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Immobilization ameliorates chemically-induced articular cartilage damage.

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We have previously shown that immobilization
protects against the development of mechanically-induced osteoarthritis following anterior cruciate ligament
transection in dogs. Herein, we examine the effect of
immobilization of the leg on the chemically-induced
degeneration of femoral articular cartilage caused by
intraarticular injection of iodoacetate in guinea pigs.
One week after the injection, cartilage from animals
which were not immobilized exhibited a decrease in
Safranin 0 staining and a 10-20% reduction in the
number of chondrocytes. Three weeks after injection,
cell death and loss of Safranin 0 staining had progressed, and surface fibrillation and osteophytes had
developed. Articular cartilage from the contralateral
(uninjected) knees of guinea pigs which received iodoacetate, and from knees of animals which were immobilized for 1 week but did not receive iodoacetate, was
histologically and histochemically normal. However,
specimens from 2 of 4 untreated knees which were
immobilized for 3 weeks showed a reduction in Safranin
0 staining. Immobilization of the knee did not alter the
loss of Safranin 0 staining seen after intraarticular
iodoacetate injection, but did reduce the depletion of
chondrocytes (P < 0.05). Furthermore, neither osteo~~
From the Rheumatology Division, Indiana University
School of Medicine, Indianapolis, Indiana.
Supported in part by grants AM 20582 and AM 27075 from
the National Institutes of Health.
James M. Williams, PhD: Rheumatology Fellow and recipient of a Postdoctoral Fellowship from the Arthritis Foundation;
Kenneth D. Brandt, MD: Professor of Medicine and Chief, Rheumatology Division, Indiana University School of Medicine, Indianapolis, Indiana.
Address reprint requests to James M. Williams, PhD,
Rheumatology Division, Indiana University School of Medicine, 541
Clinical Drive, Room 492, Indianapolis, IN 46223.
Submitted for publication January 25, 1983; accepted in
revised form August 11, 1983.
Arthritis and Rheumatism, Vol. 27, No. 2 (February 1984)
phytes nor fibrillation developed in any of the animals
which were constrained after iodoacetate injection.
Thus, immobilization was clearly protective in this
model of chemically-induced cartilage injury.
Intraarticular injection of sodium iodoacetate
(IA) has been shown to produce degenerative changes
in knee cartilage of hens (1). Recently, we reported
that repeated intraarticular injection of IA also resulted in progressive degeneration of guinea pig knees (2),
with extensive fibrillation and ulceration of the articular cartilage, depletion of chondrocytes, and diminished staining with Safranin 0, indicating a loss of
matrix proteoglycans (PG).
Immobilization by casting the knee of a normal
dog for a few weeks results in cartilage atrophy (3).
Although the articular surface remains intact, a loss of
Safranin 0 staining and decrease in uronic acid content of the cartilage are apparent, cellularity and PG
synthesis are reduced, and PG aggregation is impaired.
In addition, immobilization modifies the development
of secondary osteoarthritis (OA) produced by anterior
cruciate ligament transection in the dog (4). Thus,
when the unstable knee is placed in a cast immediately
after ligament transection, the loss of integrity of the
articular surface, the augmentation in PG synthesis,
and increased extractibility of matrix protcoglycans
usually seen in OA ( 5 ) do not occur, and osteophytes
do not develop.
In view of the protective effect of immobilization on mechanically-induced OA, the present study
was designed to examine the effect of immobilization
of the leg on the chemically-induced joint damage
caused by intraarticular injection of IA into the guinea
pig knee.
Table 1.
Effects of leg immobilization on body weight and changes in joint cartilage after intraarticular injection of iodoacetate
duration of
Group I
Group 2
Group 3
Group 4
Group 5
(no. of
Body weight
at killing, %
of initial
I (6)
3 (4)
1 (5)
3 (4)
1 (4)
3 (5)
88 _t
89 _t 2$
84 _t 2$
80 ir 3$
101 2 I
102 t I
1 (4)
3 (4)
0 (5)
Decrease in
Defects in
+ ++
+ (superficial)
+ (superficial)
+ + -t
+ ++
+ 1.
* Animals were injected with either iodoacetate (IA) or saline (S). or received no injection (NI).
t IT = interterritorial: PC = pericellular; 0 = none: + slight; + i = moderate; t r + = marked.
$: P < 0.05, determined by Student’s 1-text for paired observations.
8 Samples from 2 of the animals in this group showed an overall reduction in I T staining.
Animals. Adult male albino guinea pigs (approximately 32-40 weeks old) were housed individually in 18” x
18” x 18” stainless steel wire-bottom cages and fed Guinea
Pig Chow 5025 (Ralston Purina Company, Richmond, IN)
(ascorbic acid content, 1.0 mg/gm) ad libitum (6). Food
intake was monitored daily. The animals were randomly
divided into 5 experimental groups as described below. The
weight of each guinea pig was recorded at the beginning of
the experiment and weekly thereafter. Animals were killed
by intraperitoneal injection of T-61 euthanasia solution (Taylor Pharmacal Co., Decatur, IL).
Group 1 consisted of 10 animals whose left knee was
injected with sodium iodoacetate but not immobiliLed. These
animals were killed I week (n = 6) or 3 weeks (n = 4) after
the injection (Table 1).
Group 2 consisted of 9 guinea pigs whose left knee
was injected with IA, immediately immobilized, and maintained in a constraint until they were killed 1 week (n = 5 ) or
3 weeks (n = 4) after injection.
Group 3 consisted of 9 animals which did not receive
intraarticular IA, but whose left knee was immobilized until
killing 1 week (n = 4) or 3 weeks (n = 5 ) after immobilization.
Group 4 consisted of 8 animals which received a
weekly injection of 0.9N sodium chloride into the left knee
until they were killed 1 week (n = 4) o r 3 weeks (n = 4) after
the initial injection.
Group 5 consisted of 5 guinea pigs which served as
untreated controls and were killed at the outset of the
Both knees of each animal were examined daily
(groups 1 and 4) or weekly (groups 2 and 3) to assess mobility
and swelling.
Injection and immobilization procedures. Before intraarticular injection of IA, animals in groups 1 and 2 were
anesthetized by an intramuscular injection of ketamine hydrochloride (50 mg/kg). After the left knee was shaved and
washed with 70% isopropyl alcohol, the injection was per-
formed under aseptic conditions by passing a 26-gauge
needle attached to a tuberculin syringe through the joint
capsule lateral to the patellar ligament. A sterile solution of
0.3 mg of IA in 0. I ml of O.9N sodium chloride was injected.
Animals in group 4 were injected in an identical
manner but, instead of IA, they received 0.1 ml of sterile
0.9N sodium chloride intraarticularly .
For the immobilization procedure (groups 2 and 3)
the animals were anesthetized as described above, and the
left knee was secured against the trunk in approximately 120”
offlexion with cloth tape, which was reapplied weekly. Daily
inspection confirmed that all taped limbs remained immobilized for the duration of the experiment.
Tissue analysis. Both knees were opened immediately
after killing and examined grossly. The distal femur was then
removed and assessed for articular surface defects according
to the method of Meachim (7). Briefly, the femoral condyles
were rinsed with distilled water, dipped in a 50% solution of
India ink, rinsed again, and examined with reflected light
using a lox magnifying lens.
The femoral condyles and the parapatellar synovial
membrane were fixed for 1-3 weeks in 10% buffered formalin and embedded in paraffin. The condyles were decalcified
in Decalcifier I (Surgipath Medical Industries, Chicago, IL)
for 7-10 days before embedding. Microscopic sections (6
pm) of the femoral condyles and synovium were stained with
Safranin 0 and fast green to demonstrate matrix PGs (8). or
with hematoxylin and eosin. Sections from knees of experimental animals and from untreated controls (group 5) were
stained concurrently to control for variations in uptake of the
stain. Measurements of cell density in the uncalcified cartilage were made from analyses of 4-6 sections from the
central region of each femoral condyle, stained with hematoxylin and eosin (9).
N o n e of t h e animals d e v e l o p e d j o i n t swelling,
a n d n o gross instability or limitation of m o t i o n oc-
curred as a result of the intraarticular injection or
immobilization procedure. The daily food intake of
each animal ranged from 35-70 gm of chow for the
duration of the experiment. Untreated controls (group
5 ) , guinea pigs which were injected with only saline
(group 4), and animals which were injected with IA but
were not immobilized (group 1) maintained their body
weight until killing (Table 1). In contrast, animals with
an immobilized leg, whether or not they received an
intraarticular injection of IA (groups 2 and 3, respectively), lost 11-20% of their initial body weight during
the study (Table 1).
Effects of intraarticular IA injection. Gross examination. None of the animals in any group had a
synovial effusion at killing, and the synovial membrane in all joints appeared grossly normal. The articular cartilage from knees of all untreated animals (group
5 ) , from knees injected with saline (group 4), and from
the right (untreated) knees of animals in groups 1-3
was translucent and pink, with a smooth, grossly
intact surface.
One week after injection of IA, however, the
articular cartilage of all animals in group 1 had lost its
normal pink translucency and was diffusely white and
opaque. Similar opacity was also noted 3 weeks after
IA injection. None of the condyles was observed to
retain India ink, with the exception of 1 sample from
an animal in group 1, which showed moderate uptake
of ink on the central portion of the medial femoral
condyle 3 weeks after IA injection.
Figure 1. Schematic drawing of femoral condyles of guinea pig knee
showing synovial reflection (S). Arrow indicates the intercondylar
groove. Inset, Area from which tissue shown in Figures 4a and b was
Figure 2. Normal medial femoral condyle of a control guinea pig
(group 5 ) , stained with Safranin 0-fast green. S = subchondral
bone. Arrows indicate the tidemark (original magnification X 60).
Microscopic examination, synovial membrane.
The synovial membrane in all control joints (groups 4
and 5 , and untreated joints of groups 1-3) was histologically normal (10). It consisted of an intima of 1-6
lining cells in thickness, and a subintima of loosely
arranged collagen fibers and adipose tissue, richly
vascularized with capillary loops beneath the lining
cell layer. Occasional villi protruded into the joint
The only histologic change in synovium of
joints injected with IA was noted in the lining cell
layer: 1 week after injection of IA, focal hypercellularity of the lining cell layer was noted in 4 of the 6
samples from group 1. However, in all cases the
synovial lining exhibited normal cellularity 3 weeks
after the injection. Neither inflammation nor fibrosis
was noted in any sample.
Articular cartilage histochemistry (Figure I ) .
Femoral cartilage from control knees (group 5 ) , salineinjected knees (group 4), and from the noninjected
and/or nonimmobilized knees of animals in groups 1-3
appeared histologically and histochemically normal.
The Safranin 0 stain revealed differential staining
properties of the matrix; orange-red staining of the
calcified zone was less intense than that of the overlying uncalcified cartilage (Figure 2). Infrequently, focal
areas of reduced staining of interterritorial (IT) matrix
were observed in the control samples. With the fast
green counterstain the overlying lamina splendens, as
well as the subchondral bone, stained pale green. In
the controls, no differences in staining were noted
between cartilage from the condyles and cartilage from
the intercondylar groove or joint margins.
21 1
Figure 3. Medial femoral condyle of a guinea pig in group 1, killed 1
week after an intraarticular injection of iodoacetate stained with
Safranin 0-fast green. Note depletion of chondrocytes and absence
of intertemtorial staining throughout the uncalcified cartilage, and
loss of pericellular staining confined to the superficial zone (original
magnification x 60).
One week after IA injection (group 1) IT matrix
throughout the uncalcified cartilage from medial and
lateral condyles, including the joint margins and intercondylar groove, failed to stain with Safranin 0.
Pencellular (PC) staining in the superficial zone on
both condyles was also reduced. However, both IT
and PC staining of the calcified cartilage remained
normal (Figure 3). After 3 weeks, uncalcified cartilage
of both condyles of every joint injected with IA
showed a complete loss of PC as well as IT staining,
while the calcified zone continued to appear normal.
Furthermore, osteophytes, which stained intensely
with Safranin 0, had developed at the medial joint
margin and on the medial aspect of the intercondylar
groove of every injected joint (Figure 4).
Articular cartilage cell density. Cell densities
from normal untreated animals (group 5 ) were calculated to average 185,000 cells/mm3 in cartilage from
the medial condyle, and 178,000 cells/mrn3 in samples
from the lateral condyle (Table 2). Cartilage from all
untreated and/or nonimmobilized knees of animals in
groups 1-3, and from knees of animals which received
intraarticular saline (group 4), exhibited normal cell
density (Table 2).
In contrast, 1 week after IA injection (group I),
cell densities on the medial condyle had fallen to 69%
significant. The depletion of chondrocytes was pro-
Staining with Safranin &fast green (original magnification x 60).
Table 2.
Effects of leg immobilization on changes in cell density after intraarticular injection of iodoacetate
Cell density, uncalcified cartilage
Group 1
Group 2
Group 3
Group 4
Group 5
duration of
Medial condyle
Mean cells/
mm3 x lo-’
% of
119 (82-167)
30 (20-40)
138 (103-179)
I14 (105-124)
166 (125-195)
147 (125-172)
182 (131-215)
183 (133-220)
185 (137-224)
69 (P< 0.Ol)t
17 (P < O.05)t
70 (P < 0.05)t
Lateral condyle
Mean cells/
mm’ x 10-’
130 (91-171)
77 (30-124)
191 (142-223)
146 (120-153)
245 (1%-319)
163 (148-177)
178 (143-235)
176 (140-235)
178 (144-237)
% of
54 (P< 0.02)t
73 (P < 0.05)t
* Animals were injected with either iodoacetate (IA) or saline 6).
or received no injection (NI).
t Determined by Student’s t-test for paired observations.
gressive so that 3 weeks after the IA injection, chondrocyte counts on medial condyle cartilage were only
17% of control levels ( P < 0.05) while those on the
lateral condyle averaged 54% of the controls (P <
0.02) (Table 2 ) .
Articular surface. The articular surface was
intact in all control samples (groups 4 and 5 , and
untreated knees of groups 1-3) (Table 1). Changes in
the integrity of the articular surface also appeared after
IA injection, but developed more slowly than the loss
of chondrocytes. Thus, 1 week after IA injection
(group l), except for solitary small focal defects on the
medial condyle of each of 2 joints, the articular surface
appeared also to remain intact. However, 3 weeks
after IA injection, surface defects were clearly present
on the medial condyles of all injected joints (group 1).
These ranged from minor surface irregularity (2 joints)
to widespread vertical fibrillation extending through
the transitional zone of cartilage (2 joints) (Figure 5).
Occasionally, particles of India ink were sden trapped
in areas of fibrillation, even though staining was inapparent grossly. In contrast, the surface of the lateral
condyles remained intact in every case.
Effects of immobilization. Gross examination.
Synovial effusions were not present in knees of any
animals in groups 2 or 3, and the synovial membrane in
all instances was grossly normal. However, the loss of
translucency of the articular cartilage caused by IA
injection, as seen in group 1, was noted also in knees
of animals which were immobilized after injection
(group 2), but not in those of animals in group 3, which
were immobilized but not injected. Immobilization did
not lead to retention of India ink by the cartilage.
Microscopic examination, synovial membrane.
No histologic changes were noted in any samples of
synovium following immobilization for up to 3 weeks
(group 3).
Articular cartilage histochemistry. Articular
cartilage from knees of group 3 animals immobilized
for 1 week stained normally with Safranin 0. After 3
weeks of immobilization, however, samples from 2
animals in this group showed an overall reduction in IT
staining (Figure 6 ) . Samples from animals immobilized
for 1 or 3 weeks after IA injection (group 2) showed
clearly that splinting did not affect the loss of IT or PC
staining. No osteophytes developed as a consequence
Figure 5. Articular cartilage from a guinea pig 3 weeks after
intraarticular injection of iodoacetate (group I). Note the depletion
of chondrocytes, surface disruption, and extensive fibrillation extending down to the midzone of the cartilage. Arrows indicate the
tidemark (hematoxylin-eosin, original magnification x 60).
Figure 6. Medial femoral condyle of guinea pig after 3 weeks of
immobilization of the leg. Safranin O-fast green stain. Some reduction in Safranin 0 staining is present (compare with Figure 2)
(original magnification x 60).
of immobilization alone (group 3), or of immobilization
after injection with IA (group 2).
Articular cartilage cell density. Immobilization
(group 3 ) did not significantly affect cell density in
cartilage of either the medial or lateral femoral condyles of untreated joints (Table 2). After IA injection,
cell density in joints immobilized for 1 week (group 2)
was reduced to about 80% of the controls. In joints
immobilized for 3 weeks after IA injection, chondrocyte depletion was slightly more marked, so that cell
densities were about 70% of controls. Evidence of
chondrocyte loss in group 2 was therefore much less
extensive at this stage than in joints which had been
injected with IA but were not immobilized (Table 2).
Articular surface. The articular surface was
smooth and intact in all uninjected splinted joints
(group 3) (Table 1). In contrast to the marked surface
disruption seen in cartilage from animals injected with
IA but not immobilized (group I), all samples from
group 2 exhibited a smooth and intact surface (Figure
consequence of immobilization (group 3) was some
reduction in IT staining in 2 samples after 3 weeks of
splinting, which mimicked results obtained after relatively brief immobilization of the knee in dogs (3).
The cavian IA model developed in our laboratory is being used to study processes affecting reversibility of articular cartilage injury, and to study the
effects of mechanical factors and drugs on cartilage
repair. Although it resulted in certain morphologic
features typical of OA, the cartilage injury caused by
IA in the present study was associated with a degree of
chondrocyte loss much more extensive than that seen
in the early stages of OA. Furthermore, the spread of
cartilage damage from the joint space inward after IA
injection is not representative of OA.
The cartilage changes which develop after IA
injection can be attributed to direct chemical damage
of the chondrocyte by a cell poison with broad metabolic effects. However, some cartilage injury from
catabolin-like factors (1I), arising as a result of chemical injury of the synovium, cannot be excluded. Although the only change noted in the synovial membrane was transient focal hypercellularit y of the lining
cell layer 1 week after IA injection, earlier inflammatory changes may have been present which subsided
by the time synovium was obtained for study. Indeed,
following intraarticular injection of saline (the vehicle
used in the present study), synovitis was noted, which
subsided within 7 days (12).
Prevention of fibrillation by immobilization after IA injection was presumably due to reduction of
The above data show clearly that injection of IA
into the guinea pig knee produces progressive cartilage
degeneration with depletion of chondrocytes, loss of
matrix PGs, fibrillation, and osteophytes. Although
immobilization did not appear to affect the loss of
Safranin 0 staining after IA injection, it clearly reduced the depletion of chondrocytes and prevented
fibrillation and osteophytes. The only change seen as a
Figure 7. Medial femoral condyle of a guinea pig which had
undergone immobilization of the ipsilateral leg for 3 weeks following
an intraarticular injection of iodoacetate. Staining with Safranin 0fast green. Note the intact surface and relatively greater cell density.
Arrows indicate the tidemark (original magnification x 60).
mechanical forces acting on the chemically damaged
cartilage. The basis for prevention of osteophyte formation by immobilization of the injected knee after IA
is less clear. It has been suggested that osteophyte
formation results from an inflammatory response in
the synovial membrane (13), stretching of the synovial
membrane at its insertion (14), or mechanical instability (15,16). Notably, the osteophytes that develop in
the tendons of osteolathyric rats do not appear if the
muscles or their motor neurons are transected (17,18).
We have shown, furthermore, that osteophytes,
which appear within days after transection of the
anterior cruciate ligament in the dog (19), do not
develop if loading of the joint is reduced by immobilization of the unstable. knee in flexion immediately after
destabilization of the joint (4); this reduces the normal
loading of the joint resulting from contraction of the
muscles that span the knee and stabilize it in stance
(20). However, immobilization of rabbit knees in extension, which increases loading across the joint,
causes osteophytes (21,22).
India ink is widely used for demonstration of
surface irregularities in articular cartilage (7). In the
present study, only 1 sample showed gross uptake of
India ink 3 weeks after 1A injection, even though all
samples showed microscopic evidence of widespread
vertical fibrillation down to the radial zone at that
stage (Figure 5 ) . In contrast, we have observed striking India ink uptake by guinea pig knee cartilage after 4
weekly injections of iodoacetate (3 mglinjection),
when cartilage ulceration was grossly apparent (2).
A major consequence of the intraarticular IA
injection was the extensive depletion of chondrocytes
and loss of lacunae which were noted histologically.
Obviously, the technique used here for determination
of cell density does not reliably assess chondrocyte
viability. Thus, the numbers of viable chondrocytes
may have been lower than those reflected by the cell
counts reported in Table 2. Quantitative data concerning cell densities in articular cartilage of normal adult
guinea pigs have been heretofore unavailable. Stockwell (9), however, reported cell densities of normal
adult femoral condylar cartilage for several other
species and showed that they are inversely related to
body weight. Thus, for human, canine, and murine
femoral cartilage, chondrocyte densities averaged
14,100, 44,000, and 265,000 cells/mm3, respectively.
The cell counts for cavian cartilage in this study are
consistent with those data.
Immobilization of the leg, regardless of whether
the animal received intraarticular IA, resulted in a loss
of body weight. Since guinea pigs are prone to develop
scurvy, and guinea pigs maintained on minimal, albeit
nonscorbutic, dietary supplements of ascorbic acid
developed more severe changes of OA following destabilization of the knee than those maintained on
higher levels of ascorbic acid (23), it is important to
consider whether vitamin C deficiency may have affected development of the cartilage changes in the
present study. The recommended ascorbic acid intake
for prevention of scurvy in guinea pigs is 2.5 mg per
day (24). Even for those animals that lost weight, the
diet used in the present study provided at least 14
times that amount of ascorbic acid. Furthermore, even
though it resulted in weight loss, immobilization had a
protective, and not aggravating, effect on the cartilage
damage caused by IA, and cartilage from contralateral
(nonimmobilized) knees of animals in groups 2 and 3
was normal despite weight loss.
Differences between the medial and lateral femoral condyles with respect to the effects of intraarticular 1A injection were notable. Although decreases in
Safranin 0 staining were similar in each, both fibrillation and osteophytes developed only on the medial
condyle and medial aspect of the intercondylar
groove. Furthermore, chondrocytc depletion was not
as marked on the lateral condyle as on the medial
(Table 2).
The DNA content of normal canine cartilage
from the lateral femoral condyle is greater than that of
cartilage from the medial femoral condyle. However,
incorporation of 3H-thymidine, 35S04,and ''C-glycine
was greater in cartilage from medial condyles than
from the lateral (25). Regional differences in response
to experimentally-induced cartilage degeneration have
also been noted. Moskowitz et a1 (25) reported pitting
ulceration and osteophytosis on the medial femoral
condyle, with no macroscopic changes on the lateral, 6
weeks after partial meniscectomy in rabbits, while
incorporation of 3H-thymidine and 14C-glycine was
greater at 3 weeks on the lateral femoral condyles than
on the medial. McDevitt et a1 (26) have shown that
changes of OA following anterior cruciate ligament
transection in dogs appear first in the medial joint
compartment and later spread to other sites. Likewise,
the earliest changes in rat knees following immobilization with compression occur in articular cartilage of
the medial compartment (27).
In the present study, the loss of matrix PGs, as
revealed by Safranin 0 staining, occurred first in the
interterritorial matrix and around the most superficial
cells, while loss of staining around deeper cells in the
uncalcified zone a n d in calcified cartilage occurred
later. T h e relative resistance of t h e pericellular matrix
to loss of PGs m a y reflect t h e unique environment of
the pericellular region, in which PGs (28,29), lysozyme
(30), type V-like collagen (31,32), hyaluronic acid (331,
and chondronectin (34,35) are concentrated. In addition, fine filaments lacking t h e characteristic periodicity of collagen occur near t h e cell which, in t h e deeper
layers of cartilage, form enclosures about t h e chondrocytes and may provide part of a “cell protecting”
mechanism (36-38). T h u s , pericellular PGs may b e
relatively protected by interactions with t h e other
matrix constituents in their milieu.
We would like to thank Paula Lawson-Moore and
Suzanne Schnaitter for technical assistance, Joe Demma for
photographic assistance, and Roberta Fehrman for secretaria1 support.
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chemical, immobilization, induced, ameliorates, damage, cartilage, articular
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