Wnt signalling in rheumatoid arthritis
M. Sen
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663, USA.
Correspondence to: E-mail: msen{at}ucsd.edu
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Abstract
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Rheumatoid arthritis (RA) is a symmetrical polyarticular disease of unknown aetiology that affects primarily the diarthrodial joints. Characteristic features of RA pathogenesis are synovial hyperplasia and inflammation accompanied by cartilage loss and joint destruction. Synovial hyperplasia and inflammation are a consequence of an increase in the macrophage-like and fibroblast-like synoviocytes of the synovial intimal lining associated with infiltration of leucocytes into the subintimal space. Although therapeutic interventions are available, the disease persists despite therapy in a significant fraction of patients. Several lines of evidence have substantiated a crucial role of activated fibroblast-like synoviocytes (FLS) during RA pathogenesis. The hyperplastic FLS population potentially promotes leucocyte infiltration and retention. The rheumatoid synovium eventually transforms into a pannus that destroys articular cartilage and bone. There are no approved drugs that are known to target the FLS in RA, and the underlying mechanisms driving FLS activation remain unresolved. In this review, the importance of Wntfrizzled (Fz)-mediated signalling in the autonomous activation of FLS is discussed. Anti-Wnt/anti-Fz antibodies, Fz receptor antagonists or small-molecule inhibitors of WntFz signalling might be useful for therapeutic interventions in refractory RA.
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Overview of RA pathogenesis
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The normal synovial membrane comprises an intimal lining of two or three layers of macrophage-like and fibroblast-like synoviocytes embedded in a dense extracellular matrix. The development of rheumatoid arthritis (RA) is associated with hyperplasia and inflammation of the synovium. The cause is not known, but it is quite likely that the unique anatomical and physiological features of diarthrodial joints render them targets for RA. Activation/proliferation of synoviocytes, infiltration and retention of leucocytes and angiogenesis lead to the formation of an invasive pannus that destroys articular cartilage and bone [16].
The macrophage-like/fibroblast-like synoviocytes, dendritic cells and activated lymphocytes of the rheumatoid synovium coordinate antigen presentation and the induction of immune responses [17]. It is generally believed that antigen-driven immune responses lead to affinity maturation and terminal differentiation of the synovial B lymphocytes to become antibody-secreting plasma cells [813]. There is, however, no evidence of a particular antigen that drives the disease. A variety of antigens, both foreign and autologous, could in varying degrees contribute to the course of the disease. Autologous antigens, which are targets for antibody-mediated capture, are potentially generated from damaged joint tissues and apoptotic cells in response to joint injury, either prior to disease initiation or during its course. Antibodies bind to articular antigens, such as type II collagen and proteoglycans. High-affinity autoantibodies known as rheumatoid factor (RF) also recognize the Fc portion of IgG as antigen [14]. A characteristic feature of RA is the presence of antibodies directed towards citrulline, generated by post-translational deimination of arginine residues of proteins by peptidyl arginine deiminase [2]. Increased antigenantibody complex formation within the synovium enhances activation of the complement cascade, thus exacerbating inflammation. Although the appearance of the chronically inflamed synovium varies from patient to patient, the presence of infiltrating lymphocytes is a fairly constant feature in the great majority of RA patients with active disease [14]. The lymphocyte infiltrates are often diffuse, lacking a structural organization, with scattered B cells, T cells and antibody-secreting plasma cells interspersed among fibroblast-like and macrophage-like synoviocytes that could potentially promote lymphocyte activation/proliferation and plasma cell differentiation [14]. In about 20% of patients, however, the infiltrates are organized into large follicle-like germinal centres [14, 1013]. The chronically inflamed synovium continuously releases a number of pro-inflammatory cytokines, chemokines, metalloproteases and angiogenic regulators, which perpetuate the inflammatory response and cartilage/bone destruction. Extra-articular manifestations, including pleuritis, pericarditis and vasculitis, contribute to morbidity and mortality in the long-standing disease [14].
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Role of fibroblast-like synoviocytes in RA pathogenesis
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Although much knowledge has been gained with respect to mediators of disease pathogenesis and prognosis, the precise molecular mechanisms orchestrating and guiding sustained synovial hyperplasia and inflammation in RA have not been deciphered. Much attention has been focused on the RA fibroblast-like synoviocytes (FLS) in this regard [17, 1419]. The hyperplastic FLS population produces cytokines and chemokines such as IL-6, IL-8, IL-15 and stromal cell derived factor 1 (SDF-1), which can promote infiltration and activation of lymphocytes in the synovium. In addition, the FLS synthesize extracellular matrix proteins such as fibronectin and cell adhesion molecules such as VCAM-1, which can facilitate lymphocyte recruitment and retention. The ability of FLS to foster differentiation of B lymphocytes to plasma cells has already been demonstrated [16]. FLS also make matrix metalloproteinases such as pro-MMP3 (precursor form of MMP3 or stromelysin 1), which in its mature form enhances cartilage degradation [14]. FLS thus promote immune responses to antigens generated by continual degradation of articular cartilage. FLS have also been suggested to promote angiogenesis via expression of SDF-1 and other endothelial growth factors, such as fibroblast growth factor (FGF) and VEGF [16, 17]. There is evidence that FLS participate in osteoclastogenesis, a pivotal mediator of bone erosion in RA. Receptor activator of NF
B ligand (RANKL), which is expressed mainly on FLS and T cells, interacts with the cognate receptor RANK expressed on monocytes, initiating osteoclast differentiation and bone resorption [18, 19]. FLS thus form and operate as part of an invasive pannus that perpetuates joint destruction.
In the light of the fact that FLS share some attributes of stem cells [20, 21], it is conceivable that they promote synovial hyperplasia as part of a compensatory cell renewal mechanism in response to cell death as a result of joint damage or stress. A part of the hyperplastic FLS population perhaps arises from facilitated migration of mesenchymal stem cells/stromal cells from either the bone marrow directly through vascular channels or indirectly via the blood circulation. Although vascular channels connecting bone marrow to the synovium remain to be identified in RA patients, such channels have been observed in mice with collagen-induced arthritis [22]. Activated FLS could thus operate in setting the stage for chronic inflammation in the synovium and subsequent cartilage/bone erosion.
FLS activation: Is the Wntfrizzled system a mediator?
Mechanisms of gene induction in RA FLS have been studied [13]. Several reports have indicated that the transcriptional activator NF
B is a major inducer of cytokines/chemokines and adhesion molecules in RA FLS. Mitogen-activated protein (MAP) kinases [extracellular signal regulated kinase (ERK), Jun kinase (JNK) and p38 kinase] that regulate the production of various cytokines/growth factors and metalloproteinases are also known to be functional in RA FLS [2, 3]. The precise molecular mechanisms leading to the activated phenotype of FLS in the rheumatoid joint have, however, eluded definitive analysis. Based on the known attributes of Wntfrizzled (Fz) signalling, one might rationalize that the WntFz system is partly responsible for driving RA FLS activation. The complex WntFz system controls tissue patterning throughout embryogenesis, and plays a critical role in limb development and joint formation [2325]. Wnt comprises a family of secreted glycoprotein ligands that bind to a family of cell surface receptors, termed Fz, to initiate intracellular signalling cascades that culminate in cell differentiation and growth [2325]. WntFz signalling cascades could thus participate in initiating an activated FLS phenotype in a process of cell/tissue sustenance after joint injury or stress. Elevated signalling mediated by WntFz homologues in adult tissues has recently been associated with various forms of proliferative disorders [25]. It is quite possible that untimely activation of WntFz signalling in FLS leads to inappropriate accumulation of activated kinases, transcription factors and cell growth/differentiation factors, thereby directing FLS activation and RA pathogenesis.
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WntFz signal transduction pathways
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The Wnt and Fz family genes were first characterized in Drosophila. Over the years, studies performed on WntFz signalling in mammalian systems have yielded a plethora of information regarding signalling intermediates and regulators [2325]. Mammals express 19 different Wnt protein ligands and 12 or more Fz receptors. Wnt are secreted glycoproteins and protein Fz proteins resemble the seven transmembrane-spanning G protein-coupled receptor family proteins [2325]. It has been demonstrated that chimeric receptors containing the intracellular loops of rat Fz1 or Fz2 and the transmembrane and extracellular regions of the ß-adrenergic receptor signal through the Go, Gq and Gt classes of G proteins when activated by ß-adrenergic receptor agonists [25, 26]. It has, however, not yet been tested if natural Fz receptors in mammals signal through heterotrimeric G proteins upon activation by natural Wnt ligands. The signal transduction cascades initiated by WntFz interactions are complex, signals being orchestrated intricately by several extracellular, cytoplasmic and nuclear regulators. The consequences of WntFz-mediated signalling are diverse: these include cell differentiation, cell proliferation/survival, cell migration and cell adhesion [2325]. Wnt signalling pathways are commonly recognized as the canonical (ß-catenin-dependent) and non-canonical (ß-catenin-independent) pathways.
Wnt/ß-catenin-mediated signalling
Most reports so far have been from studies on ß-catenin-dependent Wnt signalling. A simplified version of this signalling pathway is presented in Fig. 1. Wnt proteins such as Wnt1, upon being related protien released from cells, act on the Fz/low-density lipoprotein receptor protein (LRP) complex on the surfaces of the target cells [25]. The subsequent signal transduction cascade involves several intracellular proteins, including dishevelled (Dvl), casein kinase 1 (CK1), axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3ß (GSK3ß) and ß-catenin. In resting cells, ß-catenin is phosphorylated by GSK3ß while it is assembled in a multiprotein complex with CK1, axin and APC, and targeted for ubiquitination-dependent proteolysis by the proteasome. Upon WntFz signalling, Dvl activation and concomitant dissociation of the multiprotein complex leads to inactivation of GSK3ß, resulting in accumulation of ß-catenin in the cytoplasm. Excess free cytoplasmic ß-catenin translocates to the nucleus and binds to lymphoid enhancer binding factor (LEF)/T-cell factor (TCF) transcription factors, causing transcriptional activation of target genes [25].

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FIG. 1. Wnt/ß-catenin signalling pathway. In resting cells, GSK3ß is in a complex with CK1 , ß-catenin, axin and APC. In this state, ß-catenin is primed for phosphorylation by GSK3ß. The phosphorylated ß-catenin is degraded by ubiquitination, which involves interaction with ß-Trcp. In the activated state (upon Wnt binding to Fz), WntFz and LRP coordinate Dvl (dishevelled, an adaptor protein) activation, which results in recruitment of axin to the plasma membrane. This leads to dissociation and inactivation of GSK3ß, which can no longer phosphorylate ß-catenin. Free ß-catenin translocates to the nucleus and induces gene expression in a complex with LEF/TCF family transcription factors.
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In colon cancer cells, nuclear translocation of ß-catenin is responsible for the transcriptional up-regulation of myc, cyclin D1 and other genes that promote cell proliferation [25]. In Xenopus, LEF/ß-catenin-mediated transcription regulates the production of the extracellular matrix protein fibronectin, which is important for cell adhesion and survival [27]. There is also evidence that the ERK family kinases, which participate in several cell differentiation programmes, are activated by ß-catenin-mediated signalling [28].
Several physiological inhibitors of canonical Wnt signalling have been identified. Secreted frizzled-related protein (s-FRP) homologues, also collectively known as FRZB, which bear homology to the extracellular cysteine-rich region of Fz proteins, block WntFz interactions and attenuate WntFz signalling [29, 30]. It has, however, been postulated that s-FRPs can also promote long-term Wnt signalling in certain instances through binding to Wnt proteins and protecting them from degradation [30]. Other inhibitors of the canonical Wnt pathway are the dickopf (DKK) family proteins, which block signalling upon binding to LRP homologues [31].
ß-catenin-independent Wnt signalling
Simple schemes of the ß-catenin-independent non-canonical Wnt signalling pathways are depicted in Fig. 2. Several reports have suggested that in the non-canonical Wnt/Ca2+ pathway, Wnt proteins such as Wnt5a initiate a signalling cascade that results in release of intracellular Ca2+, and activation of the calcium-sensitive enzymes calmodulin kinase II (CamKII) and protein kinase C (PKC) in a ß-catenin-independent manner [32, 33]. Recent observations suggest that Dvl is required for Ca2+ release and activation of CamKII and PKC [33]. Our experimental observations suggest that Wnt5a-mediated signalling also promotes activation of the transcription factors NF
B (M. Sen, unpublished observation). In the light of the suggested link between PKC activation and NF
B-induced gene expression [34, 35], one might conceive that Wnt5a-mediated activation of PKC contributes to transcriptional activation of NF
B-responsive genes such as those encoding the various pro-inflammatory cytokines/chemokines mentioned earlier.

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FIG. 2. Wnt/Ca2+ signalling pathway and the planar cell polarity (PCP) Wnt pathway. Upon certain WntFz interactions, activation of the cytoplasmic protein Dvl (dishevelled) results in cytosolic Ca2+ increase. Subsequent activation of the Ca2+-sensitive enzymes CamKII and PKC leads to activation of transcription factors, including NF B and NFAT, and target gene induction. Upon other WntFz interactions, certain Dvl domains activate the small GTPases Rho and Rac, as in the Drosophila PCP pathway. This leads to activation of rho kinase (ROK) and Jun kinase (JNK). Subsequently, transcription factors, including those of the AP1 family, are activated and target genes are transcribed.
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Yet another aspect of WntFz signalling, different from the ß-catenin-mediated pathway, is the planar cell polarity (PCP) pathway, which is known to regulate cytoskeletal organization [33, 36, 37]. Here, Dvl-mediated activation of the Rac and Rho family of small GTPases stimulates the activation of kinases such as JNK and rho kinase (ROK), which participate in several cell growth and differentiation programmes [36, 37].
Specificity of Wnt signalling
The course of WntFz signalling, whether canonical or non-canonical, is perhaps dictated to a great extent by the relative densities of different Fz receptors on the cell surface and the relative concentrations of different Wnt ligands in the intercellular milieu. Although studies are being performed, not much is known yet about the specificity of WntFz interaction [25]. A specific WntFz pair is not likely to be the only ligandreceptor combination in a certain cell type, on account of considerable homology between different members of the Wnt and Fz families. It is rather interesting to note that Dvl is at the branching point of three different Wnt signalling pathways [25, 33, 36]. Perhaps Dvl adopts different conformations depending on the extent of phosphorylation, thus leading to the formation of different functional protein complexes in the divergent signalling pathways. Recently, it has been reported that Wnt proteins such as Wnt5a can also interact with transmembrane tyrosine kinase receptors (derailed in Drosophila and RYK/ROR in mammals) [25]. Thus, the final outcome of Wnt signalling probably depends on the cumulative effect of multiple ligandreceptor interactions and multiple pathways.
Intercellular transport of Wnt proteins
An important but less studied aspect of Wnt signalling is the mode of transport of Wnt proteins between cells after secretion. Wnt proteins are hydrophobic molecules post-translationally modified by palmitoylation at a conserved cysteine residue [25, 38]. Vesicle-mediated intercellular transport of Wnts have been characterized in Drosophila, but such a mechanism has not been identified in mammals yet [25, 39]. However, it seems likely that heparin sulphate proteoglycans, which enrich the extracellular matrix of many connective tissues, including cartilage and synovium, bind to Wnt and coordinate their movement between cells [40].
Functional significance of Wnt signalling
It appears that Wnt signalling is a key regulator in stem cell renewal [38, 41]. Wnt proteins are major components of mesenchymal stem cells/stromal cells, a heterogeneous population of fibroblast-like cells that support the growth, differentiation and survival of different cell lineages and cell types by providing cytokines/chemokines, adhesion molecules and extracellular matrix molecules [41]. It is thus not surprising that targeted disruption of Wnt signalling by loss-of-function mutations is linked to dramatic phenotypes, ranging from embryonic lethality to severe CNS, lung, kidney and limb defects [25]. Wnt knockout phenotypes in animal models can often be explained by loss of cell proliferation/renewal, cell differentiation, cell adhesion and migration. Misregulation of Wnt signalling in adults results in serious anomalies. Mutations in APC and ß-catenin that lead to overactive Wnt signalling have been linked to colon cancer [25]. Distinct functional variants of sFRP3 and LRP have, likewise, been linked to osteoarthritis (OA) and jaw/palate abnormalities, respectively [4244]. As described in the following sections, Wnt signalling has also been implicated in RA pathogenesis [4547].
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Role of WNTFZ signalling in RA pathogenesis
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Expression of Wnt and Fz homologues in RA synovial tissue and FLS
Several different Wnt and Fz homologues have been detected at the mRNA level in synovial tissue specimens obtained from joint replacement surgery [4547]. Expression levels of some of the Wnt and Fz homologues, such as Wnt1, Wnt5a and Fz5, have been found to be higher in RA synovial specimens than in the relatively less inflamed OA synovial specimens included in these studies [45]. The expression levels of Wnt1, Wnt5a and Fz5 are higher in RA synovial tissue specimens also when compared with most normal adult tissues, perhaps partly because of the hyperplastic nature of the RA synovium [45, 47]. The same Wnt and Fz homologues are also highly expressed in the FLS isolated from the RA synovium [4547]. Expression levels increase slightly upon exposure to TNF-
and IL-1 (M. Sen, unpublished observation), which happen to be important mediators of RA pathogenesis. Nevertheless, high levels of WntFz expression and function persist in RA FLS for several passages in vitro, independently of the added cytokines [4547]. This finding implies that WntFz-mediated effects in RA could be independent of TNF-
and IL-1. More detailed studies need to be performed in order to ascertain whether increased expression of WntFz homologues correlates with the development of a specific RA phenotype or is a general feature of synovitis. Differential expression of s-FRPs that often function as antagonists of Wnt signalling has been demonstrated in both RA synovia and FLS [48; M. Sen, unpublished observation]. However, the correlation of s-FRP expression with RA pathogenesis remains to be elucidated.
Wnt signalling in RA FLS
The role of FLS in the progression of inflammation and joint damage in RA is documented [13]. However, as mentioned previously, the underlying molecular mechanisms driving inflammatory signals in FLS have not been precisely delineated. This review focuses on our current understanding of Wnt5a/Fz5- and Wnt1-mediated signalling in FLS in the context of RA pathogenesis.
Wnt5a/Fz5-mediated signalling
There is accumulating evidence that Wnt5a-mediated signalling in RA FLS contributes significantly to induction of the pro-inflammatory cytokines/chemokines IL-6, IL-8 and IL-15, which are characteristic of chronic RA [45, 46]. Transfection of non-RA FLS expressing low level of Wnt5a with a Wnt5a expression vector up-regulates the expression of the cytokines/chemokines, and transfection of RA FLS with either an antisense Wnt5a or a dominant negative (dn) Wnt5a markedly diminishes their production. Wnt5a-mediated production of the cytokines/chemokines is at least partly induced by NF
B (M. Sen, unpublished observation), which is known to be activated in RA FLS [13]. Dn-Wnt5a supposedly functions as an antagonist of Wnt5a-mediated effects by sequestering Wnt5a-binding receptors at the cell surface. Administration of anti-Fz5 antiserum to RA FLS also diminishes expression of the cytokines/chemokines of interest [46].
Because the putative Wnt receptor Fz5 has been found to synergize with Wnt5a signalling in Xenopus embryos, one might rationalize that Wnt5a signals by binding to Fz5 on the surface of RA FLS via autocrine and/or paracrine mode(s) [46]. It is, however, also possible that Wnt5a and Fz5 converge on similar signalling intermediates independently of each other. Nevertheless, these findings suggest that during RA pathogenesis, Fz5 and Wnt5a signalling in FLS might participate in promoting proinflammatory cytokine/chemokine production, thus facilitating leucocyte infiltration and activation in the rheumatoid synovium. Such a notion is supported by recent findings that Wnt5a also promotes synthesis of the chemokine SDF-1 by RA FLS (M. Sen, unpublished observation). Recent data suggest that Wnt5a-mediated signalling could also promote angiogenesis by up-regulating the expression of the angiogenic regulator VEGF (M. Sen, unpublished observation). Whether Wnt5a also signals through ROR receptor(s) in RA FLS remains to be tested.
It has been demonstrated that treatment of RA FLS with anti-Fz5 antiserum results in diminished expression of RANKL, a mediator of osteoclastogenesis [46]. One might thus hypothesize that attenuation of RANKL production through disruption of Fz5 and/or Wnt5a/Fz5-mediated signalling in FLS could inhibit osteoclastogenesis and bone erosion during RA pathogenesis.
Wnt1-mediated signalling
Constitutive activation of the TCF-responsive reporter gene TOP-flash by RA FLS suggests that the canonical Wnt1-like signalling pathway is constitutively active in RA FLS [47]. Recent reports also indicate that Wnt1-mediated signalling regulates fibronectin expression in RA FLS by the LEF/TCF/ß-catenin pathway. Briefly, transfection of RA FLS with dn variants of LEF1 and TCF4, the two transcription factors that are known to promote the canonical Wnt1 signalling pathway [25] depress fibronectin synthesis in RA FLS [47]. The application of an anti-Wnt1 antibody or an excess of the Wnt1 antagonist s-FRP1 to RA FLS results in a similar effect [47]. Fibronectin is a multifunctional protein which not only promotes cell survival but also facilitates cell attachment through integrin-mediated interactions [47, 49, 50]. Fibronectin is also a potent chemoattractant for fibroblasts and other cell types [51]. Thus, fibronectin might enhance FLS survival and promote the incorporation and retention of mesenchymal stem cells and leucocytes in the RA synovium, thereby contributing to hyperplasia, perhaps even in the absence of classical pro-inflammatory factors.
Wnt1-mediated signalling in FLS stimulates pro-MMP3 synthesis. Overexpression of Wnt1 in non-RA FLS with a Wnt1 expression vector up-regulates the synthesis of pro-MMP3, and treatment of RA FLS with either anti-Wnt1 antibody or recombinant s-FRP1 depresses its synthesis. Transfection of RA FLS with either dn LEF1 or dn TCF4, however, does not have significant effect on pro-MMP3 levels [47], implying that Wnt1-mediated pro-MMP3 gene induction does not involve the LEF/TCF/ß-catenin transcription complex. Since the pro-MMP3 gene promoter has an AP1 binding site, it is quite possible that Wnt1 mediates pro-MMP3 synthesis in RA FLS through JNK-mediated activation of the AP1 (Jun and Fos) family of transcription factors [47]. This notion is supported by the fact that JNK/AP1 activation is a characteristic feature of RA FLS [2, 3]. Thus increased secretion of pro-MMP3 due to enhanced Wnt1-mediated signalling in FLS could contribute to the pool of mature MMP3 generated by processing enzymes [52], thereby enhancing the breakdown of articular cartilage.
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Concluding remarks
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Recent findings, summarized in Fig. 3, demonstrate that Wnt signalling pathways, which are active in FLS obtained from RA patients, regulate the expression of multiple proteins that could potentially promote cell migration, retention and differentiation in the rheumatoid synovium. Based on these findings, it is reasonable to conclude that Wnt signalling pathways could potentially promote synovial hyperplasia/inflammation, pannus formation and bone/cartilage erosion during RA pathogenesis, perhaps independently of the pivotal cytokines TNF-
and IL-1. Implications of the importance of the Wnt signalling pathways in RA pathogenesis, however, are only beginning to emerge, and many important questions remain unresolved. It is crucial to understand how Wnt signalling correlates with the extent of synovitis. Studies need to be performed on both animal models and patient samples to enhance our understanding of the functional significance of Wnt signalling during the evolution of disease. For instance, it is important to verify if the Wnt5a/Fz5 and Wnt1 signalling pathways in RA FLS coordinate to form a niche for migratory lymphocytes by promoting chemotaxis and cell adhesion. If so, Wnt5a, Fz5 and Wnt1 should also be good candidates for studying the mechanism of plasma cell differentiation in the RA synovium. Furthermore, it is important to investigate if injection of retroviral or adenoviral derivatives of dn Wnt5a, dn Lef, dn Tcf or s-FRP1 can block disease progression in an animal model of inflammatory arthritis that resembles RA. The experimental results obtained from animal models could pave the way for new therapeutic interventions in the human disease with antibodies, receptor antagonists or small-molecule inhibitors of WntFz signalling. To date, studies related to the involvement of Wnt signalling in RA have focused mainly on Wnt1 and Wnt5a. In the future, it will be important to investigate if other Wnt proteins, such as Wnt14 and Wnt5b, which are required for limb and joint development [53, 54], have a role in RA pathogenesis.

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FIG. 3. Wnt5a and Wnt1 signalling in RA pathogenesis. Wnt5a signalling in RA FLS contributes to the production of IL-6, IL-8, IL-15, SDF1, RANKL and VEGF. Wnt1 signalling contributes to the production of fibronectin and MMP3. Both pathways could contribute to RA pathogenesis. The bidirectional arrow depicts possible cross-talk among the two pathways, which might occur at different stages of cell activation during pathogenesis.
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Acknowledgments
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The author acknowledges Drs Dennis Carson, Nathan Zvaifler, Gary Firestein and Maripat Corr for reading the article and helpful discussions. This work was supported by a grant from the Arthritis Foundation.
The author has declared no conflicts of interest.
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Submitted 15 November 2004;
revised version accepted 24 December 2004.