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Induction of an acute erosive monarticular arthritis in mice by interleukin-1 and methylated bovine serum albumin.

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We examined the effect of interleukin-1 (IL-1)
administration on a mild and transient inflammatory
response in the knees of mice injected intraarticularly
with methylated bovine serum albumin (mBSA). Injection of mBSA on day 0 into nonsensitized mice caused a
weak inflammatory response confined to the infrapatellar fat pads and involved infiltration by mononuclear
cells, neutrophils, and eosinophils. The response developed between days 4 and 7 and resolved by day 28. No
erosion of cartilage or subchondral bone was seen. In
contrast, mBSA-treated mice injected with recombinant
human IL-lP subcutaneously in the ipsilateral footpad
on days 0-3 developed a severe monarticular arthritis in
the antigen-injected knee. Pannus developed, extending
over the articular surfaces, and extensive erosion of
cartilage and subchondral bone occurred. Multinucleated giant cells, together with fibrin-like material, were
observed at sites of active bone erosion and debris, and
large numbers of neutrophils were seen in the joint
space. These pathologic features represent a new arthritis model in which IL-1 profoundly augments a weak
inflammatory response and induces acute erosive joint
From The Upjohn Company, Hypersensitivity Diseases
Research and Pathology and Toxicology Research 11, Kalamazoo,
Nigel D. Staite, PhD: Hypersensitivity Diseases Research:
Karen A. Richard, MS: Hypersensitivity Diseases Research;
Danielle G. Aspar, MA: Hypersensitivity Diseases Research;
Katherine A. Franz, HT-ASCP: Pathology and Toxicology Research 11; Louise A. Galinet, BSc: Hypersensitivity Diseases Research; Colin J. Dunn, PhD: Hypersensitivity Diseases Research.
Address reprint requests to Nigel D. Staite, PhD, Hypersensitivity Diseases Research, The Upjohn Company, 301 Henrietta
Street, Kalamazoo, MI 49001.
Submitted for publication June 19, 1989; accepted in revised form September 13, 1989.
Arthritis and Rheumatism, Vol. 33, No. 2 (February 1990)
destruction, supporting the hypothesis that IL-1 is an
important cytokine in the pathogenesis of arthritis.
Disordered immunoregulation is considered to
be an important element in the evolution and persistence of human rheumatoid arthritis (RA). Since interleukins have been shown to be key immunoregulatory
signals responsible for the homeostasis of the immune
response, they have been the focus of considerable
attention in arthritis research. Interleukin-1 (IL-l),
with its diverse biologic activities, has been implicated
as a pathogenic cytokine in RA (for review, see ref. 1).
Two of its important effects are those on leukocytes
and on connective tissue, IL-I promotes T lymphocyte
activation (2), B lymphocyte activation (3), natural
killer cell function (4), and neutrophil function (9,and
it augments the activity of other cytokines (6). Effects
on connective tissue include increased synovial cell
proliferation (7), increased production of prostaglandin E,, collagenase, and hyaluronate from synovial
cells and chondrocytes (%lo), suppression of chondrocyte growth (1 I ) , and increased loss of cartilage
proteoglycan and bone calcium (12,13).
Although there is much in vitro evidence that
IL- 1 could orchestrate immune activation and connective tissue destruction in arthritic disease, evidence in
vivo is limited. IL-1 is present in synovial fluid of
patients with RA (14,15), and MRL/Mp/lpr mice,
which develop autoimmune disease and spontaneous
synovitis, have an increased level of IL-Ip gene
expression (16). Partially purified or recombinant IL-l
injected into rabbit knees causes an acute synovitis
with only a transient loss of cartilage proteoglycan
(17,181. In rats with established peptidoglycanpolysaccharide-induced arthritis, IL-I exacerbates the
acute inflammatory response (19), and in mice immunized with type I1 collagen, systemic IL-1 accelerates
the onset of polyarthritis (20,21). Thus, IL-1appears
to promote the inflammatory response associated with
experimentally induced arthritis, but to date it has
been shown to augment pathologic changes only in
animals predisposed to developing arthritis. In this
study, we initially set out to investigate the effect of
IL-1 administration on the conventional methylated
bovine serum albumin (mBSA)-induced model of
monarticular arthritis in antigen-sensitized mice (22).
In the course of the study, however, it became evident
that non-antigen-sensitized animals injected intraarticularly with mBSA in 1 knee developed an acute and
severe destructive arthritis when given IL-1subcutaneously. This observation suggests that IL-1may play
an important part in the early development of erosive
Animals. SPF female C57B1/6 mice, 8-10 weeks old
and weighing between 18 gm and 25 gm, were supplied by
Jackson Laboratories, Bar Harbor, ME. The animals were
housed in laminar flow racks and fed Purina Breeder Chow
(no. 5015) together with water ad libitum. Sentinel mice
showed no serologic evidence of hepatitis, Minute, or Sendai
virus infection before or during the study.
Induction of arthritis. The mice were anesthetized
with methoxyfluorone (Metofane; Pitman-Moore, Washington Crossing, NJ). The left hind legs were cleaned with 70%
alcohol, and the skin over the knee was cut to expose the
stifle joint. Twenty microliters of BSA or mBSA (Sigma, St.
Louis, MO) at a concentration of 10 mg/ml in saline was
injected into the left rear knee joint, and the skin was closed
with a wound clip. Recombinant human IL-lp (rHuIL-lp;
Upjohn, Kalamazoo, MI) and rHuIL-1 a (Dainippon Pharmaceuticals, Osaka, Japan) were diluted in 0.9% saline
containing 0.5% normal autologous mouse serum (saline
vehicle). Endotoxin contamination in the IL-1 proteins was
83 p g h g (IL-I/?) and 169 pg/mg (IL-la), as measured by a
chromogenic limulus lysate assay (Whittaker Bioproducts,
Walkersville, MD). On the day of intraarticular mBSA
injection (day 0), 50 ~1 of IL-1 containing 5,000 lymphocyteactivating factor (LAF) units (-250 ng of IL-I) was administered subcutaneously into the left rear footpad. IL-1 injections were repeated on days 1 and 2, days 1-6, or days 1-13,
as indicated. In some experiments, IL-1 was injected into the
footpad contralateral to the mBSA-injected knee. Control
animals consisted of mice given intraarticular mBSA with
either saline vehicle alone or saline vehicle containing 250
mg of ovalbumin injected subcutaneously in the footpad.
Additional control animals were given saline intraarticularly
together with the IL-I injected in the footpad.
Autopsy and histologic assessment of arthritis. The
mice were killed by cervical dislocation, and the skin over
the left rear leg was removed. The knee joint was then
excised, and a transverse cut was made through the ligamenturn patellae to facilitate fixation of the tissues. Knees were
placed in 10% phosphate buffered formol saline prior to
being decalcified for 8 hours in 30% formic acid containing
0.28M sodium citrate. Each knee was cut sagittally, decalcified for an additional 4 hours, and dehydrated with
alcohol using an automatic tissue processor (Fisher Histomatic, Pittsburgh, PA). Finally, the specimens were
cleared with xylene and embedded in Paraplast (melting
point 36°C). Sections 5p thick were cut and stained with
hematoxylin and eosin.
The assessment of arthritis was performed on coded
knee sections by an observer blinded to the experimental
groups. Knee sections were graded 1.0 (mild) to 5.0 (severe)
for the severity of 6 components of the arthritis. Soft tissue
inflammation was evaluated in the infrapatellar fat pads,
joint capsule, and the area adjacent to the periosteal sheath
and was graded according to the extent of cellular infiltration
and angiogenesis. Synovitis was defined as hyperplasia of
the synovial lining layer but did not include pannus formation. When a global assessment of inflammation was used,
the soft tissue inflammation and synovitis scores were combined. Pannus was defined as hypertrophic synovial tissue
forming a tight junction with the articular surface. Synovial
cell proliferation that occurred distal to the margin of the
epiphyseal cartilage plate was considered to be synovitis and
not pannus. Joint space exudate was identified as leukocytes
(predominantly neutrophils) scattered discretely or in aggregtes together with fibrin-like material in the joint space.
The extent of cartilage and bone erosion was evaluated
separately on both condylar surfaces. Scoring was based on
the loss of cartilage matrix, disruption and loss of cartilage
surface, and the extent and depth of subchondral bone
erosion. The severity scores for each histologic feature
within an experimental group were averaged, and comparisons between groups were made by a pairwise, one-way
analysis of variance using Bartlett’s test for equality of
variances. Comparisons that yielded a P value of 50.05 were
considered significant.
Response to mBSA alone. Intraarticular injection of mBSA alone into the left rear stifle joint of
female C57BV6 mice resulted in a transient nonerosive
synovitis, the features and development of which are
summarized in Table 1 . A weak inflammatory response, confined mainly to the infrapatellar fat pads,
developed during the first 4 days following mBSA
injection on day 0. Between days 4 and 7, the reaction
involved diffuse mononuclear leukocyte, neutrophil,
and eosinophil infiltration, together with mild hyperplasia of the synovial lining layer (Figure 1). By day
14, however, the inflammation in the infrapatellar fat
pads had decreased and the mild synovial hyperplasia
either remained or had resolved. On day 28, the
Table 1. Development of pathologic features in the knees of mice injected intraarticularly with methylated bovine serum albumin (mBSA) with
or without subcutaneous injection of interleukin-IB (IL-I)*
Day 4
Day 7
Day 14
Day 28
+ IL- 1
+ IL- 1
+ IL-I
Soft tissue inflammation
Joint space exudate
Cartilage erosion
Bone erosion
1.0 f 0
1.0 f 0
1.0 f 0
1.0 2 0
1.0 2 0
4.7 2 0.21
2.7 2 0.6:
3.2 ? 0.71
2.5 f 0.6t
1.0 f 0
1.2 t 0.1
0.6 t 0.2"
3.0 f 0.5t
1.7 2 0.2t
0.7 f 0.2$
2.7 2 0.7t
0.3 2 0.2
0.1 5 0.1
* Mice were injected with mBSA into the left rear knee on day 0 and were given saline vehicle (control) or 5,000 lymphocyte-activating factor
units of IL-1 subcutaneously into the left rear footpad. IL-I or saline injections were repeated on control days 1 and 2. Pathologic features were
scored on days 4, 7, 14, and 28 and were graded from 1 .O (mild) to 5.0 (severe). (See Materials and Methods for details.) Values represent mean
t SEM scores for groups of 10 mice.
t P < 0.001, by painvise analysis of variance.
$ P < 0.05, by pairwise analysis of variance.
mBSA-injected knees appeared normal except for
limited synovial lining layer hyperplasia in a few
Induction of erosive arthritis with mBSA and
IL-1. The concurrent administration of rHuIL-1 p subcutaneously in the left rear footpad and intraarticular
mBSA injection, along with additional IL-1p injections
on days 1 and 2, resulted in an arthritic response that
was strikingly different from the reaction to mBSA
alone. Although rHuIL-lp had no significant impact
on the inflammatory features seen on day 4, the
pathologic changes seen on day 7 were significantly
more severe than those in non-IL-1-treated animals
(Table 1). Severe periarticular and intraarticular soft
tissue inflammation consisting of mononuclear cells,
neutrophils, and scattered foci of eosinophils was
observed in the I L - l p t r e a t e d animals (Figure 2). Cells
with a fibroblast-like morphology, containing large
nuclei and condensed chromatin, which we will refer
to herein as mesenchymal cells, together with angiogenesis, were also prominent features of this arthritic
The most notable histologic feature in ILl p t r e a t e d mice was the development of a multicellular pannus, which frequently extended over a large
portion of the femoral condyle and consisted of mesenchymal cells, mononuclear cells, and neutrophils
(Figure 2). Below this tissue, cartilage destruction,
subchondral bone erosion, and periosteal bone erosion
were clearly evident. Figure 3 shows a portion of the
cartilage surface at the leading front of the pannus.
Degradation of the articular cartilage is apparent, and
behind this area, pannus can be seen eroding subchondral bone. In other locations, erosion of subchondral
Figure 1. Sagittal section of a mouse knee 7 days after intraarticular
injection of 200 pg of methylated bovine serum albumin. A weak
inflammatory reaction developed in the infrapatellar fat pad (arrow)
together with mild synovial hyperplasia. The reaction decreased
over the next 7 days, and the inflammatory response resolved by day
28 (hematoxylin and eosin stained, original magnification x 50).
of rHuIL-la (5,000 LAF units per injection) were
substituted for rHuIL-lP, in order to compare the
arthritogenic activities of the 2 cytokines. On day 7,
the mean k SEM histologic scores for synovial and
periarticular inflammation (3.9 2 0.3), pannus (3.8 t
0.4), joint space exudate (3.3 5 O S ) , cartilage erosion
(3.1 0.4), and bone erosion (3.1 k 0.5) (n = 10) in
response to the injections of IL-la with mBSA were
not significantly different (P>0.5) from those shown in
Table 1. Thus, the pathologic changes induced by
IL-I a were indistinguishable, both in terms of severity
Figure 2. Erosive arthritis in a mouse knee joint 7 days following
intraarticular injection of methylated bovine serum albumin and
administration of interleukin-1 subcutaneously in the footpad on
days 0-2. A severe inflammatory reaction in the knee joint developed along with extensive synovial hyperplasia and pannus formation (arrow). Erosion of cartilage and subchondral bone can be seen
on the femoral condyle (hematoxylin and eosin stained, original
magnification X 50).
bone was associated with invading osteoclast-like multinucleated giant cells (Figure 4). Erosion of bone in
some areas, such as that shown in Figure 4,appeared
to be focused on specific areas of the subchondral
surface. This “tunneling” effect frequently resulted in
breakthrough by pannus into the trabecular ‘paces and
bone Inarrow (Figure 5 ) . Further evidence of joint
destruction was found in the joint space, which contained strongly basophilic fragments-possibly pieces
of cartilage, and fibrin-like material interspersed with
large numbers Of neutrophilsand
few mononuclear cells.
In additional experiments, 3 footpad injections
Figure 3. Detail of Figure 2, showing the pannus4artilage interface
above the arrow. Loss of cartilage matrix can be seen to the right of
the leading front of the pannus, juxtaposed to the remaining “intact” articular surface above. At the bottom, pannus can be seen
eroding subchondral bone, where no articular cartilage remains.
Cells with large nuclei containing condensed chromatin (‘hesenchymal” cells) can be seen throughout the pannus, together with
mononuclear cells and neutrophils (hematoxylin and eosin stained,
original magnification x 500).
and features, from those induced by IL-1p. To exclude
the possibility that the response induced by IL-1 was
due to a nonspecific reaction to xenogeneic protein,
250 ng of ovalbumin in saline vehicle was substituted
for subcutaneous IL-I. The knee joints of the animals
receiving ovalbumin demonstrated a weak inflammatory reaction on day 7 that was identical to that seen in
animals receiving mBSA alone. Conversely, animals
that received 20 p1 of saline intraarticularly together
with subcutaneous IL- 1p in the footpad developed
only a mild synovial hyperplasia that was no different
from animals given intraarticular saline alone. The
substitution of BSA for mBSA for the knee injection
also failed to evoke an arthritis in I L - l p t r e a t e d animals. Only a mild synovial hyperplasia was evident,
Figure 5. Extensive erosion of subchondral bone, resulting in penetration of the articular surface and invasion by inflammatory cells
into the bone marrow of a mouse with arthritis induced by methylated bovine serum albumin and interleukin-lP. Parts of the articular
surface can be seen at the left and right of the figure. Epiphyseal
growth plate cartilage is at the bottom. Above the articular surface,
pannus has proliferated to fill the joint space (hematoxylin and eosin
stained, original magnification x 125).
Figure 4. Erosion of subchondral bone in the knee of a mouse with
arthritis induced by methylated bovine Serum albumin and interleukin-lp. Erosion frequently involved "tunneling" of the pannus into
bone (P). Multinucleated giant cells with an eosinophilic cytoplasm
were often seen at these locations (arrow) (hematoxylin and eosin
stained, original magnification x 500).
and no evidence of cartilage damage or joint erosion
was seen (data not shown).
Response to continued IL-1 administration. T o
see whether continued 1L-1 administration would exacerbate the arthritis or alter its pathologic features,
groups of mice were given intraarticular mBSA followed by 3, 7, or 14 consecutive daily subcutaneous
injections of IL-1p(5,000 L A F units) into the footpad.
The arthritic response induced in mice treated for 7
days with J L - l p was similar in severity on day 7 to that
in the animals treated for 3 days with 1 ~ - 1 (Table
The arthritis in animals subjected to 14 days of IL-Ip
treatment was also similar in appearance to that in the
3-day treatment group (data not shown). By day 14,
Table 2. Effect of various dosages of interleukin-1p (IL-Ip) on the
arthritic response of mice injected intraarticularly with methylated
bovine serum albumin (mBSA)*
IL- 1p dosage
3 x 500
(n = 15)
(n = 35)
(n = 20)
Cartilage erosion
Bone erosion
3.2 f 0.2t
1.9 f 0 . 3 t
1.4 -C 0 . 3 t
0.8 -C 0.3t
4.0 -C 0.1
3.1 f 0.2
2.4 5 0.2
2.6 -C 0.3
f 0.2
f 0.2
2 0.3
* Animals were injected intraarticularly with mBSA on day 0,
together with 3 or 7 daily subcutaneous footpad injections of IL-lp,
as shown. Units refers to the number of half-maximum lymphocyteactivating units associated with the protein, as determined in a
C3HIHeJ thymocyte costimulator assay. The arthritic features were
scored by histologic examination of the knee joint on day 7, using a
scale of 1.0 (mild) to 5.0 (severe). Values represent mean SEM
pathology scores for each group.
t P < 0.005 versus other 2 groups, by pairwise analysis of variance.
regardless of whether IL-I injections were administered for 3, 7, or 14 days, the inflammatory response
had abated, and resolution of cartilage matrix degradation and bone resorption was apparent. By day 28, no
evidence of joint inflammation could be seen. Thus,
prolonged 1L-1 administration did not increase the severity or the chronicity of the arthritic response to mBSA.
Reduction of the amount of IL-1 from 5,000 to
500 LAF units per injection for 3 days resulted in less
severe arthritis, although the extent of the inflammatory response was still much greater than in mice given
mBSA alone. Pannus and active cartilage and bone
erosion were still apparent; however, the thickness of
the tissue and the extent of joint erosion were clearly
diminished (Table 2).
Administration of IL-1 to the ipsilateral footpad, with respect to the mBSA-injected knee could
result in a localized action of 1L-1 on the popliteal
lymph node or even on the knee itself. To examine this
possibility, the results of both ipsilateral and contralateral IL- 1 footpad injections were compared using
both rHuIL-1 a and rHuIL-1 p. The arthritic responses
observed on day 7 were similar regardless of which
footpad was used for IL-1 administration, and no
differences were observed between animals treated
with IL-la or IL-1p.
Antigen-induced arthritis can be provoked in
mice immunized and challenged with mBSA, whereas
nonimmunized animals given antigen intraarticularly
develop only mild joint inflammation with no erosive
component (22-24). In this study, we have demonstrated that in nonimmunized mice injected intraarticularly with mBSA, co-administration of subcutaneous
IL-1 resulted in an acute erosive monarthritis. This
IL-l-induced arthritis was characterized by an intense
inflammatory reaction in the antigen-treated knee together with the development of a proliferative pannus
extending from the synovial margins and covering
large areas of the joint surface. At this tissue interface,
significant erosion of cartilage and subchondral bone
was observed. These features and the intensity of the
arthritis strongly resemble the early pathologic features described by Brackertz et al, which occurred
7-14 days after mBSA antigen challenge in the conventional antigen-sensitized arthritis model (22). An
important difference between the 2 models, however,
is that IL- l/m-BSA-induced arthritis resolves between
7 and 14 days, whereas mBSA antigen-induced arthritis is sustained for 60-90 days in sensitized mice (22).
To a limited degree, therefore, IL-1 appears to substitute
for immunization with mBSA emulsified in adjuvant.
Although the augmentation of a mild inflammatory response to mBSA by IL-1 described here bears
some similarity to the acceleration of type I1 collageninduced arthritis by IL-1 (20,21), an important difference between the 2 models is that intraarticular mBSA
alone does not result in erosive pathologic changes,
whereas collagen arthritis can be induced in non-IL- 1treated animals. In the studies described herein, 1L-1
was shown to be capable of inducing erosive articular
pathologic changes in the absence of established or
developing erosive arthritis. The mechanism by which
IL-1 transforms a mild inflammatory reaction into an
acute destructive arthritis is unclear. Other investigators have shown that subcutaneous injection of 1L-1 in
mice and rats leads to sustained serum and tissue
levels of IL-1 for up to 7 hours (25,26). Although, IL-1
could gain access to the knee joint and mediate direct
effects such as loss of cartilage matrix and bone
resorption (9,13,27),this seems unlikely since single or
even multiple injections of IL-1 directly into the knee
joint lead only to mild inflammation and transient loss
of cartilage proteoglycan over 72 hours (18), without
macroscopic cartilage or bone erosion. Furthermore,
in our studies, subcutaneous administration of 1L-1,
together with intraarticular administration of saline,
failed to produce any knee inflammation or arthritis.
A more attractive hypothesis for the mechanism of action of IL-1 would be the stimulation of local
or systemic immunity to intraarticular mBSA. In our
study, intraarticular BSA failed to induce an inflam-
matory response in conjunction with IL-1. Methylation is known to promote the localization of BSA in
joint cartilage and connective tissue due to the cationic
charge of the protein (24). Methylated BSA is also
processed and presented by antigen presenting cells
more efficiently than is native BSA (28), and mBSA is
a T cell-dependent antigen (29). Thus, antigen retention and efficient presentation might result in limited T
cell activation, which might be augmented by exogenous IL-I. The observation that IL-1 injections in the
contralateral footpad were as effective as injections in
the ipsilateral footpad raises the possibility that stimulation of antigen-reactive cells may take place systemically in lymph nodes and the spleen as well as
within the mBSA-injected knee. Whether such stimulation involves the action of IL-1 on CD4+, Th2 T
helper cells or a direct effect of IL-1 on B cells is not
yet clear (30,31).
We also cannot exclude the possibility that IL-1
induces the release of other cytokines, such as IL-2,
IL-4, IL-6, or y-interferon, which are responsible for
the arthritic response. The delay between the last
injection of IL-1 (day 3) and the maximum arthritic
response (day 7) would allow sufficient time for the
induction of secondary cytokines. In this respect, we
noted accumulations of eosinophils in the periarticular
tissues of mBSA/IL- 1-treated arthritic mice, which
would be consistent with the induction of eosinophil
chemotactic and differentiation factors such as IL-5
and IL-3 (32,33).
One interesting feature of the arthritis described
herein is the lack of chronic inflammatory and erosive
disease. Despite the fact that severe inflammation and
aggressive joint destruction were seen on day 7, the
intensity of the reaction diminished by day 14. There
w a s not only a reduction in the inflammatory response
but also partial repair of bone erosions with new,
woven bone. This “healing” phase was almost complete by day 28, although articular cartilage was not
replaced. Despite continued daily administration of
IL-1, we were unable to prolong the arthritis beyond 7
days. Since mBSA persists in hyaline cartilage for at
least 28 days (24), it is not clear why continued IL-1
administration does not maintain pannus growth and
joint erosion. One possibility is that repeated 1L-1
injections stimulate the production of an endogenous
IL-I inhibitor, such as that produced by human monocytes (34), which down-regulates the biologic response
to the cytokine. Down-regulation might also occur via
the antiinflammatory and immunosuppressive actions
of elevated corticosterone levels, which can be in-
duced by IL-1 (35,36). An alternative explanation is
that although IL-1 can induce an early erosive arthritis, other cytokines are necessary for the maintenance
of chronic inflammation.
In conclusion, we believe our results provide
new evidence to support the role of IL-1 in the
development of early erosive arthritis. Recently, disease activity in human rheumatoid arthritis has been
shown to correlate with plasma levels of IL-10 (37).
Thus, in human disease, elevated 1L-1 production
could transform mild joint inflammation into erosive
joint destruction. A clearer understanding of the mechanism of action of IL-1 in this animal model should
provide insight into its contribution to the pathogenesis of rheumatoid arthritis.
We thank Loran Killar for helpful discussions concerning IL-I and collagen-induced arthritis in mice, and
Barbara Mundo for secretarial assistance.
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albumin, bovine, induction, erosive, mice, methylated, arthritis, serum, interleukin, monarticular, acute
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