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