Autoimmunity Reviews 9 (2010) 207210

Contents lists available at ScienceDirect

Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev

The Wnt signaling pathway and rheumatoid arthritis

Francieli de Sousa Rabelo a, Licia Maria Henrique da Mota a,, Rodrigo Aires Corra Lima a,
Francisco Aires Corra Lima a, Gustavo Barcelos Barra b, Jozlio Freire de Carvalho c,
Anglica Amorim Amato d
a

Department of Rheumatology, University Hospital of Braslia, Braslia, Brazil

Sabin Laboratory of Clinical Analysis, Braslia, Brazil
Department of Rheumatology, University of So Paulo School of Medicine, Hospital das Clnicas, So Paulo, Brazil
d
Department of Endocrinology, University Hospital of Braslia, Braslia, Brazil
b
c

a r t i c l e

i n f o

Article history:
Received 16 July 2009
Accepted 2 August 2009
Available online 13 August 2009
Keywords:
Rheumatoid arthritis
Wnt proteins
Frizzled receptors

a b s t r a c t
The Wnt signaling pathways play a key role in cell renewal, and there are two such pathways. In patients with
rheumatoid arthritis (RA), the synovial membrane expresses genes such as Wnt and Fz at higher levels than those
observed in patients without RA. The Wnt proteins are glycoproteins that bind to receptors of the Fz family on the
cell surface. The Wnt/Fz complex controls tissue formation during embryogenesis, as well as throughout the
process of limb development and joint formation. Recent studies have suggested that this signaling pathway
plays a role in the pathophysiology of RA. Greater knowledge of the role of the Wnt signaling pathway in RA could
improve understanding of the differences in RA clinical presentation and prognosis. Further studies should also
focus on Wnt family members as molecular targets in the treatment of RA.
2009 Elsevier B.V. All rights reserved.

Contents
1.
Introduction . . .
2.
The Wnt signaling
3.
The Wnt signaling
4.
Conclusions . . .
Take-home messages .
References . . . . . .

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pathway . . . . . . . . . . . .
pathway and rheumatoid arthritis
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1. Introduction
Rheumatoid arthritis (RA) is a chronic and progressive systemic
inammatory disease of unknown etiology. Primarily affecting the
synovial membrane, RA can lead to bone and cartilage destruction.
Other systems may also be occasionally affected. It is a common
condition (RA occurs in 0.51.0% of the world population, and,
depending on the age group being investigated, the prevalence can be
as high as 5%), and affects all ethnic groups [1].
The progressive character of RA makes it a potentially disabling
disease that affects quality of life and life expectancy of patients; in
addition, RA takes a signicant toll on society and economy, in the

JF carvalho received a grant from Federico Foundation.

Corresponding author. SHIS QI 23 Conjunto 02 Casa 09, 71660-020 Lago Sul, Braslia
DF, Brazil. Tel.: +5561 3208 5568.
1568-9972/$ see front matter 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2009.08.003

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form of medical expenses, decreased work productivity and early

retirement due to disability [2].
In recent decades, there have been notable advances toward a
deeper understanding of the pathophysiology of RA. This better
understanding has led to changes in the approach to and management
of the disease. The initial phase of the disease (lasting 12 months,
according to most authors), known as early RA, is a period of time
in which the initiation of appropriate treatment results in marked
clinical improvement; therefore, early diagnosis and treatment can
change the course of the disease. Laboratory and imaging methods
that can diagnose RA early and determine the prognosis of the disease
have been developed [3]. In addition, there have been signicant
changes in the therapeutic approach to the disease, with new classes
of drugs coming into use [4].
Despite these advances, delays in diagnosis and in the initiation of
appropriate treatment, as well as the difculty in managing drug treatment regimens during patient follow-up, continue to be obstacles to

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F.S. Rabelo et al. / Autoimmunity Reviews 9 (2010) 207210

obtaining a favorable therapeutic response. The diagnostic and

prognostic markers that are currently available (clinical, radiographic
and laboratory markers) have a limited value in establishing an early
diagnosis and an individual prognosis, thereby limiting the therapeutic
effects of the medications available [5]. A better understanding of the
genetic and pathophysiological factors related to the disease would be of
great value in identifying treatments that are more effective and in
initiating such treatments in a timely manner.
2. The Wnt signaling pathway
The Wnt gene was originally identied as a segment polarity gene
in Drosophila melanogaster, and its function is linked to embryogenesis
and adult limb formation during metamorphosis [6].
Approximately 25 years ago, Nusse and Varmus identied the int-1
gene as the site of mouse mammary tumor virus (MMTV) integration
[7]. Subsequently, the int-1 gene and the so-called wingless gene were
found to be homologous in Drosophila spp., and the name Wnt was
coined as a combination of wingless and int [8].
The Wnt signaling pathway plays a key role in cell renewal. There are
two Wnt signaling pathways, known as the canonical (beta-catenindependent) and noncanonical (beta-catenin-independent) pathways
[9].
The canonical Wnt pathway begins with the binding of Wnt to a
receptor of the Fz family and to co-receptors known as low-density
lipoprotein receptor-related protein 5 (LRP5) and low-density
lipoprotein receptor-related protein 6 (LRP6). This bond promotes
signal transduction via cytoplasmic proteins: glycogen synthase
kinase 3 beta (GSK-3); axin 1; adenomatous polyposis coli (APC);
dishevelled, dsh homolog 1 (Drosophila) (DVL1); casein kinase 1,
alpha 1 (CSNK1A1); and beta-catenin [9].
In resting cells, GSK-3 forms a complex with axin 1, APC, CSNK1A1
and beta-catenin. In the absence of Wnt signaling, the cytoplasmic levels
of beta-catenin are low, because beta-catenin is rst phosphorylated
by GSK-3 and subsequently degraded by the proteolytic activity of
beta-transducing repeat containing protein (-Trcp) [9].
In WntFz/LRP signaling, DVL1 (the key component of the
membrane associated with the Wnt receptor complex) is activated,
leading to the inhibition of the complex of proteins formed by axin 1,
GSK-3 and APC, resulting in the recruitment of axin 1 to the plasma

membrane. This leads to the dissociation and inactivation of GSK-3,

and no beta-catenin phosphorylation occurs. The accumulated betacatenin enters the nucleus, where it binds to the lymphoid enhancer
binding factor (LEF)/T-cell factor (TCF) transcription factors, causing
the transcription of certain genes [9].
There are various inhibitors of the canonical Wnt signaling, e.g.,
the proteins of the Dickkopf family and the secreted Fz-related
proteins (collectively also known as frizzled-related proteins), which
inhibit the WntFz interaction and attenuate Wnt signaling [9].
Studies have suggested that in the noncanonical Wnt pathway, the
Wnt-type MMTV integration site family, member 5A (Wnt5A)
initiates the signaling cascade, most likely mediated by DVL1,
resulting in the liberation of intracellular Ca+2 and in the activation
of calcium/calmodulin-dependent protein kinase II alpha (CAMK2A)
and of protein kinase C (PKC) [10]. The signaling mediated by Wnt5A
also promotes PKC activation, which in turn activates of NF-B
transcription factors. The latter induce the expression of various genes
encoding proinammatory cytokines/chemokines [9].
Another form of noncanonical pathway signaling can occur via the
planar cell polarity pathway, which regulates the organization of the
cytoskeleton [9,11]. The proteins Rac and Rho, members of the small
GTPase family, are activated by DVL1, stimulating the activation of
mitogen-activated protein kinase 8, and Rho kinase, which are
involved in cell differentiation and growth [9,12].
Approximately 20 Wnt proteins and more than 12 Fz proteins
have been identied. The exact Wnt/Fz ligandreceptor pairs remain
unknown, since Wnt proteins can interact with multiple Fz receptors
[9]. Therefore, the nal result of the signaling, which has a direct
effect on the pathogenesis of rheumatoid arthritis, depends on the
type of Wnt/Fz complex, the signaling site and the pathway involved
(Fig. 1).
3. The Wnt signaling pathway and rheumatoid arthritis
Normal synovial membrane contains macrophage-like synoviocytes, which derive from the bone marrow, and broblast-like
synoviocytes (FLS), which derive from the mesenchyme. In longstanding RA, activation and proliferation of FLS produce cytokines and
chemokines, such as interleukin (IL)-6, IL-8 and IL-15, as well as
extracellular matrix proteins, such as cell adhesion molecules, leading

Fig. 1. The Wnt signaling pathways: noncanonical (left); canonical (center); and Ca+ 2 (right). AP1: activator protein 1; CAMK2A: calcium/calmodulin-dependent protein kinase II alpha;
PKC: protein kinase C; LRP5: low-density lipoprotein receptor-related protein 5; LRP6: low-density lipoprotein receptor-related protein 6; GSK-3: glycogen synthase kinase 3 beta; APC:
adenomatous polyposis coli; DVL1: disheveled, dsh homolog 1 (Drosophila); CSNK1A1: casein kinase 1, alpha 1; RhoA: ras homolog gene family, member A; MAPK8: c-Jun N-terminal
kinase; ILs: interleukins; MAP3K7: mitogen-activated protein kinase 7; NLK: nemo-like kinase; NFAT: nuclear factor of activated T-cells; NF-B: nuclear factor-kappa B.
Adapted form Kikuchi A. Multiplicity of the interactions of Wnt protiens and their receptors Cellular Signaling 2007;19:659-671.

F.S. Rabelo et al. / Autoimmunity Reviews 9 (2010) 207210

to the inltration and retention of leukocytes, as well as to angiogenesis, resulting in pannus formation and therefore destroying
articular cartilage and bone. In addition, FLS secrete metalloproteins
that, in their mature form, contribute to cartilage degradation and
tissue invasion [13,14].
In patients with RA, the synovial membrane expresses higher
levels of genes such as Wnt and Fz than it does in patients without RA
[14]. The Wnt proteins are glycoproteins that bind to receptors of the
Fz family proteins on the cell surface. The Wnt/Fz complex controls
tissue formation during embryogenesis, limb development and joint
formation [9].
The activation of Wnt signaling contributes to osteophyte formation
and might be related to the anabolic model in joint remodeling observed
in patients with ankylosing spondylitis, whereas the blockade of Wnt
signaling facilitates bone erosion and might contribute to the catabolic
model in the bone remodeling observed in patients with RA [15]. The
activation of the Wnt/beta-catenin signaling in the chondrocytes
induces cartilage matrix degradation similar to that which occurs in
osteoarthritis and RA [16].
Nakamura et al. found that there was a signicant upregulation of
Wnt7B in the cartilage of osteoarthritis patients and in the synovium of
RA patients; when the authors transferred Wnt7B in the chondrocytes
and synovial cells to control patients, they observed and increased
expression of the proinammatory cytokines tumor necrosis factoralpha, IL-1B and IL-6, all of which are known to play a role in the
pathogenesis of RA [17].
Cheon et al. reported that the expression of Wnt1-inducible
signaling pathway protein 3 (WISP3) is greater in the synovium of RA
patients than in that of osteoarthritis patients or that of control
individuals without rheumatic diseases, and that WISP3 is induced in
vitro by proinammatory cytokines [18]. Polymorphisms in WISP3 are
related to susceptibility to polyarticular juvenile idiopathic arthritis [19].
Sen et al. studied the function of Wnt5A, the signaling of which
occurs via noncanonical pathway (PKC), in the activation of FLS,
which results in the production of proinammatory chemokines in
the joints of RA patients [20]. The authors found that blockade of
Wnt5A/Fz homolog 5 (Drosophila) signaling decreases the expression
of IL-6, IL-15 and receptor activator of nuclear factor-kappa B ligand,
as well as decreasing the activation of synoviocytes [20].
The Wnt1-induced signaling of Wnt proteins is known to promote
cell adhesion, growth and survival. In RA patients, Wnt1 is overexpressed, stimulating the production of bronectin and pro-matrix
metalloproteinase-3 [14].
Various studies have suggested that Wnt signaling increases bone
formation by regulating the proliferation and differentiation of
osteoblasts and osteoclasts [8,2123]. The removal of beta-catenin
from the progenitor cells of osteoblasts prevents the differentiation of
osteoblasts that express osteocalcin. In addition, Wnt signaling can
promote upregulation of the expression of osteoprotegerin in
osteoblasts. Since osteoprotegerin inhibits the differentiation of
osteoclasts, Wnt signaling can partially increase bone mass by
inhibiting osteoclast-mediated bone resorption [21].
There are other extracellular proteins that modulate Wnt/betacatenin signaling activity. Such proteins can interact with Wnt, Fz,
LRP5 and LRP6, either activating or inhibiting signaling. Several of
these proteins play key roles in regulating bone formation and bone
resorption. The proteins of the Dickkopf family, the Wise protein and
sclerostin (the product of the SOST gene), regulate Wnt/beta-catenin
signaling [2224]. Dickkopf homolog 1 (Xenopus laevis) (DKK1) is a
soluble inhibitor of Wnt/beta-catenin signaling; DKK1 inhibits Wnt/
beta-catenin signaling by binding to the Wnt co-receptor LRP5.
Increased DKK1 levels promote increased bone resorption, whereas
decreased DKK1 levels promote increased bone formation. Mutations
in LRP5 cause syndromes characterized by high bone mass. Osteoporosis mediated by estrogen and glucocorticoid deciency is probably
related to the activation of DKK1 in osteoblasts [22,25,26].

209

The Wnt signaling pathway is also involved in lipid metabolism

and glucose homeostasis, and LRP5 mutations can lead to the development of diabetes and obesity [27].
Polymorphisms in LRP5 have been linked to obesity, whereas LRP6
mutations have been linked to the risks of bone loss, coronary disease
and metabolic syndrome. In addition, Wnt5B polymorphisms have
been linked to the risk of type 2 diabetes [27].
Among the proteins involved in the Wnt/beta-catenin signaling
pathway, transcription factor 7-like 2 (TCF7L2) has been the subject of
recent studies involving human diseases. Within the Wnt signaling
pathway, TCF7L2, also known as TCF-4, acts as a nuclear receptor of
beta-catenin [28].
Recent studies have demonstrated that genetic variants of TCF7L2
correlate with susceptibility to type 2 diabetes [2937]. The aberrant
expression of TCF7L2 has also been linked to the risk of cancer [3840].
Grant et al. found the T allele of the TCF7L2 gene polymorphism
rs7903146 to be correlated with type 2 diabetes in Denmark, the USA
and Iceland [29,30]. The same correlation was found among populations in Europe, Scandinavia, East Asia and West Africa [3137].
The T allele of the TCF7L2 gene polymorphism rs7903146 also
seems to play a role in the incidence of malignant neoplasm by
regulating cell proliferation. Agalliu et al. investigated the T allele of
the TCF7L2 gene in terms of its relationship with prostate cancer and
reported that, although the genotype did not increase the risk of
developing prostate cancer, it did seem to be correlated with a risk of
the disease being more aggressive when present [38]. The TCF7L2
gene polymorphism rs7903146 has also been linked to an increased
risk of non-diabetes-related colon cancer [39], as well as of familial
breast cancer [40].
The mechanisms by which the T allele of rs7903146 in TCF7L2
gene inuence type 2 diabetes and malignant neoplasm susceptibility have yet to be investigated. Considering that the two diseases
have in common the inammatory response (and the role of the Wnt/
beta-catenin signaling pathway in this response), the TCF7L2 gene
might be related to the clinical presentation of RA and comorbidities,
as well as being a marker of disease severity, with potential clinical
application. Further studies should be carried out in order to
investigate this issue.
4. Conclusions
The Wnt signaling pathway plays a role in organogenesis, bone
formation, bone resorption and tumorigenesis. Recent studies have
suggested the role of the Wnt signaling pathway in the pathophysiology of RA. A better understanding of the role of the Wnt signaling
pathway in RA can improve understanding of the differences in
clinical presentation and prognosis of the disease. In addition, further
studies investigating RA treatment are warranted and these studies
should also focus on the members of the Wnt family as molecular
targets in the treatment of RA.
Take-home messages
The Wnt/Fz signaling pathway plays a role in embryogenesis, bone
homeostasis, and tumor development, and has been recently suggested to be involved in glucose homoeostasis.
Studies have suggested that molecules of the Wnt pathway may
play a role in the pathophysiology of RA, since increased expression
of Wnt genes being found in the synovial membrane of RA patients.
Experimental blockade of the Wnt signaling pathway reduces the
expression of interleukins and receptor activator of nuclear factorkappa B (NF-B) ligand in RA synoviocytes.
The study of the Wnt signaling pathway can greatly aid in characterizing the clinical spectra of RA and possibly in establishing RA
prognosis.

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F.S. Rabelo et al. / Autoimmunity Reviews 9 (2010) 207210

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Detection of autoantibodies against cyclophilin A and triosephosphate isomerase in sera from breast cancer patients by proteomic analysis
Much interest is presently being shown toward identifying markers for the detection of breast cancer. To detect autoantibodies that could represent
diagnostic markers for breast cancer, Tamesa MS. et al. (Electrophoresis 2009; 30: 216881) comprehensively analyzed serum autoantibodies
showing immuno-reactivity to proteins in tumor tissues of breast cancer. Tumor tissues were obtained from 40 patients with breast cancer, along
with sera from 30 other patients with breast cancer and 22 healthy donors. Proteins from tumor tissues were separated by 2-DE. After blotting onto
PVDF membranes, tissue proteins were immunoblotted with sera from patients or healthy donors. By comparing each immunoblot pattern, three
immuno-reactive spots displayed stronger staining intensity with patient sera than with sera from healthy donors. The matched protein spots on
2-DE gels were digested and used for LC-MS/MS analysis, and identied as cyclophilin A (peptidyl-prolyl cis-trans isomerase A), triosephosphate
isomerase and ubiquitin-conjugating enzyme E2N. Immunoblot analysis was then performed using commercially available puried proteins,
conrming the specicity of anti-cyclophilin A and anti-triosephosphate isomerase antibodies in sera from patients.

High-dose dexamethasone inhibits BAFF expression in patients with immune thrombocytopenia

B-cell activating factor belonging to the TNF family (BAFF) is elevated in several autoimmune diseases including immune thrombocytopenia (ITP).
High dose dexamethazone (HD-DXM) has shown its clinical efficacy in ITP patients. In this study, Zhu XJ. et al (J Clin Immunol 2009; 29: 60310)
the plasma BAFF concentration and mRNA were measured in ITP patients before and after oral administration of 40 mg/day DXM for four
consecutive days by ELISA and RT-PCR. Moreover, the authors evaluated the effects of DXM on BAFF expression and proliferation of lymphocytes
by ELISA, RT-PCR and cell proliferation respectively in in-vitro experiment. Both plasma BAFF concentration and BAFF mRNA were signicantly
increased in active ITP patients at pre-therapy when compared with controls (pb 0.001). After 4-day treatment with HD-DXM, the BAFF and BAFF
mRNA were decreased, and lower than that for controls. In in-vitro assays, DXM was found to inhibit BAFF, IFN-gamma expression, and the
proliferation of lymphocytes in a dose-dependent manner. These results suggest that BAFF expression is increased in ITP patients with active
disease, and DXM is an effective inhibitor of BAFF production. As immunosuppressant, DXM may play its role in ITP treatment partly through
regulating BAFF expression.