tissue) remodeling is The crucial time for application of continuous
important in promoting healing. Care was taken passive motion to get true healing was in the first
to avoid artificial interpretation of the radiologic week. There was little difference shown whether
restoration of joint space. Increased range of the joint was passively moved for one week or one
motion, decrease in pain and disability, and month. The cells that putatively promote healing
evidence of a new articular surface (previously are totipotential undifferentiated cells in the
denuded of cartilage) correlated well with the bone marrow. Presumably the cells migrate from
roentgenogram evidence. Garcia-Mortea et al’*’ the marrow into the region of cartilage injury.
reported three more juvenile patients with secon- Six months later the passive-motion treated ani-
dary OA who enjoyed hip joint restoration, with mals had normal cartilage, while those immobil-
filling in of pseudocysts, joint remodeling, and ized or allowed to move freely had OA.
marked clinical improvement. Their improve-
ment was not completely sustained after four Osteotomy. Hanging Hip Operation, Abductor
years; one patient experienced new damage. Muscle Cutting Procedures, Arthroplasty
The common factor in the treatment of these McMurray osteotomy in OA of the hip has
children was emphasis on exercise, especially been shown to result in a radiologic increase in
muscle strengthening, increased weight bearing, joint space, a relief of symptoms and signs.
avoidance of wheel chair, and vigorous applica- healing of pseudocysts, improvement in bone
tion of physical and occupational therapy. This outline (remodeling-out or loss of osteophytes)
suggests that the balance between anabolic heal- and a restitution of bony trabecular pattern.‘2K “”
ing processes and enzymatic destruction was The improvement is presumed to be due to
favorably turned by exercise and use, probably moving the weight-bearing site to another more
also strongly influenced by attitude and enthu- normal area of the femoral head. Cup arthro-
siasm. plasty has the same end result. Such operations
Figure 11 illustrates the investigators first are expected to restore the surface to normal
experience with reversibility in OA occurring in contour, with a reasonably smooth hyaline and
an 85year-old man. fibrocartilage coating the surface of the joint. It
is not of great importance how the stability is
Experimental OA obtained, whether by moving the weight to
Eflect of continual passive motion on healing another site in the femoral head, by osteophytic
of cartilage. Salter et al55 in a five-year study overgrowth. or by insertion of a smooth cup to
of experimental OA in rabbits showed that con- equalize and spread the pressure on the bearing
tinuous passive motion is a powerful stimulus for surface while healing occurs. In almost all cases
healing and regeneration of hyaline cartilage. in which the operation is done by an expert. the
The distal femoral cartilage of each rabbit was femoral head will recloth itself. All three may
damaged with four full thickness drill holes (into contribute to the end result either in concert or
subchondral bone). One group was immobilized separately.
postoperatively since immobilization of joints The hanging hip procedure is another way to
causes a type of OA. In these rabbits the bone alter faulty biomechanics. Its application is lim-
healed slowly and the cartilage did not heal at all; ited and requires experience and clinical judg-
OA REVIEW
Fig 11. The hip joint of an 85-year-old man in 1972 and 1975. Striking clinical and radiologic improvement
a vigorous conservative program.
ment in addition to precise and meticulous mea-
surement. This method also, in the right circum-
stances, results in healing and recoating with
fibrocartilage and occasionally hyaline carti-
lage.“’ Osteotomy continues to be effective and
preferable to total joint replacement, provided
the preparation, radiologic assessment, and spe-
cific indications are proper. It is particularly
useful in young patients.“* It is not a forgiving
operation and not for the inexperienced
orthopedic surgeon. Total hip replacement
forgiving but not as likely to last! Success with
osteotomy of the knee requires careful surgical
planning, but technical execution is easier and
the overall results exceed those seen in hip osteo-
tomy.
Friederich Pauwels” and his student and col-
league Paul Macquet5* have perfected the art
and science of these various procedures to reverse
OA and have developed a high degree of predict-
ability. Stress-reducing operations, when prop-
erly performed, give excellent results with the
obvious advantage of preserving the patient’s
own bone, cartilage, and other articular tissues,
ie, a physiologic healing, a healing with living
bone and cartilage. These investigators’ tech-
niques, measurements, and radiologic assess-
ments deserve more widespread application (Fig
12).
SPARING EFFECT OF STROKE, POLIOMYELITIS,
NERVE INJURY, AND AMPUTATION IN OA
There is a complex interplay between immo-
bilization and mechanical stimulation in the
development of OA. Patients who are hemiplegic
and later develop primary generalized OA do not
121
followed use of
develop Heberden and Bouchard nodes on the
paralyzed side.59 This is true also of RA following
hemiplegia.“’ There is some evidence that preex-
isting Heberden nodes have diminished or disap-
peared on the paralyzed side following a stroke.
This protective effect is also seen in poliomyelitis
and peripheral nerve injury.‘34 The phenomenon
is not a consequence of the paralysis alone since
neither OA nor RA develop in the affected side
in patients who are rehabilitated with return to
is normal function.
Paralysis, prolonged rest, or immobilization do
not protect against OA. In fact, removal of
mechanical stimuli results in degradation of car-
tilage, osteophyte formation, and eburnation.
Experimental immobilization in dogs and rabbits
results in decrease in metachromatic matrix and
increasedlJ5 SO, incorporation (active matrix
synthesis).5,h Palmoski and Brandt showed that
in the immobilized dog leg, water content of
cartilage increased (as in OA) and uranic acid
and overall progeoglycan synthesis decreased.
Newly synthesized and total tissue proteoglycan
had reduced ability to form aggregates, perhaps
related to some abnormality of the hyaluronate
binding region of the core proteins.“’
Lower limb amputees have a sparing effect in
joints above the level of amputation.‘3B~‘39 Disuse
osteoporosis may be a factor here, since osteopor-
osis protects against developing OA, perhaps
related to increased compliance of osteoporotic
bone.“‘%‘4
Immobilization Efects
Ely and Mensor ‘42 in 1933 showed that an
immobilized joint will develop cartilage changes
 BLAND AND COOPER

Fig 12. (A) An illustration of a severely valgus knee with narrow lateral compartment space, dense subchondral bone, a
clinically crippling problem; two years postosteotomy (B) shows marked increase in the lateral joint space via remodeling of
the very dense, eburnated subchondral bone, disappearance of osteophytes and realignment of the femoral condyle and the
tibia1plateau. Reprinted with permission of Dr Paul Maquat, Liige. Belgium.”

similar to those of OA. In both OA and immobili- witz” showed that immobilization for long peri-
zation arthropathies the cartilage shows fibrilla- ods resulted in proliferation of fibro-fatty tissue
tion, flaking, fissuring, and overall thinning. In that fills the joint and grows over the cartilage
OA, however, the chondrocytes proliferate in surface. This tissue has the same characteristics
clones or brood clusters and overproduce their as the pannus of RA, ultimately eroding the
macromolecules. In immobilization the chondro- cartilage by enzymatic degradation. Even slight
cytes degenerate and die within a short time, movement of the joint slows the process down.
suggesting that they require mechanical stimula- Compression, in addition to immobilization,
tion to survive. OA develops over years while accelerates it.h2 Palmoski and Brandt’43 showed a
immobilization arthropathy is characterized by marked decrease in the rate of synthesis of
an acute onset, presumably due to the abrupt proteoglycan in three weeks in immobilized dog
alteration of joint function. Immobilization knees. The proteoglycan aggregates (with hyal-
arthropathies are most probably a consequence uronate) no longer formed in the cartilage and
of nutritional failure. Avascular cartilage, did not aggregate normally with exogenous hyal-
behaving like a water filled sponge, gives off fluid uronate. On return to use and weight bearing.
on compression and takes it up on release of proteoglycan aggregation returned to normal, a
pressure. Alternate compression and reexpansion clinically important point. However, increased
allows supply of nutrients and removal of meta- water content and loss of aggregability of proteo-
bolic waste products. Thus, immobilization, rela- glycans did not return to normal if the animals
tive or absolute, has a profound affect on the (instead of normal weight bearing) were sub-
health and well being of the chondrocyte. These jected to vigorous exercise. Vigorous treadmill
physiologic data may be effectively applied clini- exercise resulted in continued thinning of carti-
cally. lage, decreased uranic acid content, and abnor-
Salter and Field6’ and Enneking and Horo- mal Safranin 0 staining, even though net proteo-
OA REVIEW
glycan synthesis increased. This suggests that
cartilage having the immobilization lesion is vul-
nerable to loading and that excessive exercise at
that point could accelerate the OA sequence.
Ha1163showed that immobilization in chicks by
injection of paralyzing drugs (tubocurare)
resulted in the transformation of cartilage into a
bone-like tissue. The matrix lost its proteoglycan,
accumulated collagen, and ossified. The artic-
ular chrondrocytes reduced in size and resembled
osteoblasts having alkaline phosphatase activity.
This study emphasizes the adaptation of a highly
labile, metabolically active tissue to functional
demands.
In Vitro Culture of Chondrocytes
Both rabbit and human chondrocytes can be
grown in cell or organ culture, and they continue
to express their phenotypic properties. They not
only grow readily, but also show a youthful vigor
and aggressive will to live as displayed by high
plating efficiency and ready growth in soft
agar.‘44.‘45 An important phenomenon was
observed when monolayer cultures were trans-
ferred to spinner bottles in which mechanical
stimulation replaced the inert environment of the
monolayer flask culture. In spinner cultures ten
times more sulfated proteoglycan was secreted
into the media and >50 times as much was
adherent to the cells. The types of proteoglycan
produced correlated closely with those produced
in whole untreated cartilage. When a certain
amount of connective tissue matrix was pro-
duced, the rates of synthesis fell, indicating
feedback regulatory control. Anchorage seems to
promote cell division, and mechanical stimula-
tion promotes synthesis. These data provide in
vitro support for exercise and use of joints in OA.
Chondrocytes from three month-old rabbits did
not differ in any way from chondrocytes from
three year-old rabbits, suggesting retention of
chondrogenic expression despite age. A pilot
study of human chondrocyte culture disclosed no
differences in morphology, in DNA-RNA turn-
over, proline hydroxylation of collagen, or pro-
teoglycan synthesis in chondrocytes from sub-
jects 265 years of age and children zz 15 years.‘46
Homotransplanted isolated chondrocytes in-
jected into muscle synthesized hyaline cartilage
in the muscle. Therefore, the possibility exists of
123
growing cartilage from an animal and reinjecting
it without the problems of graft rejection.
Prins et a114’ studied the effect of three puri-
fied peptide growth factors: fetal calf serum,
insulin, and ascorbic acid (vitamin C) on rabbit
chonrocytes in monolayer cultures. Results were
impressive but variable. The growth factor stim-
ulated both proteoglycan synthesis and prolifera-
tion and was concentration dependent. Ascorbate
had an anabolic effect, increasing all growth
(proliferation and increase in proteoglycan syn-
thesis) not suppressed by higher concentration of
the calf’s serum. In addition to in vitro effects,
Schwartz et a114*in a study of experimental OA
in guinea pigs, found that cartilage erosion was
much less and the overall histologic and bio-
chemical changes in and around the OA joint
was milder in animals kept on high doses of
vitamin C. Presumably, vitamin C may protect
against the erosion by increasing chondrocyte
synthetic rates. Krystal et a1’49 confirmed the
importance, indeed necessity, for an excess of
ascorbic acid in both human and rabbit chondro-
cyte protein synthesis.
Neuromuscular Reflex Mechanism of
Absorbing Shock of Impulsive Loading
Cartilage failure results from either excessive
loading of normal cartilage or physiologic load-
ing of abnormal cartilage. Impulsive loading can
cause cartilage to degenerate in vivo and in vitro.
Therefore the study of mechanisms of shock
absorption (beyond the mechanical stimulation
a necessary to maintain normal cartilage) is
important to understanding normal regulation of
cartilage metabolism and the acceleration by
relative overload in the OA process.
Shock is absorbed mainly by reflexly con-
trolled neuromuscular mechanisms, active
lengthening of muscle while maintaining tension.
Unexpected or unprepared for the impulsive
load, minor shock may be damaging, ie, going
downstairs in the dark and mistaking the last
step for the landing. Serious injuries can occur
without normal neuromuscular control. In the
patient who is unfit, has muscle atrophy, or slow
and delayed reflexes, the ordinary activities of
daily living, walking, sitting, stair climbing, rela-
tively minor insults may become major ones.
Repetitive tasks by untrained people, resulting in
124 BLAND AND COOPER

fatigued muscles, can diminish active shock-

\
absorbing mechanisms. If we jump from a height
! Block and tackle
of one foot and land stiffly, injury occurs; if we
jump and land on toes and flex ankles, knees, and - Electromagnet

hips, the shock is harmlessly absorbed. Since

Handle
older people are generally less and less fit, the
increased incidence of OA may result, at least in
part, from relatively poor neuromuscular reflex
mechanisms, and consequent cumulative small
stresses that lead to subchondral bone microfrac-
tures, callus, stiffening and more microfractures,
with ultimate fatigue failure of the cartilage
itself.
Jones and Watt15’ did some elegant and simple
experiments that disclosed that normal, healthy
young subjects could sustain significant injury in
an unexpected fall if the height was too short to
allow normal reflex muscle contraction and
absorption of the shock. Figure 13 illustrates the
rationale of the experiment. By raising the height
of the fall there was enough time for the reflex to
occur and the shock was easily absorbed. The Fig 13. Diagram of apparatus of experiment to study
experiment has pertinence to the management of the “functional stretch reflex,” a mechanism for landing
OA and points to the necessity to maintain from unexpected falls. A block and tackle suspends an
electromagnet and a hanging handle or strap. The gastro-
optimum musculoskeletal fitness at all ages. cnemius muscle is attached to an electromyograph which is
Contrary to the usual excessive rest programs in connected to the electromagnet. A force plate, also coordi-
OA, we propose that well-governed and prac- nated, records the force and time of landing from various
heights. The subjects knows he is going to fall but not when
ticed exercise and mechanical stimulation of the he will fall. The time in microseconds is recorded between
involved tissues may aid in arrest or reversal of the release of the electromagnet and the landing and the
the process. force plate records the force on landing. In landing from <g
cm to 13 cm in height there was always a painful jolt in
healthy subjects, ie, the muscular reflex occurred too late
to take up the shock there was on landing, and mild injury
Drug and Hormone Effects on Chondrocytes occurred. Landing from falls 15 to 18 cm and higher were
35S glycosaminoglycan synthesis is suppressed not associated with pain or injury, the reflex occurred
before the landing and there was less force than at the
by sodium salicylate; however, the addition of lower heights. See text for theory from these data applied
beta-D xyloside overcomes this inhibition and to etiology and pathogenesis. Reprinted with permis-
markedly stimulates proteoglycan synthesis.‘5’ sion.lM

The clinical implications are obscure. Aspirin

has been shown to have a protective and possibly lage.“’ Homocysteic acid promotes growth of
reversal effect on the OA process in both experi- epiphyseal cartilage and collagen in tails of
mental and clinical OA. Chrisman et al have rats.“’ It also increases somatomedin activity.
been the principle investigators.‘52m’56 Although Growth hormone favorably influences estab-
there is disagreement, opposing views are derived lished cartilage lesion.‘59 Corval et a116’identified
from experiments using different invesitigative a pituitary growth promoting factor for articular
systems making valid comparison difficult.‘57~‘58 chondrocytes in monolayer culture. There are
The issue remains controversial and a point of other endocrine, drug, and vitamin effects on
ongoing research. chondrocytes and cartilage noted in the sections
Specific estradiol receptors have been demon- on pathogenetic theories of OA, pathophysiology
strated in the cytoplasm of articular chondro- of OA, and current concepts of normal physiol-
cytes in vitro.93 Benoxaprofen reportedly stimu- ogy of articular tissue. Transplanted articular
lates proteoglycan synthesis in normal carti- cartilage in dogs responds to growth hormone by
OA REVIEW 125

a tenfold increase in collagen and proteoglycan ligament, and capsule respond to mechanical
synthesis.‘6’ Chronic L Dopa administration stimulation and use at all ages by increasing
results in increased plasma growth hormone rates of synthesis augments tensile and compres-
which via somatomedin may have a chondrocyte sive strength.‘72m’75 However, there are no studies
impact.‘62 Most nonsteroidal antiflammatory demonstrating differences in this response
drugs suppress prostaglandin synthesis and many related to aging.
suppress proteoglycan synthesis in cartilage.‘63 The weakest and oldest among us can become
some kind of athlete but only the strongest can
Response of Muscle, Bone, and Joint to
survive as spectators, only the hardiest can
Training in the Aged and Middle Aged
withstand the perils of inertia, inactivity, and
Since a major thrust in the management of immobility.
OA is achievement and maintenance of optimum
fitness, cardiovascular and musculoskeletal,
MANAGEMENT PROGRAM DEVISED
some knowledge of what can be done is impor-
ACCORDING TO THE CELL BIOLOGY AND
tant. Mobility is second in importance to intellec-
PATHOPHYSIOLOGY INVOLVED IN OA
tual powers and the OA patient must be aggres-
sive in maintaining it. Proper attitudes toward This section is designed to apply the available
perceived health, body image, physical activity, information on the cell biology and pathophysiol-
anxiety, and life satisfaction have been studied in ogy involved in OA, to a treatment regimen that
men and women 60 years of age and older.‘64 A optimizes the possibility of reversal of the pro-
group of 124 subjects volunteered for endurance cess. It appears that OA constitutes a tandem
training. Virtually all measures of fitness manifestation of two processes, synthesis and
improved in 83% over a 14-week period, includ- anabolic activity v degradation and catabolic
ing maximum oxygen uptake, blood pressure, activity. When the latter exceeds the former the
pulse rate, general sense of musculoskeletal stiff- damage to joint tissues acclerates and crippling
ness, anxiety “titers,” relief of tension, and feel- and deformity occur. Thus, the question “Can
ing of well being.16’ cartilage repair itself” is paramount? Can osteo-
Sophisticated application of knowledge of phytes, once formed, be remodeled away? Can
nutritional requirements in the aged and in OA is subchondral bone once thickened, and less com-
of major importance.‘66”67 Malabsorption is com- pliant, reverse that process? Hyaline cartilage
mon, affecting fat-soluble vitamins, folic acid, and lens of the eye are peculiar tissues in that
and vitamin B,,. Alcoholism is subtle and also they are avascular, aneural, and alymphatic;
common with consequent malnutrition. Restric- healing is different than in other tissues. For
tion of food increases the life span of rats and instance, skin, liver, lung, kidney, and brain
other laboratory rodents and delays appearance repair themselves with a collagen scar while
or slows progression of those diseases believed to other tissues, connective tissues specifically,
limit the life span of the anima1.‘66 repair themselves with a tissue resembling the
Physical activity in the aged (ages 55 to 94 parent tissue, bone, tendon, and synovial mem-
years) prevents and slows bone loss and even brane. The process is clearly one of cell activity,
increases bone accretion, a little appreciated fact fibroblast, osteoblast, chondrocyte synthesizing
in the management of OA.‘67a Rates of mineral the materials that result in repair. These are
loss in the aging osteoarthritic can be favorably “new” cells, either evolving from the differentia-
affected.‘68.‘69 The increased calcium intake tion of precursor cells that have migrated into the
requirement and assurance of its absorption are area, or by replication and division of existing
achievable goals in managment of OA.“’ Defi- cells.
cient vitamin C intake is common and may be The chondrocyte in OA behaves differently
associated with a defect in collagen proline than the same chondrocytes involved in the nor-
hydroxylation, reflected in the known increased mal homeostasis and remodeling of cartilage, ie.
excretion of proline-rich collagen-derived pep- synthesizing the materials in the right propor-
tides, thus likely compromising connective tissue tions and the enzymes in sufficient amounts to
repair, a necessity in OA.“’ Muscle, tendon, maintain the tissue. The question is, are the
 BLAND AND COOPER

chondrocytes, fibroblasts, osteoblasts, and syno- receptors for estrogen in chondrocytes), pituitary
vial cells temporarily turned to different syn- dysfunction, calcium pyrophosphate dihydrate
thetic mechanisms or are they, like brain and crystal deposition disease, or occult gout; possible
muscle cells, permanently and irreversibly immunologic mechanisms, genetic factors, envi-
“switched off.” The evidence presented in this ronmental contributions that may have been
review suggests that the switch is not broken but acquired, ie, old injury, torn meniscus, old frac-
is temporarily turned in an inappropriate direc- ture, subluxations, congenital dislocation; and
tion. Certainly chondrocytes can mount a brisk the frequent occurrence of general nutritional
and significant repair response and can replicate and specific vitamin C deficiency in the elderly
their DNA-RNA to form new cells. The stimuli readily correctable and possibly contributing to
regulating articular chondrocyte activity are the failure of healing.
myriad, ie, increased or decreased rates of pro-
teoglycan synthesis occur by such widely diverse Avoid Episodic, Stuttering Care
and varying factors as mechanical stimulation,
The OA patient deserves the same kind of
changes in hydrostatic pressure, alterations in
continuing thoughtful, thorough follow-up as
pH, change in calcium concentration, presence
does the patient with RA. Set up objective
or absence of growth hormone, thyrotropin,
parameters of progress, or lack of it, and list the
insulin, parathyroid hormone and many others,
patients’ assessments and measurements, ie, leg
varying oxygen tension, vitamin E, ascorbate,
length, circumference of joints, walking time,
cortisol, etc. This suggests that if the right “but-
hand movement facility, quantitative measure of
tons” are pushed the cells are capable of reorient-
thoracic, cervical, and lumbar spine movement,
ing, switching back to their normal synthetic and
sleep pattern, pain changes, stiffness on immobil-
degradative functions. The program is designed
ization, body weight, overall functional capacity,
to manage OA from every conceivable point that
fatigue (accurate and complete records).
may influence the disease. Until the last chon-
drocyte is dead, the complete therapeutic effort
is worth a full trial.
Early Recognition
Patient Education The earlier recognition of OA occurs, the more
It is of the utmost importance for the patient to probable is arrest or reversal of the process.
understand in some degree the function of syno- Realizing that any change in the microenviron-
viocyte, chondrocyte, osteoblast, osteoclast, and ment of the chondrocyte will trigger the process,
fibroblast - to know that repair can occur - to a survey of genetic factors predisposing to OA,
develop sufficient optimism that is based on prompt management of injuries, the presence of
scientific fact. Compliance with the program is any other form of rheumatic disease-all should
assured if the patient understands that by receive attention and management, thereby
mechanical stimulation he can in fact alter the enhancing the possiblity of prevention, arrest. or
physiology of the involved cells producing the reversal.
abnormality. The education of the older popula-
tion with the role of maintenance of optimum Rest Program
overall fitness is probably the greatest deterrent A rest program such that the rehydration of
to the development of OA. cartilage may occur every four to six hours,
depending on the severity of disease. Teach the
Complete Clinical, Laboratory, and patient that on nonweight bearing the com-
Radiologic Study pressed cartilage reexpands and absorbs the
Each patient must be thoroughly examined to nutrients necessary for chondrocyte health and
identify any of the many possible contributing function. We lie down once a day for six to eight
factors (ie, endocrine or metabolic disorders that hours during which time the cartilages through-
may subtly contribute)-hypothyroidism and out the body rehydrate. If one wants to optimize
myxedema, menopausal manifestations (note this effect, then two to four times of nonweight
OA REVIEW 127

bearing for periods of one hour or more may proteoglycan and collagen synthesis; there is a
promote cartilage maintenance and repair. probable early release of degradative enzymes.
Exercise and physical therapy. In the case
of monoarticular or pauciarticular OA special Management
exercises are prescribed for the joints involved. 1. Study patient thoroughly for all possible
Appropriate application of cold for acute inflam- etiologic and pathogenetic factors; at this stage
mation with the use of heat primarily for muscle the chondrocyte has been “switched off” and is
relaxation should be undertaken. Stretching marching to different music than that of the
exercises are also important as a routine, at least normal chondrocyte. We believe that the switch
morning and night. has not been permanently turned in the wrong
direction and that reversal remains at least a
Fitness Program possibility. When possible, treat underlying
A general as well as local program should be pathogenic factors.
followed, including postural exercises, and main- 2. Stretching exercises morning and night.
taining optimum neuromuscular function. The Rest prescription alternating with exercise: one
physician should examine reflex capability and hour of rest for four hours up and about.
work up measures of fitness for each patient, ie, 3. Optimum fitness maintained; “business as
resting pulse, blood pressure, sense of well being, usual” as nearly as possible.
body weight, and body composition using skin 4. Maximum patient education concerning
fold measurements. Weight loss associated with etiology and pathogenesis.
a program of maximum fitness should be 5. Aspirin in full doses, ie, approximately 4 g
achieved. Appliances such as lifts, wedges in the daily in divided doses on the presumption that
shoes, cane or crutches should be used when degradative enzymes are released at this stage.
possible as a mechanism of arriving at a point Stage of development: cartilage erosion
where they will not be needed. begun: phospholipase and cyclooxygenase me-
diated release of prostaglandins and leucotrienes.
Drug Therapy Osteoblastic synthesis of subchondral bone with
Aspirin, nonsteroidal antiinflammatory drugs, decreased compliance, increased microfractures
certain hormones in the right place, and vitamins with new callus, and increased stiffness of bone.
with emphasis on vitamin C should also be used. Osteophyte formation at joint margins. Early
An outline of management follows as it relates compromise of lubricating mechanism.
to stage of disease and the cell biology involved. Early synovitis: synovial cell activation, prolif-
Stage of OA development: initial changes eration and switch of cell to probable collage-
occur in the chondrocyte microenvironment. nase-prostaglandin synthesis. Enzyme release
into cartilage. Fibrotic proliferative response of
Management capsule, tendon, ligament (the connective tissue
Identify the presence of possible initiating in and around the joint).
mechanisms ie, calcium pyrophospate dihydrate Degradation products resulting in antigenic
crystal deposition, crystal, hydroxyapatite, mon- stimulation and activation of immune mecha-
osodium urate, trauma, endocrine, metabolic or nisms. Synovial cell transformation (metaplasia)
genetic influences and correct as far as possible. to a cell producing the material of osteophyte,
Note at this point there is no evidence of active coating the bony material with fibrocartilage,
inflammation and thus aspirin and nonsteroidal sometimes closely resembling hyaline cartilage.
antiinflammatory drugs are not indicated. Begin
conservative program of alternating rest and exer- Management
cise. Education as to how to achieve results and 1. Continue and increase the alternating rest-
maintain optimum overall fitness. exercise program; mechanical stimulation of car-
Stage of OA development: chondrocyte tilage to tolerance; maintain optimum fitness,
mitosis, clones (brood clusters appear), increase appropriate local exercise in most involved joints;
in the rates of turnover of DNA-RNA and train for reflex response; do not permit atrophy of
128 BLAND AND COOPER

muscle, tendon, ligament and bone, add exercise and pathophysiology in OA are sufficiently well
against resistance; consider isokinetic exercise to developed that the physician may initiate appro-
maximize tensile strength of involved tissues. priate therapy after clinical, laboratory, and
2. Aspirin in full doses. radiologic assessment of the stage of disease. It is
3. Consider muscle strengthening exercises, evident that the chondrocyte can and does switch
isometric, isotonic, and isokinetic, should prog- from a cell with little potential for cell replication
ress be in doubt. into one that increases DNA-RNA synthesis.
4. Consider low-dose corticosteriod therapy, probably not becoming permanently switched
ie, antiinflammatory agent and mild immuno- off, and increased rates of proteoglycan and
suppressant (5 to 10 mg single dose in the collagen synthesis are instrinsic to the process. as
morning for three months), stop for one month though there is a growth increase in the self-
and consider retrial depending on clinical, labo- contained normal remodeling capability of the
ratory, and radiologic assessment of results. chondrocyte. The mechanisms of triggering this
5. Consider adding a second antiinflamma- common pathway are legion. There is sufficient
tory agent, indomethacin, phenylbutazone inter- evidence that in at least some circumstances the
mittently, other nonsteroidal antiinflammatory process will reverse itself or arrest. Superficial
drugs. injury to the cartilage does not heal, nor does it
6. Consider intraarticular corticosteroids for go on to the OA process. Deep lacerations pene-
mono- and pauciarticular OA and maximal local trating the subchondral bone result in an exten-
antiinflammatory effect. sive. exuberant healing response: the new cells
probably arising from the bone marrow, undif-
WAVE OF THE FUTURE
ferentiated primitive cells making their way into
The wave of the future includes the use of the cartilage. They can produce a hbrocartilage
somatomedin which via growth hormone stimu- and hyaline cartilage-like material that is ser-
lation may accentuate synthesis over degrada- viceable as a bearing. If the defect is not exten-
tion; uridine diphosphoglucose has been shown to sive the new “cartilage-like” material fills the
manifest prolonged stimulation of proteoglycan defect and repairs the surface. but may later
synthesis in cartilage and may develop a clinical show a localized, nonprogressive focus of OA.
role. Homocysteic acid also stimulates cartilage Thus far drugs for OA have been aimed only
and somatomedin release.“” Enzyme inhibition at the later developments and probable secon-
and synthesis stimulation drugs presently in dary inflammation. The evidence suggests that
study; autotransplants of cartilage. ie, growing the earliest changes in the cartilage matrix and
human cartilage from the patient for possible the chondrocyte arc not inflammatory.“‘ If
replacement in joints; and Levodopa may have a drugs are to be truly healing to the damaged
role: thyrotropin-like hormones may become use- cartilage they should be aimed at restoring the
ful as well as anabolic steroids. Certainly vitamin normal function early in the course of OA. It
C is always indicated and is harmless in adequate becomes important to identify potential OA
doses. Baker et al’7h showed that an electrical patients before the cartilage is wholly lost, while
field could accelerate the repair of deep defects new synthesis can go on. New life styles. diet.
in cartilage. Subchondral defects in the distal exercise, and drug intervention in the young
end of the femur in rabbits with an electrode could enable such potential patients or their
placed in the bone beneath the defect through a children to avoid the initial microdamage precip-
channel created in the femoral shaft resulted in itating the final common pathway of OA. I.ike
accelerated healing of the defect. compared with other common, so called degenerative diseases.
controls. The histologic study showed the healing OA may be arrested or reversed and prevention is
material to be hyaline cartilage. closer than we think: applied to all patients but
particularly to the susceptible populations.
DISCUSSION AND CONCLUSION
Physicians who fail to carry out optimum
The basic knowledge of the mechanisms of clinical assessment and maximal management of
initiation and continuation of the cell changes OA or initially rush to total joint replacement are
OA REVIEW 129

unaware of the more recent developments in physicians to study each clinical case of OA,
physiology, biochemistry, pathology, and cell attempting to identify all possible etiologic fac-
biology of this interesting and fascinating dis- tors and deal with them therapeutically, to make
ease. OA can appropriately be regarded as a OA sparkle and receive the interest, enthusiasm,
state of altered physiology, potentially amenable excitement, and research effort that this almost
to correction, control, and even reversal, a com- universal disorder deserves.
plex system of interacting mechanical, biologic,
biochemical, endocrine, and enzymatic feedback
loops. One or more of the systems fail and the ACKNOWLEDGMENT
clinical events follow. We thank Mary Skovira for her bibliographic and editorial
Our hope is that this review will stimulate skills in the preparation of this manuscript.

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