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Vol 9 No 4Research article
Expression and function of junctional adhesion molecule-C in
human and experimental arthritis
Gaby Palmer1*, Nathalie Busso2*, Michel Aurrand-Lions3, Dominique Talabot-Ayer1,
Véronique Chobaz-Péclat2, Claudia Zimmerli3, Philippe Hammel3, Beat A Imhof3 and Cem Gabay1
1Division of Rheumatology, Department of Internal Medicine, University Hospital, 26 avenue Beau-Séjour, 1211 Geneva 14, Switzerland and
Department of Pathology and Immunology, University of Geneva School of Medicine, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland
2Division of Rheumatology, Department of Medicine, University Hospital, Nestlé 05-5029, 1011 Lausanne, Switzerland
3Department of Pathology and Immunology, University of Geneva School of Medicine, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland
* Contributed equally
Corresponding author: Cem Gabay, firstname.lastname@example.org
Received: 9 Mar 2007 Revisions requested: 11 Apr 2007 Revisions received: 11 Jun 2007 Accepted: 5 Jul 2007 Published: 5 Jul 2007
Arthritis Research & Therapy 2007, 9:R65 (doi:10.1186/ar2223)
This article is online at: http://arthritis-research.com/content/9/4/R65
© 2007 Palmer et al.; licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Junctional adhesion molecule-C (JAM-C) is an adhesion
molecule involved in transendothelial migration of leukocytes. In
this study, we examined JAM-C expression in the synovium and
investigated the role of this molecule in two experimental mouse
models of arthritis. JAM-C expression was investigated by
immunohistochemistry. The effects of a monoclonal anti-JAM-C
antibody were assessed in antigen-induced arthritis (AIA) and K/
BxN serum transfer-induced arthritis. JAM-C was expressed by
synovial fibroblasts in the lining layer and associated with
vessels in the sublining layer in human and mouse arthritic
synovial tissue. In human tissue, JAM-C expression was
increased in rheumatoid arthritis (RA) as compared to
osteoarthritis synovial samples (12.7 ± 1.3 arbitrary units in RA
versus 3.3 ± 1.1 in OA; p < 0.05). Treatment of mice with a
chain reaction and
monoclonal anti-JAM-C antibody decreased the severity of AIA.
Neutrophil infiltration into inflamed joints was selectively
reduced as compared to T-lymphocyte and macrophage
infiltration (0.8 ± 0.3 arbitrary units in anti-JAM-C-treated versus
2.3 ± 0.6 in isotype-matched control antibody-treated mice; p <
0.05). Circulating levels of the acute-phase protein serum
amyloid A as well as antigen-specific and concanavalin A-
induced spleen T-cell responses were significantly decreased in
anti-JAM-C antibody-treated mice. In the serum transfer-induced
arthritis model, treatment with the anti-JAM-C antibody delayed
the onset of arthritis. JAM-C is highly expressed by synovial
fibroblasts in RA. Treatment of mice with an anti-JAM-C antibody
significantly reduced the severity of AIA and delayed the onset
of serum transfer-induced arthritis, suggesting a role for JAM-C
in the pathogenesis of arthritis.
The recruitment of leukocytes to inflamed tissues is a highly
regulated multistep process, which includes leukocyte rolling
on the vascular endothelium, activation of leukocytes and sub-
sequent firm adhesion to endothelial ligands, transendothelial
migration from the vascular lumen into the surrounding tissue,
and migration of inflammatory cells through the tissue in
response to chemokine gradients [1,2]. The successive
events in this cascade are mediated by coordinated interac-
tion of adhesion molecules expressed by leukocytes, endothe-
lial cells, and the surrounding tissues. In particular, endothelial
transmigration involves the interaction of leukocytes with
adhesion molecules expressed on the endothelial cell surface,
whereas their retention likely involves interaction with adhe-
sion molecules present on different cell types residing within
the target tissue.
AIA = antigen-induced arthritis; ConA = concanavalin A; DMEM = Dulbecco's modified Eagle's medium; ELISA = enzyme-linked immunosorbent
assay; ICAM-1 = intracellular adhesion molecule-1; IFN-γ = interferon-gamma; Ig = immunoglobulin; IHC = immunohistochemistry; IL-10 = interleukin-
10; i.p. = intraperitoneal; JAM = junctional adhesion molecule; LFA-1 = lymphocyte function-associated antigen-1; mBSA = methylated bovine serum
albumin; OA = osteoarthritis; PBS = phosphate-buffered saline; PCR = polymerase chain reaction; PECAM-1 = platelet endothelial cell adhesion
molecule-1; RA = rheumatoid arthritis; RT = reverse transcriptase; SAA = serum amyloid A; Tc = technetium; VEGF = vascular endothelial growth
Arthritis Research & Therapy Vol 9 No 4 Palmer et al.
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Transendothelial migration of leukocytes involves several
endothelial adhesion molecules regulating the paracellular
trafficking, such as CD99, platelet endothelial cell adhesion
molecule-1 (PECAM-1), or the junctional adhesion molecules
(JAMs) [3-6]. The JAM protein family consists of three mem-
bers called JAM-A, JAM-B, and JAM-C, which are immu-
noglobulin (Ig) superfamily molecules with two extracellular Ig
domains and a short cytoplasmic tail, ending with a PDZ-bind-
ing motif, involved in cytoskeletal and signal transduction inter-
actions . JAM-C was initially described as an adhesion
molecule localized at interendothelial contacts and as an
integrin ligand mediating interactions between vascular cells
and leukocytes [5,8]. JAM-C is also expressed in mesenchy-
mal and epithelial cells, suggesting that in addition to its role
in inflammatory cell recruitment, it might contribute to the
retention of leukocytes within inflamed tissues [9,10].
Soluble JAM-C has been demonstrated to inhibit neutrophil
transmigration both in vitro and in vivo . Similarly, mono-
clonal antibodies directed against JAM-C reduced the accu-
mulation of leukocytes in alveoli during acute pulmonary
inflammation in mice , prevented leukocyte influx in a
murine model of allergic contact dermatitis , and
decreased inflammatory cell recruitment and tissue injury in
cerulein-induced acute pancreatitis .
Uncontrolled activation of leukocytes and endothelial cells is a
feature of pathologic chronic inflammation, such as observed
in rheumatoid arthritis (RA). The mechanisms regulating
recruitment and retention of leukocytes in the joint in experi-
mental models of inflammatory arthritis and the role of various
adhesion molecules in human RA are still poorly understood.
The aim of the present study was to investigate the role of
JAM-C in arthritis. We describe the expression of JAM-C in
human and mouse synovium and synovial fibroblasts. Further-
more, we observed that a monoclonal anti-JAM-C antibody
decreased the severity of mouse antigen-induced arthritis
(AIA) and delayed the onset of K/BxN serum transfer-induced
Materials and methods
Male C57BL/6 mice were obtained from Janvier (Le Genest-
St-Isle, France) and used between 9 and 11 weeks of age.
KRN T-cell receptor transgenic mice, developed in the labora-
tory of Diane Mathis and Christophe Benoist, were kindly pro-
vided by the Institut de Génétique et de Biologie Moléculaire
et Cellulaire (Strasbourg, France)  and were maintained
on a C57BL/6 background (K/B). Progeny bearing the Vβ6
transgenic T-cell receptor were identified by cytofluorometry
of peripheral blood lymphocytes using antibodies labeled with
anti-CD4 phycoerythrin (clone L3T4; BD Pharmingen, San
Diego, CA, USA) and anti-Vβ6 fluorescein isothiocyanate
(clone RR4-7; BD Pharmingen). NOD/Lt mice were pur-
chased from The Jackson Laboratory (Bar Harbor, ME, USA).
All mice were housed under conventional conditions, and
water and standard laboratory chow were provided ad libitum.
All animal experiments were approved by the Animal Ethics
Committee of the Geneva University School of Medicine and
by the Geneva Veterinarian Office.
Mice were injected intradermally at the base of the tail with
100 μg of methylated bovine serum albumin (mBSA) (Fluka,
part of Sigma-Aldrich, St. Louis, MO, USA), emulsified in com-
plete Freund's adjuvant (Difco Laboratories Inc., now part of
Becton Dickinson and Company, Franklin Lakes, NJ, USA)
containing 5 mg/ml Mycobacterium tuberculosis. Heat-killed
Bordetella pertussis organisms (0.2 × 109) (Berna, Bern,
Switzerland) were injected intraperitoneally as an additional
adjuvant. On day 7, a booster injection of 100 μg of mBSA in
incomplete Freund's adjuvant (Becton Dickinson and Com-
pany) was given at the base of the tail. On day 21, arthritis was
induced by intra-articular injection of 100 μg of mBSA in 10 μl
of phosphate-buffered saline (PBS) into the left knee joint of
mBSA-immunized mice, the right knee being injected with
sterile PBS alone. The monoclonal anti-JAM-C antibody H36
 or an isotype-matched control antibody (9B5, rat IgG2a
anti-human CD44) was injected (150 μg/mouse, intraperito-
neal [i.p.]) 1 hour before intra-articular injection of mBSA into
the left knee and of PBS into the right knee. Mice were sacri-
ficed 4 or 8 days after induction of arthritis, the latter group
receiving a second injection of antibodies on day 4. The devel-
opment of arthritis was followed by measuring technetium-
99m (Tc) uptake in the knees on days 1, 3, and 7 after intra-
articular mBSA injection as previously described .
K/BxN serum transfer-induced arthritis
Arthritic K/BxN mice were obtained by crossing K/B mice with
NOD/Lt (N) animals. Arthritic adult K/BxN mice were bled and
the sera were pooled. Recipient C57BL/6 mice were injected
with pooled serum (100 μl of serum i.p. on days 0 and 6). The
monoclonal anti-JAM-C antibody H36 or an isotype-matched
control antibody (9B5) was injected (150 μg/mouse, i.p.) 1
hour before the first injection of serum on day 0 and then again
on days 4 and 8. Mice were sacrificed on day 13. The devel-
opment of arthritis was assessed daily, and the severity of
arthritis was scored in a blinded fashion for each paw on a 3-
point scale, in which 0 = normal appearance, 1 = localized
edema/erythema on one digit or over one surface of the paw,
2 = edema/erythema involving more than one surface of the
paw, and 3 = marked edema/erythema involving the whole
paw. The scores of all four paws were added for a composite
Histological grading of arthritis
At sacrifice, the knees (AIA) or the paws (K/BxN serum trans-
fer-induced arthritis) were dissected and fixed in 10% buffered
formalin for 7 days. Fixed tissues were decalcified for 3 weeks
in 15% EDTA (ethylenediaminetetraacetic acid), dehydrated,
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tion, as in AIA, the inhibitory effect of anti-JAM-C antibodies
occurred when mice were treated after sensitization and
before challenge, thus indicating that JAM-C interferes with
the effector phase and not the initial antigen presentation .
JAM-C is expressed on synovial and other types of fibroblasts,
fibroblastic reticular cells of lymph nodes, and smooth muscle
cells [10,23]. All these cells have in common an immunoregu-
latory function, and the role of fibroblastic cells in the establish-
ment and maintenance of micro-environmental 'niches'
contributing to inflammatory diseases, including RA, has been
extensively discussed in recent reports [29-31]. Though spec-
ulative, one could imagine that anti-JAM-C treatment delivers
signals to mesenchymal cells, which in turn control the out-
come of the immune response by modulating expression of
adhesion molecules, chemokines, and cytokines . Such a
hypothesis is in agreement with recent findings showing that
anti-JAM-C treatment decreases inflammation in various
mouse inflammatory models such as cerulein-induced pancre-
atitis, thioglycollate-induced peritonitis, or allergic contact der-
matitis [11-13] and that the protein may be involved in other
diseases such as obstructive nephropathy or atherosclerosis
[10,33]. An alternative explanation for the systemic pro-inflam-
matory function of JAM-C relates to its active role in favoring
diffusion of small molecules across the paravascular space.
Indeed, we have previously shown that the enrichment of the
protein at interendothelial cell-cell contacts correlates with
increased paracellular permeability and is induced by factors
inducing vascular leakage such as vascular endothelial growth
factor (VEGF) [20,34]. These results have been confirmed in
a recent study showing that antagonizing JAM-C function
results in inhibition of increased vascular permeability induced
by VEGF or histamine . Thus, it is possible that treatment
of arthritic mice with the anti-JAM-C antibody results in
decreased diffusion of inflammatory mediators in the blood,
inducing a systemic immunosuppressive effect. Although this
attractive hypothesis requires more investigation, our results
uncover a link between JAM-C expression in arthritic lesions
and local and systemic anti-inflammatory effects of an antibody
directed against this protein.
There is accumulating evidence that leukocyte trafficking to
the inflamed synovium is adhesion molecule-dependent, and
the blocking adhesion molecules that mediate the accumula-
tion of leukocytes in inflammation can thus be expected to
have therapeutic potential in human RA. However, the few clin-
ical trials performed so far have not met expectations. For
instance, efazulimab, a humanized monoclonal antibody
against LFA-1, did not significantly reduce arthritis in a cohort
of patients with psoriatic arthritis . Anti-ICAM-1 (intracellu-
lar adhesion molecule-1) monoclonal antibodies have been
evaluated in a phase I/II open-label study and had only limited
effects in patients with RA . Finally, a randomized, pla-
cebo-controlled trial of an antisense oligodeoxynucleotide
ICAM-1 inhibitor could not demonstrate clinical efficacy
beyond that of placebo in patients with active RA . Among
the possible explanations for this low efficacy are the redun-
dancy and overlapping functions of molecules that are
involved in leukocyte extravasation, due to which selective inhi-
bition of single adhesion molecules might not be sufficient to
efficiently prevent leukocyte recruitment. In the present study,
we observed that treatment with an anti-JAM-C antibody
induced anti-inflammatory effects, which seem to extend
beyond local inhibition of leukocyte adhesion. This observation
fits with the concept that the signaling activity of adhesion
molecules, in addition to their adhesive properties, may be
important for their function.
JAM-C is highly expressed by synovial fibroblasts in RA. Treat-
ment of mice with an anti-JAM-C antibody significantly
reduced the severity of AIA and delayed the onset of serum
transfer-induced arthritis, suggesting a role for JAM-C in the
pathogenesis of arthritis.
The authors declare that they have no competing interests.
GP, NB, and MA-L performed the experiments, designed the
study, and drafted the manuscript. DT-A, VC-P, CZ, and PH
performed the experiments. BAI and CG designed the study
and drafted the manuscript. All authors read and approved the
final manuscript. GP and NB contributed equally to this work.
KRN mice were kindly provided by Diane Mathis and Christophe Benoist
through the Institut de Génétique et de Biologie Moléculaire et Cellulaire
(Strasbourg, France). This work was supported by Swiss National Sci-
ence Foundation grant 3200-107592/1 (to CG), grant 3200-067231
(to NB), grant 310000-112551/I (to MA-L), and grant 3100AO-
10069712 (to BAI), by the Krebsforschung Schweiz (grant to BAI), and
by the Thorn Foundation (grant to MA-L).
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