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Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis. Implications for local actions of tumor necrosis factor ╨Ю┬▒

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Implications for Local Actions of Tumor Necrosis Factor a
Objective. We have previously described the location of tumor necrosis factor a (TNFa)-producing
cells in synovial tissue and cartilage-pannus junction in
rheumatoid arthritis (RA). To further understand the
local actions of TNFa, we investigated the expression of
TNF receptors (TNF-R) on cells in the same compartments in patients with RA.
Methods. The expression of both p55 TNF-R and
p75 TNF-R was determined using alkaline phosphataseconjugated mouse anti-alkaline phosphatase (APAAP)
and double immunofluorescence staining techniques
with monoclonal antibodies.
From The Mathilda and Terence Kennedy Institute of
Rheumatology. Bute Gardens and Sunley Research Centre. London. England.
Supported by the Arthritis and Rheumatism Council of
Britain. Dr. Deleuran's work was supported by the University of
Aarhus and by the Danish Rheumatism Association.
Bent W. Deleuran. MD: Research Fellow, The Mathilda
and Terence Kennedy Institute of Rheumatology (current address:
Department of Rheumatology. University of Aarhus, Denmark):
Cong-Qiu Chu. MD. PhD: Research Scientist, The Mathilda and
Terence Kennedy Institute of Rheumatology. Bute Gardens; Max
Field, BSc, MD, MRCP: Senior Lecturer and Consultant Rheumatologist. The Mathilda and Terence Kennedy Institute of Rheumatology (current address: Centre for Rheumatic Diseases, Glasgow
Royal Infirmary, Glasgow, Scotland): Fionula M. Brennan. BSc.
PhD: Senior Research Scientist. The Mathilda and Terence Kennedy Institute of Rheumatology. Sunley Research Centre: Tracey
Mitchell, BSc: Research Assistant, The Mathilda and Terence
Kennedy Institute of Rheumatology, Bute Gardens: Marc Feldmann. MD, PhD. FRCPath: Professor, The Mathilda and Terence
Kennedy Institute of Rheumatology. Sunley Research Centre;
Ravinder N . Maini. MB, FRCP: Professor and Director. The
Mathilda and Terence Kennedy Institute of Rheumatology, Bute
Address reprint requests to Ravinder N . Maini, MB. FRCP.
The Mathilda and Terence Kennedy Institute of Rheumatology. 6
Bute Gardens, Hammersmith. London W6 7DW. UK.
Submitted for publication February 18, 1992: accepted in
revised form May 20. 1992.
Arthritis and Rheumatism, Vol. 35, No. 10 (October 1992)
Results. In RA synovial membrane, both p55
TNF-R and p75 TNF-R were detectable in up to 90% of
the cells in the lining layer, and were demonstrated on
cells in deeper layers of the membrane, including vascular endothelial cells. Cells in lymphoid aggregates
expressed both TNF-R, but with a predominant expression of p75 receptor. At the cartilage-pannus junction,
the majority of pannus cells, especially those invading
cartilage, expressed both the p55 and the p75 TNF-R.
Sequential section and double immunofluorescence
staining showed that the TNF-R-expressing cells were in
the vicinity of TNFa-containing cells, and some TNFacontaining cells also expressed TNF-R. TNF-Rexpressing cells were also detected in osteoarthritic and
normal synovial tissue, but in smaller numbers and at a
lower intensity.
Conclusion. These results provide histologic evidence that both p55 TNF-R and p75 TNF-R are expressed by a variety of cell types in RA synovial tissue,
reflecting the fact that a wide range of cells are potential
targets for T N F a in this tissue. This study further
supports the hypothesis that T N F a plays a major role in
the pathogenesis of RA.
Tumor necrosis factor a (TNFa) is a pleiotropic
cytokine which has been implicated in the pathogenesis of rheumatoid arthritis (RA). Many of its biologic
properties indicate that T N F a may be involved not
only in regulation of immune and inflammatory responses in rheumatoid synovitis, but also in cartilage
and bone destruction ( I ) . Elevated levels of biologically active T N F a have been detected in RA synovial
fluid (2,3). Our previous studies demonstrated that
T N F a is locally produced by synovial tissue cells
(4-6). and it is likely that the production of T N F a is
i m p o r t a n t in v i v o f o r t h e p r o d u c t i o n o f o t h e r proinflammatory c y t o k i n e s , s u c h as interleukin-I (1L-I) a n d
g r a n u l o c y t e - m a c r o p h a g e colony-stimulating f a c t o r .
by synovial cells (5.7). Based on t h e s e o b s e r v a t i o n s , it
w a s therefore h y p o t h e s i z e d that TNFa is a pivotal
c y t o k i n e in t h e p a t h o g e n e s i s o f RA (S,7).
TNFa m e d i a t e s its effects via binding t o cell
surface TNF r e c e p t o r s (TNF-R). T w o T N F - R , with
m o l e c u l a r weights o f 55 kd (pSS) a n d 75 k d ( ~ 7 3h,a v e
been cloned recently (8-10). T N F - R are widely distribu t e d , b u t with t h e availability of specific monoclonal
a n t i b o d i e s ( M A b ) , differences in t h e cellular e x p r e s s i o n of p5S T N F - R a n d p75 T N F - R h a v e become
a p p a r e n t . B o t h TNF-R are p r e s e n t on lymphocytic cell
lines, peripheral blood m o n o c y t e s ( I I ), a n d natural
killer cells (12). Resting l y m p h o c y t e s h a v e v e r y f e w
TNF r e c e p t o r s , but u p o n activation, p7S TNF-R is
preferentially i n d u c e d ( I I,l3,14).TNFa ( I S ) , IL-I,
phorbol 12-myristate 13-acetate (16), bacterial lipopolysaccharide (17). and a c t i v a t o r s of protein kinase C
(18) d o w n - r e g u l a t e s u r f a c e TNF-R e x p r e s s i o n ,
w h e r e a s interferon-y (19) a n d IL-2 (20) i n c r e a s e its
We h a v e previously described t h e location of
TNFa-producing cells in r h e u m a t o i d synovial tissue
a n d a t s i t e s o f tissue d e s t r u c t i o n , s u c h as t h e cartilagep a n n u s j u n c t i o n (6). TNFa e x e r t s its a c t i o n s locally.
To u n d e r s t a n d f u r t h e r t h e local effects of TNFa, w e
investigated t h e presence and cellular distribution o f
b o t h pS5 and p7S T N F - R in r h e u m a t o i d synovial tissue
and cartilage-pannus j u n c t i o n , in an a t t e m p t to m a p
t h e potential t a r g e t s of TNFa. B o t h pS5 T N F - R a n d
p7S TNF-R were f o u n d to be e x p r e s s e d b y a large
number of synovial cells in r h e u m a t o i d synovial memb r a n e and a t t h e cartilage-pannus j u n c t i o n .
Reagents. Mouse MAb to human pS5 T N F - R
(HTR-9) and p75 TNF-K (UTR-I) have been described
previously ( I I ). Affinity-purified polyclonal rabbit antiT N F a antibody was generated by repeated injection of
human recombinant T N F a (Genentech. South San Francisco, CA). as previously described (6). Goat anti-mouse
IgG. alkaline phosphatase-conjugated mouse anti-alkaline
phosphatase complex (APAAP). mouse antLCD68 antibody
(EBMI 1). rabbit anti-human von Willebrand factor. and
fluorescein-conjugated swine anti-rabbit IgG were all obtained from Dakopatts (Copenhagen, Denmark). Normal
mouse lgGl and goat anti-mouse IgG linked to biotin were
obtained from Sigma (Poole. UK). Streptavidin-linked Texas
red was purchased from Amersham (Buckinghamshire, UK).
Patients. Synovial tissue from the knee joint was
obtained at arthroplasty o r arthroscopy in 12 patients with
RA, and cartilage-pannus junction samples were obtained
from 5 of the 12. All patients fulfilled the American College
of Rheumatology (formerly, the American Rheumatism Association) 1987 criteria for RA (21). Patients were treated
with methotrexate ( n = 2). D-penicillamine (n = 3), sodium
aurothiomalate (n = 2 ) . azathioprine (n = I ) , and corticosteroids ( n = 4): 2 patients were not receiving any second-line
antirheumatic drugs.
Synovial tissue was also obtained from 8 osteoarthritis (OA) patients. who had received nonsteroidal antiinflammatory drugs, acetaminophen, o r a combination of these
drugs. None had received steroid treatment. Normal synovial membrane and cartilage-synovium junction samples
were obtained from the knee joints of 7 patients undergoing
amputation for osteogenic sarcoma at a site distant from the
knee joint (samples kindly provided by Dr. M. Bayliss.
Kennedy Institute). All samples were snap frozen in isopentane cooled in liquid nitrogen and stored at -80°C until use.
Imrnunohistochemical techniques. Five-micrometer
cryostat sections were washed in 0.05M Tris buffered saline
(TBS). pH 7.36. for 1 minute at 4°C in order to remove
soluble receptors, then fixed in acetonehethanol at -20°C
for 10 minutes and blocked for 20 minutes with 20% normal
goat serum (NGS). The sections were incubated overnight at
4°C with anti-p55 TNF-R MAb (HTR-9; I5 pg/ml), anti-p75
TNF-R MAb ( U T R - I ; 20 pg/ml), o r antLCD68 MAb
( E B M I I : 3 pg/ml). Binding was detected by 30-minute
incubation of the sections at room temperature with goat
anti-mouse IgG diluted in 2%) NGS. followed by APAAP, for
30 minutes. In order to amplify the signal, the incubation
with goat anti-mouse IgG and APAAP was repeated once.
The sections were then incubated for up to 15 minutes with
I m g h l fast red (Sigma) in TBS, pH 8.2, containing 0.6M
dimethylformamide. 0.02M naphthol phosphate, and 0.001M
levamisole. The reaction was stopped with distilled water
and the sections were counterstained in hematoxylin. Normal mouse IgGI at equivalent protein concentration was
included as a control.
For double immunofluorescence staining, the RA
synovial membrane and cartilage-pannus junction sections
were treated and incubated as above with anti-TNF-R MAb
(H'IR-9 and UTR-I) and rabbit anti-TNFa o r rabbit antihuman von Willebrand factor antibodies. Binding of HTR-9
and UTR-I was detected with biotin-labeled goat anti-mouse
IgG and streptavidin-linked Texas red. Rabbit anti-TNFa
and rabbit anti-human von Willebrand factor antibodies were
detected with fluorescein-conjugated swine anti-rabbit IgG.
Statistical analysis. The numbers of TNF-R-positive
and CDh8-positive cells were determined by counting up to
500 cells in each area of the tissue examined, and the results
were expressed as a percentage of positive cells over the
total cells. Data were analyzed using the Wilcoxon rank
sum test.
Localization of p55 TNF-R-expressing cells in
synovial membrane. Staining with HTR-9 antibody
(p55 T N F - R ) o f t e n s h o w e d a c y t o p l a s m i c p a t t e r n , with
Table 1.
Distribution of tumor necrosis factor receptor (TNF-R)- and CD68-expressing cells in synovial membrane*
p55 TNF-R
50 5 10
50 2 21
35 2 22t
15 2 14t
85 2 21
60 2 22
50 2 23
45 t 35$
35 2 24$
15 t 3 t
102 5t
70 t 12
40 2 20
10 2 9
55 2 12
202 7
45 t 10
I5 2 3
% of subjects positive
Mean 2 SD % of cells positive
Lining layer
Vascular endothelium
Lymphoid aggregate
p75 TNF-R
55 5 23
20 2 10
* The distribution of p55 TNF-R-, p75 TNF-R-, and CD68-positive cells was determined in the synovial lining layer, interstitium, blood vessels,
and lymphoid aggregates of synovial tissue from patients with rheumatoid arthritis (RA) (n = 12). patients with osteoarthritis (OA) (n = 8). and
healthy controls (C) (n = 7), as described in Patients and Methods. NP = lymphoid aggregates were not present in tissue sections.
t P < 0.01 versus RA and OA.
$ P < 0.01 versus RA.
increased intensity around the nucleus. Synovial membrane samples from 1 1 of 12 RA patients, 7 of 8 OA
patients, and 6 of 7 normal controls contained the
TNF-R-expressing cells (Table I ) . In RA synovium,
the p55 TNF-R-expressing cells were equally represented in the lining layer (mean t SD 55 t 23%
positive) (Figure IA) and on cells in the interaggregate
areas (mean 50 2 21% positive), whereas in lymphoid
aggregates, only 20 5 10% of the cells were positive
for p55 TNF-R (Figure IC). Most of vascular endothelial cells stained for p55 TNF-R (Table I).
In OA synovium, the cell density was lower
than that observed in RA synovium, and no cell
aggregates were found. Furthermore, the staining intensity of p55 TNF-R (Figure 2A) was lower than that
seen in RA samples, although a similar proportion of
cells were positive and a similar cellular distribution
was observed. In normal synovial membrane samples,
the staining was found to be weak compared with that
in RA and OA sections, and significantly fewer cells in
the lining layer, interstitial layer, and vessels were
positive (P < 0.01) (Table I and Figure 2B).
Localization of p75 TNF-R-xpressing cells in
synovial membrane. UTR- I antibody (p75 TNF-R)
showed a homogeneously granular cytoplasmic staining pattern. Positive staining was identified in synovial
membrane samples from 1 1 of 12 RA patients, 7 of 8
OA patients, and 5 of 7 normal subjects (Table I ) . RA
samples exhibited p75 TNF-R-expressing cells in a
mean 2 SD of 85 ? 21% of the lining layer cells
(Figure IB), but also in 60 22% of the cells in the
interaggregate areas and 50 t 23% of the lymphoid
aggregate cells (Figure ID). In OA synovium, the
number of p75 TNF-R-expressing cells in the lining
layer and deeper layers of the membrane was signifi-
cantly reduced compared with that in RA samples ( P
< O . O l ) , and the staining was less intense.
As with staining for p55 TNF-R, a high level of
p75 TNF-R expression was observed in association
with blood vessels, in which up to 90% of the vessels
were found to be positive for p75 TNF-R in both RA
(Figure IE) and OA synovial membrane samples. In
normal synovial membranes, the staining intensity for
p75 TNF-R was very weak, and positive staining was
expressed by only a few cells compared with RA and
OA samples ( P < 0.01) (Table I ) . Approximately 15%
of the blood vessel endothelial cells also stained for
p75 TNF-R.
Localization of p55 and p75 TNF-R-expressing
cells at the cartilage-pannus junction. In the invasive
cartilage-pannus junction samples from RA patients (n
= 5 ) , most of the cells in the interface of cartilage and
pannus, as well as cells invading cartilage, expressed
both p55 TNF-R (mean 85% of cells positive) (Figure
3A and Table 2) and p75 TNF-R (mean 70% positive)
(Figure 3B and Table 2). The chondrocytes were also
positive for p55 TNF-R in a mean of 30% of the cells
(range 1040%) and for p75 TNF-R (Figure 4C) in a
mean of 35% of the cells (range 1045%). This was in
contrast to the normal cartilage-synovium junction,
where none of the cells in the junction area expressed
either TNF-R, and 10% of the chondrocytes were
positive for p55 TNF-R or p75 TNF-R (Table 2).
Characterization of cells expressing p55 TNF-R
and p75 TNF-R. The monocyte/macrophage marker,
CD68, was detected in 70 2 12% (mean 5 SD) of the
lining layer cells in RA synovial tissue, 55 2 12% in
OA synovial tissue, and 45 t 10% in normal synovial
tissue (Table I). In the cartilage-pannus junction of
RA patients, 60% of the cells were CD68 positive
Figure 1. Distribution of tumor necrosis factor receptors (TNF-R) in rheumatoid synovial membrane. In the lining layer, most of the
cells stain for both pSS TNF-R ( A ) and p7.5 TNF-R ( B ) . In the lymphoid aggregate. some cells stain for pS5 TNF-R (C) (arrows), and most
stain for p7S TNF-R (D).
Staining for p75 TNF-R is found on endothelial cells of blood vessels and on perivascular cells (E).Normal
mouse IgG I failed to stain any cells (F). (Alkaline phosphatase-conjugated mouse anti-alkaline phosphatase stained, hematoxylin
counterstained; original magnification x 160 in A . B. and F. and x 320 in C. D. and E . )
(Table 2). Staining of sequential sections from RA
samples showed that most of the p55 TNF-R- and p75
TNF-R-expressing cells were in the areas of CD68positive cells, both in the lining layer and at the
cartilage-pannus junction. Some TNF-R-expressing
cells in the lining layer, the interaggregate area, and at
the cartilage-pannus junction were CD68 negative and
showed a fibroblast-like cell morphology.
Double imrnunofluorescence staining of RA
synovial membrane sections using a combination of
Figure 2. Representative sections of osteoarthritic (A) and normal (B) synovial membrane, showing pS5 tumor necrosis factor receptor
expression. The perinuclear staining pattern is particularly marked in the osteoarthritic synovium (Alkaline phosphatase-conjugated mouse
anti-alkaline phosphatase stained, original magnification x 160.)
Figure 3. Localization of tumor necrosis factor receptors (TNF-R) at the cartilage-pannusjunction in the rheumatoid joint. A, Cells expressing
p5S TNF-R at the interface of cartilage (C) and pannus (P)and B, those expressing p75 TNF-R at the site of the cartilage lesion are seen. C.
Some chondrocytes express p7S TNF-R (arrows); p55 TNF-R showed a similar staining pattern. D,Normal mouse lgGl failed to stain these
cells (Alkaline phosphatase-conjugated mouse anti-alkaline phosphatase stained. hematoxylin counterstained: original magnification x 160 in
A. B, and D. and x 320 in C . )
Figure 4. Double immunofluorescence staining of rheumatoid synovial lining layer. demonstrating that cells expressing p55 tumor necrosis
factor receptor (TNF-K) ( A ) are in the vicinity of TNFa-containing cell\ ( B ) . and some cells costain for T N F a and p5.5 TNF-R. (Original
magnification x 2.50.)
HTR-9 or UTR-I with polyclonal rabbit anti-TNFa
showed that p5S TNF-R- and p75 TNF-R-expressing
cells were often in the vicinity of TNFa-positive cells,
and 60% of the TNFa-positive cells were also labeled
with both HTR-9 and UTR-I antibodies (Figures 4 A
and B). Double staining using a combination of HTR-9
or UTR-I with rabbit anti-von Willebrand factor antibodies confirmed that both receptors were also localized to the endothelium of blood vessels.
In the present investigation. using specific
monoclonal antibodies, we have detected pS5 TNF-R
and p75 TNF-R in diseased and normal synovial
tissue, and demonstrated that both TNF-R are increased on cells in rheumatoid synovial membrane and
at the cartilage-pannus junction. Both TNF-R were
Table 2. Expression of tumor necrosis factor receptors (TNF-K)
and CD68 at the cartilage-pannu\ junction and in chondrocytes of
patients with rheumatoid arthritis*
Cart Ilage-pan n u \
junction cell\
* The distribution of p55 7°F-K-. p75 TNF-K-. and CD6X-positive
cells was determined at the cnrtilage-pannu\ junction in patients
with rheumatoid arthritis ( K A ) ( n = 5 ) and at the normal synoviumcartilage junction in healthy controls tC) ( n = 7). as described in
Patients and Methods. Re\ult\ are expre\sed a\ the mean (range)
percentage of cell\ po\itive.
expressed by cells in the region where their ligand,
TNFa, was also immunolocalized.
The major site of TNF-R expression in the
inflamed synovial membrane in RA is the lining layer,
in which up to 90% of the lining cells expressed both
pSS and p75 TNF-R. Of the 2 cell types that constitute
the lining layer. macrophages are in the majority,
although fibroblast-type cells are also present (22).
Serial section staining indicated that TNF-Rexpressing cells are mostly CD68-positive macrophagehonocyte. TNFa is produced by 40% of the
lining layer cells, most commonly macrophages (6);
double staining for TNFa and TNF-R indicated that
TNFa-producing cells were in the vicinity of the
TNF-R-expressing cells, and a significant proportion
of cells stained for both TNFa and the receptors. This
would imply that these cells are subject to paracrine
and autocrine stimulation. Increased expression of
TNFa and TNF-R in the rheumatoid synovial lining
layer would enable activation of macrophages and
fibroblast growth (23), and induce the production of
collagenase and prostaglandin (24).
In the deeper layers of the synovial membrane
(interaggregate area), the frequency of p75 TNF-Rpositive cells was decreased, whereas pS5 TNF-R
expression was unchanged on cells in this area. The
presence of p7S TNF-R expressed by a larger number
of cells (and to a lesser degree for pS5 TNF-R) within
the aggregate areas indicates that RA synovial lymphocytes predominantly express p75 TNF-R. This has
been confirmed by flow cytometric analysis (25) which
indicated that isolated synovial lymphocytes (mainly
CD3 positive) predominantly expressed p75 TNF-R.
TNFa induces IL-2 receptor expression, and therefore
could act as a growth factor for T cells (26). Thus, the
fact that a high proportion of lymphocytes express p75
TNF-R in these aggregates suggests that TNFa may be
involved in the continued T cell activation.
Vascular endothelial cells play an important
role in chronic rheumatoid synovitis by allowing inflammatory cell trafficking into the inflamed tissue
(27). TNFa induces expression of adhesion molecules
on endothelial cells (28,29), thus increasing binding of
inflammatory cells such as lymphocytes and monocytes to endothelial cells and facilitating diapedesis.
Repeated intraarticular injection of TNFa into experimental animals produced a massive infiltration of
mononuclear cells into the synovial tissue (30). TNFa
also stimulates endothelial cells to produce 1L-l (31)
and IL-8 (32). which are important mediators in rheumatoid synovitis. It is likely that these TNFamediated effects on endothelial cells are involved in
RA synovitis. since 90% of the blood vessel endothelial cells in synovial membrane and pannus tissue
expressed both TNF-R. Furthermore, TNFa is produced by perivascular cells and by endothelial cells
themselves (6); this further emphasizes its ability to
participate in the many pathologic processes that can
occur in the synovium.
The cartilage-pannus junction is the site at
which RA joint injury takes place. Cells (predominantly macrophages and fibroblasts) in erosive pannus
produce proteolytic enzymes, causing degradation o f
the underlying cartilage. As in the lining layer, most of
those CD68-positive macrophages and cells with fibroblast morphology in the pannus showed a highly
increased expression o f both pS5 TNF-R and p75
TNFa has been implicated in the severe joint
destruction seen in RA, since it is found at the cartilage-pannus junction (6) and, in vitro, it induces
cartilage and bone erosion (33,34). Thus, in RA,
locally produced TNFa may act on these macrophages
and fibroblast-like cells to release destructive enzymes. Administration of TNFa into rabbit knee joints
causes proteoglycan degradation and cartilage injury
( 3 3 , supporting this hypothesis. In addition, the results of in vitro studies have suggested that TNFa acts
directly on chondrocytes (33). Herein we provide
evidence that RA chondrocytes also bear TNF-R;
thus, TNFa released by pannus cells may directly
cause cartilage damage.
TNFa may also be involved in the pathogenesis
of OA, but there are conflicting reports on this (36,37).
In previous studies we demonstrated that TNFa can
be found in OA synovial membrane cells, but at a
lower quantity than in RA cells (5,6). The present
studies have shown that TNF-R can be found in a
similar distribution to that seen for TNFa itself in the
lining layer and in the endothelial cells. However,
samples from RA patients had much greater staining
intensity for TNF-R compared with those from OA
patients, suggesting that the number of TNF-R per cell
is also smaller in OA synovial cells. This is consistent
with the findings of flow cytometric analyses of isolated synovial membrane cells from RA and OA patients (25).
In normal synovial membrane, the staining intensity for TNF-R was weak, and was confined to the
lining layer and vessels. Only a few of the cells in
normal synovium expressed p75 TNF-R, in contrast to
its expression on a large number of cells in RA
synovial membrane. suggesting that this TNF-R, in
particular, is up-regulated during inflammation.
These results showing increased expression of
TNF-R in RA synovial tissue indicate that a wide
variety of synovial cells are potential targets for
TNFa. This reflects the wide range of involvement
that TNFa appears to have in the synovitis and tissue
destruction in RA, and supports the notion that TNFa
is a major mediator in the pathogenesis of this disease.
I t is not known at present how the expression of
TNF-R on RA synovial cells is regulated. This important question is currently under investigation.
We thank Dr. M. Brockhaus (Hoffmann-La Roche.
Basel. Switzerland) for providing the HTR-9 and UTR-I
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implications, patients, tissue, necrosis, pannus, local, factors, junction, arthritis, localization, action, receptors, synovial, cartilage, tumors, rheumatoid
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