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Experimental arthritis induced by polysaccharide macromolecules.

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679
EXPERIMENTAL ARTHRITIS INDUCED BY
POLYSACCHARIDE MACROMOLECULES
ROY K. AARON, CLEMENT B. SLEDGE, and SONYA SHORTKROFF
Several polysaccharide macromolecules are capable of inducing synovial inflammation. Characteristics of polysaccharides that have this capacity were
studied in an in vivo rabbit model. The ability to induce
synovial inflammation was positively correlated with the
presence of sulfate and with high molecular weight.
Understanding the characteristicsof molecules that produce inflammation may help in the investigation to
determine what mechanisms initiate the inflammatory
response.
Synovial inflammation is a prominent feature of
many pathologic articular processes. Understanding
the nature of this response is potentially of great
importance, since inflamed synovial tissue is capable
of degrading hyaline cartilage in vivo and in vitro
(1-3). Neither the mechanism of production of
synovial inflammation nor the mediating systems by
which inflammation is effected are fully known. Several macromolecular polysaccharides appear to be
capable of producing an inflammatory synovitis (4-6);
From the Department of Orthopaedics and Rehabilitation,
Brown University, Rhode Island Hospital and Veterans Administration Hospital, Providence, Rhode Island, and the Department of
Orthopaedic Surgery, Harvard Medical School and Brigham and
Women’s Hospital, Boston, Massachusetts.
Roy K. Aaron, MD: Assistant Professor, Department of
Orthopaedics and Rehabilitation, Brown University, Rhode Island
Hospital and Veterans Administration Hospital; Clement B. Sledge,
MD: Professor and Chairman, Department of Orthopaedic Surgery,
Harvard Medical School and Brigham and Women’s Hospital;
Sonya Shortkroff, MS: Research Assistant, Department of Orthopaedic Surgery, Brigham and Women’s Hospital.
Address reprint requests to Roy K. Aaron, MD, Department of Orthopaedics and Rehabilitation, Rhode Island Hospital,
593 Eddy Street, Providence, RI 02902.
Submitted for publication October 23, 1984; accepted in
revised form December 5, 1986.
Arthritis and Rheumatism, Vol. 30, No. 6 (June 1987)
however, the biologic significance of polysaccharideinitiated inflammation, its duration and degradative
capabilities, and the mechanism by which it occurs are
unclear. The polysaccharide-induced inflammation
model affords the opportunity to define the molecular
characteristics that may be important in initiating an
inflammatory response in synovium. We studied the
influence of variations in molecular weight and charge
(sulfate) on the ability of polysaccharides to produce
an inflammatory synovitis, and we examined the articular cartilage degrading potential of synovium that was
inflamed as a result of poly saccharide treatment.
MATERIALS AND METHODS
Materials. Dextran and dextran sulfate (average molecular weight 500,000) were obtained from Sigma (St.
Louis, MO). They were prepared in physiologic saline, at a
concentration of 60 mg/ml.
Carrageenan, in molecular weights of 10,000, 30,000,
160,000, and 300,000, was kindly supplied by Marine
Colloids (Rockland, ME). Carrageenans are negatively
charged polymers of sulfated galactose and 3,6-anhydrogalactose. Two main fractions, kappa and lambda, are generally present in crude preparations. Kappa carrageenan
contains a relatively high proportion of anhydrogalactose.
Lambda carrageenan consists mainly of 1,3-1inked galactose-2-sulfate and 1,Clinked galactose2,6-disulfate; it contains approximately 3540% sulfate and 0.4% anhydrogalactose. Pure lambda carrageenan was used in our studies. The
molecular weights of the carrageenans were determined by a
viscometric method, using a Cannon-Fenske capillary
viscometer (Marine Colloids: personal communication). The
carrageenans were dissolved in saline at a concentration of
10 mg/ml. The polysaccharide solutions were sterilized by
passage through a 0 . 4 5 - ~ mMillipore filter.
Animal studies. Fifty New Zealand white rabbits
were divided into groups of 6 or 7. Three times per week
for 4 weeks, they were anesthetized with 1.5 ml of
acepromazine-ketamine intramuscularly and were given
AARON ET AL
Table 1. Gross anatomic findings in the knees of New Zealand white rabbits treated with dextran,
dextran sulfate, or carrageenan*
~~
Treatment, time of
measurement
Dextran
4 weeks
8 weeks
Dextran sulfate
4 weeks
8 weeks
Carrageenan, 10,000 MW
4 weeks
8 weeks
Carrageenan, 30,000 MW
4 weeks
8 weeks
Carrageenan, 160,000 MW
4 weeks
8 weeks
Carrageenan, 300,000 MW
4 weeks
8 weeks
~~
Effusion
Synovitis
Cartilage
erosions
-
-
-
-
-
+
+
+
+
+
+
-
-
-
-
-
-
-
-
-
-
-
-
-
+
+
+
+
+
+
+
+
+
+
+
+
-
Osteoph ytes
-
+
+
-
+
* Measurements at 4 weeks were taken immediately at the conclusion of treatment; measurements at 8
weeks were taken 4 weeks after the conclusion of treatment. - = absent; + = present.
intraarticular injections of 0.5 ml of saline in 1 knee and
polysaccharide in the contralateral knee. Animals were
killed either at the conclusion of the injection series or 4
weeks after the last injection. The joints were examined for
the presence of effusion, synovitis, and synovial invasion of
the perichondrial margins. Joint fluid was obtained for bacteriologic culture. The articular cartilage was inspected for
erosions and osteophytes. Samples of synovium were taken
for histologic examination (by hematoxylin and eosin staining) and for enzyme determinations. The thickness of the
synoviocyte surface layer was measured with a calibrated
reticule (1405A; American Optical). The joints were removed and the articular cartilage was examined for clefts
and chondrocyte abnormalities and stained with Safranin 0
for estimation of proteoglycan content.
Lysosomal enzymes. Synovial samples were minced
in the cold and homogenized in Triton X-100 with a motordriven glass tissue homogenizer. Synovial acid phosphatase
content was determined colorimetrically by hydrolysis of the
substrate, p-nitrophenyl phosphate (7). pglucuronidase content was measured by the liberation of phenophthalein from
phenophthalein mono-pglucuronic acid (8). Absorption was
determined in a Zeiss spectrophotometer at 410 nm and 550
nm. Results are expressed as the mean
SEM in
units/m1/100 mg weight of synovium (as specified in technical
bulletins 104 and 325; Sigma). Student’s I-test was used for
comparisons.
*
RESULTS
Cultures for bacterial pathogens produced negative results in all joints. The knees injected with
saline demonstrated no gross or microscopic evidence
of inflammation. The lysosomal enzyme content of
synovial samples taken from knees injected with saline
was minimal. Tables 1 and 2 show the results of gross
anatomic and histologic examinations, respectively.
The lysosomal enzyme contents of the synovia are
presented in Table 3.
Dextrans. At the conclusion of the 4-week injection series, the knees injected with dextran were
grossly normal. Mild synoviocytic hyperplasia was
observed histologically. The synovial acid phosphatase content was significantly higher than the enzyme
content of synovia treated with saline, but the synovial
pglucuronidase content was not different from that of
the saline control knees.
Four weeks after the end of the injection series
(8 weeks from the beginning of the study), the dextraninjected knees were grossly and histologically normal.
The synovial acid phosphatase content was significantly lower at 8 weeks than at 4 weeks, but was still
elevated over the level seen at 8 weeks in the saline
controls. The synovial P-glucuronidase content was
not significantly different in the dextran-treated knees
versus the saline-treated knees at 8 weeks.
The knees injected with dextran sulfate exhibited hypertrophic synovitis with effusion at the conclusion of the injection series. In 6 of the 7 knees in
this group, patellar dislocation, presumably due to
underlying hypertrophic synovitis and effusion, was
POLYSACCHARIDES AND ARTHRITIS
68 1
Table 2. Histologic findings in the knees of New Zealand white rabbits treated with dextran, dextran
sulfate, or carrageenan, and in the knees of controls*
Treatment, time of
measurement
Saline control
4 weeks
8 weeks
Dextran
4 weeks
8 weeks
Dextran sulfate
4 weeks
8 weeks
Carrageenan, 10,000 MW
4 weeks
8 weeks
Carrageenan, 30,000 MW
4 weeks
8 weeks
Carrageenan, 160,000 MW
4 weeks
8 weeks
Carrageenan, 300,000 MW
4 weeks
8 weeks
Synovial membrane
hyperplasia
(w, mean 2 SEM)t
Hypervascularity
Inflammatory
infiltrate
40 t 10
20 t 10
Safranin
0 staining
N
N
90 k 30
20 t 10
+
300 t 60
260 t 40
+
+-
N
N
+
+
N
D
N
N
40 t I0
20 2 10
+
110 2 40
20 t 10
N
N
-
+
+
+
+
370 2 70
300 t 70
420 t 80
270 f 50
+
D
D
2
+
+
D
D
~~
* N = normal; D = diminished. See Table 1 for other definitions and explanations.
t Dextran values differed significantly (P < 0.01) from dextran sulfate values at 4 weeks and
at 8
weeks; carrageenan, 30,000 MW values differed significantly (P < 0.01) from carrageenan, 160,000
MW and carrageenan, 300,000 MW values at 4 weeks and at 8 weeks.
seen (Figure 1). Erosive changes were observed at the
patellar trochlea and medial femoral condyles. Histologically, synoviocytic hyperplasia was seen, with
edema and hypervascularity of the subsynovial layer
and an inflammatory infiltrate. The synovial acid
phosphatase and pglucuronidase contents were significantly elevated compared with both the saline-treated
knees and those treated with dextran.
Table 3. Lysosomal enzyme contents in the knees of New Zealand white rabbits treated with
dextran, dextran sulfate, or carrageenan, and in the knees of controls*
Acid phosphataset
p-glucuronidaset
Treatment
4 weeks
8 weeks
4 weeks
8 weeks
Saline control
Dextran
Dextran sulfate
Carrageenan, 10,000 MW
Carrageenan, 30,000 MW
Carrageenan, 160,000 MW
Carrageenan, 300,000 MW
0.13 c 0.02
0.46 t 0.09
0.77 t 0.04
0.65 2 0.05
0.79 2 0.07
1.62 0.22
1.41 t 0.08
0.08 t 0.02
0.25 t 0.02
0.72 2 0.1 1
0.50 f 0.11
0.61 2 0.08
1.37 2 0.15
1.25 2 0.10
0.06 t 0.01
0.11 2 0.03
1.04 t 0.15
0.67 -t 0.10
1.00 t 0.14
1.20 -t 0.30
1.20 f 0.22
0.04 ? 0.03
0.05 t 0.02
1.02 t 0.22
0.29 2 0.06
0.43 t 0.04
0.89 f 0.10
0.91 t 0.08
*
* Values shown are mean f SEM Sigma units/m1/100 mg wet weight synovium. See Table 1 for
explanations.
t Dextran values differed significantly (P< 0.05) from control values and from dextran sulfate values
at 4 weeks and at 8 weeks. Dextran value at 8 weeks differed significantly (P< 0.01) from dextran
value at 4 weeks. Carrageenan, 10,000 MW values differed significantly (P< 0.05) from control values
at 4 weeks and at 8 weeks. Carrageenan, 30,000 MW values differed significantly (P < 0.05) from
carrageenan, 160,000 MW and carrageenan, 300,000 MW values at 4 weeks and at 8 weeks.
t Dextran sulfate values differed significantly (P < 0.01) from control values and from dextran values
at 4 weeks and at 8 weeks. Carrageenan, 10,000 MW value differed significantly (P < 0.05) from
control value at 4 weeks. Carrageenan, 30,000 MW value differed significantly (P < 0.05) from
carrageenan, 160,000 MW and carrageenan, 300,000 MW values at 8 weeks.
682
AARON ET AL
Carrageenan. At 4 weeks, the 6 knees that
received injections of carrageenan with a molecular
weight of 10,000 appeared grossly normal. Histologically, a very mild synoviocytic hyperplasia was observed. The synovial acid phosphatase and pglucuronidase contents of these knees were both
significantly elevated compared with the saline-treated
knees. The knees remained grossly normal at 8 weeks,
with no synovitis or cartilage destruction. The intimal
hyperplasia seen at the conclusion of the injection
series had resolved. There was significant reduction in
the synovial contents of both p-glucuronidase and acid
phosphatase, but these were still greater than the
enzyme contents of the saline-treated control knees.
The knees treated with carrageenan at 30,000
molecular weight appeared normal on gross examination at the conclusion of the injection series. Synovial
Figure 1. Patellar dislocation and synovitis in dextran sulfatetreated knee of a New Zealand white rabbit, at the conclusion of
treatment.
Four weeks after the conclusion of the injection
series, all 7 of the dextran sulfate-treated knees demonstrated residual hyperemic synovitis and associated
patellar dislocation. Marginal erosions were present at
the articular periphery, with cartilage destruction and
excavation, particularly along the medial femoral
condyles (Figure 2). Erosions on the weight-bearing
portions of both the tibia1 and femoral articular cartilage were also seen at 8 weeks (Figure 3). Histologically, the subsynovial edema, synoviocytic hyperplasia, and inflammatory infiltrate persisted (Figure 4).
Diminished Safranin 0 staining of the articular cartilage was observed, together with clefts, hypercellularity , and cloning of chondrocytes. The lysosomal
enzyme content of the synovia demonstrated a persistent
Of both acid phosphatase and pglucuronidase, with values essentially identical to
those that were seen at 4 weeks.
Figure 2. Marginal erosions in dextran sulfate-treated knee of a
New Zealand white rabbit, 4 weeks after the conclusion of
treatment.
POLYSACCHARIDES AND ARTHRITIS
683
hyperplasia and subsynovial edema were seen on all
microscopic sections. The synovial lysosomal enzyme
content was elevated when compared with the saline
control knees and with the knees treated with carrageenan of 10,000 molecular weight. Gross examination of the 6 knees 4 weeks after the conclusion of the
injection series demonstrated marginal erosions in 2
knees, without pitting of the articular surface. The
other knees in this group were grossly normal. Histologically, some animals exhibited resolution of inflammation, while subsynovial edema and cellular infiltration persisted in others. There were significant
reductions in both the P-glucuronidase and the acid
phosphatase contents of the synovium compared with
those seen at the conclusion of the injection series.
At the conclusion of the injection series, the
knees injected with carrageenan of molecular weight
Figure 4. Synovial inflammation in dextran sulfate-treated knee of
a New Zealand white rabbit, 4 weeks after the conclusion of
treatment.
Figure 3. Cartilage erosions in dextran sulfate-treated knee of a
New Zealand white rabbit, 4 weeks after the conclusion of
treatment.
160,000 demonstrated an active synovitis which
caused distention of the joint capsules and erosions of
the articular cartilage (Figure 5). On histologic examination, intense hypercellularity of the synovium and
an inflammatory infiltrate were observed (Figure 6).
The synovial contents of acid phosphatase and pglucuronidase were significantly different from those
of the saline-treated knees and the knees treated with
10,000 molecular weight carrageenan. The acid
phosphatase content, but not the p-glucuronidase content, was also significantly different from that of the
knees treated with carrageenan of 30,000 molecular
weight. Examination of these knees 4 weeks after the
conclusion of the injection series revealed persistent
synovitis and erosions of the articular cartilage. Occasional osteophytes were seen. Synovial hyperplasia
and inflammatory infiltration persisted. Diminished
Safranin 0 staining was evident, along with clefts in
684
AARON ET AL
creased over controls, but were not different from
those of the knees treated with carrageenan of 160,000
molecular weight. The knees examined 4 weeks after
the conclusion of the injection series revealed persistent synovitis, marginal erosions, and osteophyte formation (Figure 8). The synovial hypercellularity and
inflammatory infiltrate persisted. The synovial content
of lysosomal enzymes remained elevated, with levels
similar to those measured at the conclusion of the
injection series.
DISCUSSION
Dextran and carrageenan with various sulfate
contents and molecular weights were studied, to examine the importance of these 2 molecular characteristics in producing articular inflammation that leads to
cartilage degradation. Intraarticular administration of
Figure 5. Synovitis in carrageenan (molecular weight 160,000t
treated knee of a New Zealand white rabbit, at the conclusion of
treatment.
the cartilage. The synovial p-glucuronidase content
was reduced compared with that seen at the conclusion of the injection series; however, this reduction
was not as great as the reductions observed with the
lower molecular weight carrageenans. The acid
phosphatase content of this synovium was mildly
reduced from the levels seen at the conclusion of the
injection series.
At 4 weeks, the knees injected with carrageenan of molecular weight 300,000 demonstrated
hyperemic, hypertrophic synovium with capsular distention. Erosions were seen at the margins of the
cartilage as well as on the patellae. Histologically,
there was hypercellularity of the synoviocytes and an
intense inflammatory
in the subsynovial layer
(Figure 7). The %'novial
contents of both acid Phosphatase and pglucuronidase were significantly in-
Figure 6. Inflammatory infiltrate in camageenan (molecular weight
1@,000&treated knee of a New Zealand white rabbit, at the conclusion of treatment.
POLYSACCHARIDES AND ARTHRITIS
685
unsulfated dextran resulted in a mild, transient inflammation that had largely resolved within 4 weeks after
the conclusion of the injection series. No evidence of
cartilage degradation was present. In contrast, intraarticular administration of sulfated dextran of the same
molecular weight produced an inflammatory synovitis
that persisted 4 weeks after the last injection. Cartilage
degradation was observed, and there were gross erosions and histochemical evidence of proteoglycan loss.
These observations suggest that the presence of sulfate in the dextran molecule greatly enhances the
production of synovial inflammation.
Schorlemmer et a1 have shown that dextran
sulfate is capable of inducing hydrolase release from
cultured macrophages (9). This capacity is related to
both the molecular weight and the degree of sulfation
of the molecule, with unsulfated dextran being inac-
Figure 8. Marginal erosions and osteophyte formation in carrageenan (molecular weight 300,000ttreated knee of a New Zealand
white rabbit, 4 weeks after the conclusion of treatment.
Figure 7. Synovial inflammation in carrageenan (molecular weight
300,000ttreated knee of a New Zealand white rabbit, at the conclusion of treatment.
tive. Burger et a1 have similarly shown that the ability
of dextran sulfate to activate C3 in the alternative
complement pathway is related to the concentration of
sulfate groups in the dextran molecule (10). The role
played by sulfate content in the in vitro activation of
inflammatory systems corroborates our finding that
sulfation of the polysaccharide molecule greatly enhances its inflammatory potential in vivo.
With the administration of carrageenans of increasing molecular weight, we observed the development of synovitis of progressively greater severity.
The lower molecular weights produced a minimal,
transient inflammation without evidence of cartilage
degradation. The 'ynovitis produced by camageenans
of 160,000 and 300,000 molecular weights was characterized by an intense inflammatory cell infiltration,
AARON ET AL
large elevations in synovial lysosomal enzyme content, and evidence of cartilage matrix damage.
Carrageenan is a well-established agent for the
production of synovial inflammation and cartilage degradation. Elevations in synovial cathepsin and acid
phosphatase levels after intraarticular injection of carrageenan of unfractionated molecular weight (average
molecular weight approximately 300,000) have been
reported (11). Gillard and Lowther (12) found that
carrageenan-treated synovium can degrade articular
cartilage, with loss of matrix proteoglycan. Our studies suggest that the ability of carrageenan to induce an
inflammatory synovitis with degradative potential is
related, at least in part, to the molecular weight of the
molecule. It seems unlikely that the ability of the
higher molecular weight carrageenan to produce
synovitis is related to inability of the larger molecule to
be cleared from the joint, however, since carrageenan
of 300,000 molecular weight is rapidly cleared from
joints by phagocytosis by migrating macrophages and
other monocytes (6).
The role of molecular weight in inducing
synovitis may not be limited to carrageenan alone, but
may be a more generalized requirement. In vitro
studies with dextran sulfate have indicated that the
ability of the molecule to release lysosomal enzymes is
related also to molecular weight between 8 x lo4 and
2 x lo6, independent of the degree of sulfation (9). The
ability of dextran sulfate to activate C3 did not increase in proportion to molecular weight, but there
does appear to be a critical size: In Burger’s study,
molecules smaller than 5 x lo’ were completely inactive, regardless of sulfate content (10).
It appears that, in the polysaccharides we studied, both the relatively large molecular weight and the
presence of sulfate in the molecule are important to the
ability to produce synovial inflammation and cartilage
degradation. The mechanisms by which sulfated
polysaccharides produce arthritis are not definitively
known. However, these molecules have been shown
to activate both cellular and humoral inflammatory
pathways which are of direct relevance to human
articular inflammation.
Lysosomal enzymes from inflammatory cells
have been implicated in acute and chronic experimental and human synovitis (13). Increased activity of acid
phosphatase and pglucuronidase, among other enzymes, has been demonstrated in rheumatoid arthritis,
and correlations between synovial lysosomal enzyme
activity, clinical activity, and the degree of articular
damage have been described (2,14).
Carrageenan has been shown to mobilize
neutrophils within 1 hour of introduction into the
pleural cavity. These cells remain part of the inflammatory process for about 36 hours after a single dose.
Monocytes appear within 5 hours and remain present
for over 48 hours (15). In other models of acute
inflammation, carrageenan has been shown to cause
the release of lysosomal enzymes, particularly pglucuronidase, from recruited inflammatory cells
(16,17). Similarly, dextran sulfate has been shown to
release lysosomal enzymes from macrophages (9).
Lowther has recently shown that the intraarticular
injection of carrageenan causes neutrophils to enter
the joint. Upon contact with articular cartilage, the
neutrophils are stimulated to release elastase, which
degrades cartilage proteoglycan (ref. 18 and Lowther
D: personal communication). Thus, in several inflammatory systems, including synovitis, sulfated polysaccharides have been shown to stimulate lysosomal
enzyme release from recruited inflammatory cells.
These enzymes play a major role in articular damage.
We have shown that the magnitude of lysosomal
enzyme elevations is related to molecular weight and
sulfate content of the polysaccharides.
A large body of data suggests that the Hageman
factor-kinin pathways have a significant role in the
inflammatory response (19-23). These substances
have both vasodilatory and chemotactic properties.
There is also substantial evidence that the kinin system plays a role in acute articular inflammation and
arthritis (24,25). Increased kinin activity has been
found in the joint fluid of patients with acute gout (26),
and in synovial tissue and joint fluid of patients with
rheumatoid arthritis (25).
The fact that molecular sulfate content affects
articular inflammation suggests that sulfated polysaccharides may activate the Hageman factor-kinin system. A variety of sulfated polysaccharides, including
cellulose sulfate, carrageenan, chondroitin sulfate,
heparin, and chitin sulfate, have been shown to activate Hageman factor in human plasma (27-29). The
ability of these sulfated polysaccharides to generate
bradykinin in plasma and synovial fluid, dependent
upon intact Hageman factor, has been demonstrated.
Further, the polysaccharide moieties of human articular cartilage may themselves produce an inflammatory synovitis, through the generation of bradykinin by
Hageman factor activation. Human articular cartilage,
cartilage extract, and chondroitin sulfate have been
shown to generate kinin activity in vitro (29).
Nossel et a1 (30) have shown that negatively
POLYSACCHARIDES AND ARTHRITIS
charged sites are critical for activation of Hageman
factor and that inhibition results from neutralization of
these sites with positively charged agents. They further noted that inhibitory activity is a function of
molecular weight, as well as of charge (30). Other
studies have demonstrated that the generation of
plasma kinin by sulfated polysaccharides can be
blocked with positively charged agents (31,32). We
have previously shown that sulfated polysaccharides
are capable of increasing cell membrane electronegativity and anionic migration of cellular blood
elements in an electrophoretic field (33,34). Sulfated
poly saccharides are highly negatively charged, and
charge configuration, determined in part by molecular
size and sulfate content, is probably important in the
ability of these molecules to generate Hageman
factor-dependent inflammatory peptides.
While the process by which synovial inflammation is produced by sulfated polysaccharides is still not
definitively known, there is a suggestion that both
humoral and cellular effector mechanisms may be
involved. The generation of soluble chemotactic and
vasoactive factors may act t o facilitate the recruitment
of inflammatory cells which contain enzymes shown to
result in articular damage. The presence of sulfate and
large molecular weight, and possibly electronegative
charge, can b e implicated in the production of
bradykinin and perhaps other Hageman factordependent substances and in the recruitment of inflammatory cells and release of lysosomal enzymes. These
molecular characteristics may play a role in the production of inflammation by other agents, including
bacterial polysaccharides and cartilage degradation
products; thus, the use of these molecules may be of
help in the investigation of the mechanisms which
activate inflammation.
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