Autoimmunity

ISSN: 0891-6934 (Print) 1607-842X (Online) Journal homepage: http://www.tandfonline.com/loi/iaut20

Therapeutic targets for rheumatoid arthritis: Progress and promises Abdullah Alghasham & Zafar Rasheed To cite this article: Abdullah Alghasham & Zafar Rasheed (2014) Therapeutic targets for rheumatoid arthritis: Progress and promises, Autoimmunity, 47:2, 77-94, DOI: 10.3109/08916934.2013.873413 To link to this article: https://doi.org/10.3109/08916934.2013.873413

Published online: 20 Jan 2014.

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http://informahealthcare.com/aut ISSN: 0891-6934 (print), 1607-842X (electronic) Autoimmunity, 2014; 47(2): 77–94 ! 2014 Informa UK Ltd. DOI: 10.3109/08916934.2013.873413

REVIEW ARTICLE

Therapeutic targets for rheumatoid arthritis: Progress and promises Abdullah Alghasham1 and Zafar Rasheed2 1

Department of Pharmacology and Therapeutics and 2Department of Medical Biochemistry, College of Medicine, Qassim University, Buraidah, Saudi Arabia Abstract

Keywords

Recent therapeutic advancements in understanding of molecular and cellular mechanisms of rheumatoid arthritis (RA) have highlighted the strategies that aim to inhibit the harmful effects of up-regulated cytokines or other inflammatory mediators and to inhibit their associated signaling events. The utility of cytokine as therapeutic targets in RA has been unequivocally demonstrated by the success of tumor necrosis factor (TNF)-a blockade in clinical practice. Partial and non-responses to TNF-a blocking agents, however, together with the increasing clinical drive to remission induction, requires that further therapeutic targets be identified. Numerous proinflammatory mediators with their associated cell signaling events have now been demonstrated in RA, including interleukin (IL)-1 and IL-12 superfamilies. Continued efforts are ongoing to target IL-6, IL-15 and IL-17 in clinical trials with promising data emerging. In the present review, we focus on IL-7, IL-18, IL-32 and IL-10 family of cytokines (IL-19, IL-20 and IL-22) as they are implicated in contributing to the pathogenesis of RA, which could be targeted and offer new therapeutic options for RA therapy. Recent evidences also suggest that multiligand receptor for advanced glycation end products (RAGE), several adipokines and various components of immune system play a critical role in the pathophysiology of RA; therefore we have also highlighted them as therapeutic targets for RA therapy. Components of subcellular pathways, involve in nuclear transcription factor (NF)-kB, mitogen-activated protein kinases (MAPKs) and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway have also been discussed and offer several novel potential therapeutic opportunities for RA.

Adipokines, cytokines, JAK-STAT, MAPKs, NF-kB, RAGE, rheumatoid arthritis, therapeutic targets

Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder, characterized by inflammation of synovial membrane and the release of inflammatory cytokine and other inflammatory mediators that results in joint destructions and disability [1]. Targeting of cytokines and their associated inflammatory mediators are now established as a feasible method for treating RA which may occur due to the imbalance of pro- and anti-inflammatory mediators and leads to the development of chronic synovial inflammation and joint destruction [2]. Although the precise cause of RA remains unknown, the importance of inflammatory cytokines and their associated factors in the pathogenesis of RA has been documented in numerous studies [3,4]. Inflammatory cytokines, that include tumor necrosis factor (TNF)-a, interleukin (IL)-1, IL-6, IL-17 and the downstream inflammatory mediators produced by activated cells in the arthritic joints are an essential component of the milieu that drives cartilage and bone destruction. The effect of cytokine neutralization as a

Correspondence: Zafar Rasheed, Department of Medical Biochemistry, College of Medicine, Qassim University, P. O. BOX 6655, Buraidah 51452, Saudi Arabia. E-mail: [email protected]

Received 16 May 2013 Revised 24 September 2013 Accepted 28 November 2013 Published online 15 January 2014

driving force for inhibition of inflammation was first exemplified by the use of anti-TNF-a as the first biologic therapy to be licensed for RA treatment [5]. This approach has been subsequently extended to include IL-1 and IL-1 receptor (IL-1R) targeting. Now these agents are also used to treat a variety of autoimmune and chronic inflammatory disorders [6,7]. In RA, TNF blockade in the clinic is clearly associated with reduced synovial joint inflammation as well as cartilage and subchondral bone damage with improvement in quality of life measures [8]. A variety of in-vitro and in-vivo models used in the elucidation of TNF dependent networks in RA synovitis are now being employed to validate the therapeutic potential of other inflammatory cytokines that have also been implicated in the disease pathogenesis [5]. In contrast to TNFblockade as anti-rheumatic agents, partial or non-responses were seen in clinical practice [9,10]. The partial success of anti-TNF biologics on one hand, and their short comings on the other, triggered an enormous research effort to identify additional novel potential targets. Other cytokine targets such as IL-6, IL-17, IL-15 and IL-23 have also been validated and are in the process of being testing for the last 5 years [11,12]. On the other hand, adipokines, proteins produced by white adipose tissues (WAT) have attracted the attention as therapeutic target for RA pathogenesis [13]. Our rapidly growing

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History

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knowledge of adipokine biology is revealing the complexity of these proteins, thereby redefining WAT as a key element of the inflammation and immune response in RA. Adipokines exert potent modulatory actions on target tissues and cells involved in RA, including cartilage, synovium and bone [14]. In addition, multiligand receptor for advanced glycation end products (RAGE) axis has now emerged as a novel pathway involved in a wide spectrum of diseases including RA [15,16]. Ligation of RAGE triggers a series of cellular signaling events, including activation of mitogen activated protein kinases (MAPKs) and nuclear factor (NF)-kB, leading to the production of proinflammatory mediators and causing inflammation [4,17]. Now it is also reported that specific siRNA or other inhibitors targeting RAGE decrease inflammation [18,19]. Of these, strategies that target RAGE and its associated signaling events in our opinion will serve as potential therapeutic target for RA. However, there remains a significant unmet clinical need for new therapies as existing regimens are effective in only a proportion of patients and crucially leave the host at significantly higher risk of overwhelming infection. Moreover, the high cost, short halflife and i.v. application of these biologics have made it necessary to consider alternative treatments such as orally active small molecule inhibitors of signaling cascades relating to these important inflammatory mediators [7]. Much interest has focused on inhibitors of the MAPKs primarily because they have been implicated as key regulators of proinflammatory cytokines, chemokines and matrix metalloproteinases (MMPs) [4,20,21]. Indeed, p38MAPK was initially discovered as the target of pyridinyl imidazoles, a class of compounds that inhibits the production of TNF-a and IL-1 by activated human monocytes and p38-MAPK inhibitors are undergoing phase II trials for RA therapy (www.sciosinc.com/ scios/pr1046376591). However, some of the current inhibitors under trial are likely to induce side effects due to cross inhibition of subclasses of p38-MAPKs (a,b,g,) in different arthritic models [20,22]. These data highlight the complexity of MAPKs signaling in arthritis and provide a basis for the design of novel strategies to treat human RA. Of note, inhibition of the p38a isoform seems to be particularly effective with regard to cartilage and bone destruction [23], since a selective p38a inhibitor reduced bone loss, numbers of osteoclasts and serum levels of cartilage breakdown metabolites in arthritic mice [21]. Of these, strategies that target specific subclasses of p38, ERK, JNK- MAPKs provide several potential therapeutic opportunities for RA therapy. Whereas, activation of NF-kB is facilitated by phosphorylation and subsequent dissociation of its inhibitor, IkB. Pharmacologic inhibition of the IkB-phosphorylation kinase IKK subsequently prevents NF-kB activation and has proven to be a successful approach for the reduction of inflammatory disease activity and bone destruction in mice with collagen induce arthritis (CIA) [24]. Other kinases associated with the NF-kB system might also represent future therapeutic targets [25]. Furthermore, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway seems to a selective target for therapeutic intervention in RA since the tissue destruction of this pathway is restricted and different JAKs transfer the signals of different cytokines. Of notes, JAK-STAT signaling induces an autoregulatory loop that

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leads to expression of suppressor of cytokine signaling (SOCS protein) [21,26], which could also represent attractive targets for RA therapy. This article reviews the highlight of recent research activities in the clinical development of novel cytokines, adipokines and multiligand receptor RAGE in the pathogenesis of RA. This review also focuses on the MAPKs, NF-kB and JAK-STAT signaling pathways, emphasizing their role in inflammation and damage to articular tissues and their modulation with therapeutic agents currently in use, and potential future strategies.

Cytokines Interleukin-7 The role of IL-7 and IL-7R has been implicated in the pathogenesis of RA [27]. Now it is well reported that IL-7 level is high in the joints of patients with RA and also in other inflammatory arthritis [28–30]. In contrast, circulating levels of IL-7 in RA remain a point of debate [31]. IL-7 has many roles in T cell, dendritic cell and bone biology in humans [30,32]. Reduced levels of circulating IL-7 probably underlie a number of the dysfunctions associated with circulating T cells in RA and may provide a mechanism for some of the unexplained systemic manifestations of the disease [30]. In joint disease like RA, IL-7, via immune activation, can induce joint destruction. Now, it has also been demonstrated that activated human articular chondrocytes from arthritic patients produce IL-7 [28,33]. IL-7 stimulates production of proteases by IL-7 receptor expressing RASFs, synovial macrophages and chondrocytes, thereby enhancing cartilage matrix degradation (Figure 1). Beside this, IL-7 induces cytokines produced by arthritogenic T cells (e.g. interferon c (INNc, IL-17), T cell differentiating factors (e.g. IL-12), chemokines capable of attracting inflammatory cells (e.g. macrophage induced gene (MIG), macrophage inflammatory protein (MIP)-1a) as well as molecules involved in cell adhesion, migration, and costimulation (e.g. lymphocyte function associated antigen (LFA)-1, CD40, CD80). Recently, it is also demonstrated that RA patients with greater disease activity have higher levels of IL-7 and IL-7R in RA monocytes [27]. In addition, IL-7 induces bone loss by stimulating osteoclastogenesis that is dependent on receptor activator of nuclear factor kB ligand (RANKL) [30]. IL-7 induces TNF-a secretion by T cells and by macrophages after T cell dependent synovial monocyte/ macrophage activation suggesting that IL-7 is an important cytokine in RA, as it is capable of inducing inflammation and immunopathology. To date no clinical trial has been conducted anti-IL-7 agent in humans, however, a vaccination strategy has been developed to enhance patients’ anti-tumor activity against melanoma [33]. The foregoing discussion indicates that it is not clear to what extent IL-7 mediates the unique proinflammatory activity in RA pathogenesis and its utility as a monotherapy in RA but data clearly suggest its role in RA and supports further studies. Interleukin-18 IL-18 is a member of IL-1 superfamily that enhances both innate and acquired immune response. IL-18 is highly

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Figure 1. Cytokines network and its associated inflammatory mediators are the potential intercellular targets for RA therapy. The diagrammatic representation of the rheumatoid joint (upper left) is enlarged to show the major cellular inflammatory events occurring within the synovial pannus. Black arrows (curve arrow) indicate activation, green arrows (thick arrows) indicate production of cellular products, and red squares (small squares) denote therapeutic targets. Abbreviations: RA, rheumatoid arthritis; IL, interleukin, IFN, interferon, RASF, RA synovial fibroblast; PGE2, prostaglandin E2; TNF, tumor necrosis factor; MMP, matrix metalloproteinase; RANKL, receptor activator of nuclear factor kB ligand; AGEs, advanced glycation end products; NO, nitric oxide; BLYs, B-lymphocytes stimulator; APRIL, a proliferation-inducing ligand; HMGB-1, high mobility group protein B1.

expressed in sera, synovial fluids and synovial tissues of RA patients and these high levels are also well correlated with disease activity [34,35], indicating an important role of IL-18 in the pathogenesis of RA. Recent data have demonstrated the importance of IL-18 in the induction and perpetuation of chronic inflammation during experimental and clinical rheumatoid synovitis and in the bone destruction in experimental arthritis [35–37]. Activation of RA synovial fibroblasts (RASFs) by IL-18 produces TNF-a, IL-1, chemokines and adhesion molecules, which thereby, induce inflammation and cartilage destruction (Figure 1). IL-18 also activates memory T-cell stimulation in damaged joints to produce various proinflammatory cytokines, such as IFN-g and TNF-a (Figure 1). Besides this IL-18 also act on various other cell types such as keratinocytes, osteoclasts and chondrocytes [38] but often in synergy rather than independently, therefore some of its activities remains unclear. In synovial compartment IL-18 functions with numerous cytokines including IL-12 and IL-15 and as such it serves to amplify ongoing inflammatory responses [39]. Numerous in-vivo studies using both IL-18-gene-targeted mice and neutralizing agents such as anti-IL-18 antibody or IL-18 binding protein, implicate IL-18 in components of host defense and in responses in autoimmune models of disease [40], increasing interest in it as a

therapeutic target. Generation of anti-IL-18 monoclonal neutralizing antibodies represents an attractive approach, although at this time clinical studies have not yet commenced. Directly targeting the IL-18 receptor, e.g. via antibody or specific antagonist, is also of potential interest, although shared utilization with other IL-1 cytokine, e.g. IL-1F7, may reduce the specificity of such an approach. Small molecules approach includes inhibitors of caspase-1 and generation of inhibitors to components of the IL-18 receptor signaling pathway. The latter approaches will provide limited specificity for IL-18 since generation and release of other IL-1 superfamily members may also be inhibited. Whether this offers therapeutic disadvantage in RA however is unclear and need not be assumed. Interleukin-10 family members The IL-10 family of cytokines consists of nine members: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26 and the more distantly related IL-28A, IL-28B, and IL-29. These cytokines have indispensable functions in many infectious and inflammatory diseases [41]. IL-19, IL-20 and IL-22 are now well considered to be a proinflammatory cytokine, which, play an inflammatory role in RA [42–44]. IL-10, in contrast, is a

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potent anti-inflammatory cytokine [45] that has been shown to regulate endogenous proinflammatory cytokine production in RA synovial tissue [46]. IL-19 is a novel cytokine and was first originally cloned by searching EST database for IL-10 homologue. Liao et al. [47] were the first to report proimflammatory nature of IL-19 in monocytes as it upregulated the production of potent inflammatory cytokines TNF-a and IL-6. Recently, it was demonstrated that IL-19 blockade attenuates experimental induced autoimmune arthritis [48] and now it is well reported that IL-19 produced by synovial cells, promotes joint inflammation in RA by inducing IL-6 secretion and decrease synovial cell apoptosis [49]. It is also reported that activation of monocytes with IL-6, TNF-a, IFN-g, LPS or GM-CSF resulted in induction of IL-19 [50]. In summary, however, the broad functional activity and expression of IL-19 in RA, together with the elegant work thus far performed to elucidate its activities, render it an interesting potential target. IL-20 and all three of its receptors are expressed in synovial membranes and RASFs derived from the synovial tissue of RA patients and in rats with CIA [44,48]. IL-20 was expressed at significantly higher levels in synovial fluid of RA patients and it was demonstrated that RASFs and synovial macrophages produce IL-20, which acts on RASFs using an autocrine pathway, inducing the production of MCP-1 and IL-8 causing more severe inflammation [48]. In addition, it was also demonstrated in CIA that administration of soluble IL-20 receptor type 1 significantly reduced disease, indicative of in-vivo blockade of disease [48]. Furthermore, recently dysregulation of IL-20 signaling is implicated in several inflammatory diseases including RA [51]. In view of these, IL-20 may also be considered to be a target for RA therapy, however, clearly warrants further studies. Recently, numerous studies regarding the role of IL-22 in autoimmune diseases including RA are emerging and several reports clearly suggest that IL-22 plays a critical role in the inflammation and proliferation cascade in RA [42,52–55]. A recent report written by Xie et al. [53] pointed out almost all recent evidences, which clearly suggest that IL-22 is a good biomarker for assessment of activity in RA, and IL-22 seems to be a potential therapeutic target for RA. Recently, it was reported that IL-22 levels of IL-22 were increased in patients with RA and this higher levels were well correlated with clinical arthritic measures and the presence of bone erosions was associated with high IL-22 levels [55]. Similar relationship between IL-22 and RA activity was also reported by many other recent studies, where IL-22 levels were found to be higher RA patient’s serum as well as in synovial fluid as compared with controls [56–58] and high IL-22 levels correlated with bone erosions [59]. In RA patients, Th17 cells were recognized to produce higher IL-22 [59]. Th22 cells also produced IL-22 and the expression of Th22 cells [60]. More importantly, Th17/22 cells showed positive correlations with IL-22, C-reactive protein, and arthritic activity [60]. In addition, natural killer (NK)-22 cells in vitro can secrete higher levels of IL-22 and TNF-a, and their supernatant can induce the proliferation of RASF; however, addition of IL-22 antibody plus TNF-a antibody inhibited the proliferation of RASF induced by the NK-22 supernatant [61]. Moreover, in-vivo model of arthritis (IL-1Ra/) displayed a progressive

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erosive arthritis characterized by upregulation of IL-22 in severely inflamed synovia; and anti-IL-22 treatment of IL-1Ra/mice significantly reduced the inflammation and bone erosions [62]. Furthermore, in RA patients, drug rituximab reduced expression of IL-22 and Th17-positive cells in synovial tissue, and this correlated with better clinical outcomes. In vitro, rituximab strongly reduced IL-17 and IL-22 production induced by Candida albicans [63]. These studies therefore indicate a novel role of this proinflammatory member of the IL-10 family in RA and further indicate that some of the effects would be insensitive to IL-10 immunoregulation. Interestingly, IL-22 expression has been identified in murine T cells, with substantially higher expression levels in Th17 cells, as compared with Th1 and Th2 counterparts [64]. It is also reported that this cytokine acts synergistically with IL-17 to induce genes associated with innate immunity in primary keratinocytes and this may have implications for defining their roles in RA [64]. These findings suggest therapeutic potential for patients with RA, and suggest a role for IL-22 in development of RA. Further studies are needed to clarify the role of IL-22 in RA. Therapeutic agents targeting IL-22 might result in innovative new therapies for RA. In view of these, it is clear that IL-10 family members have potential roles in RA, however the clinical efficacy of targeting these cytokines in humans, remains to be determined. Interleukin-32 Recent investigations on IL-32 in RA clearly pointed out that it contributes to the pathogenesis of RA owing to its increasing generation of autoimmune-related components such as pro-inflammatory cytokines and chemokines [65–68]. IL-32 injected into knee joints of RA mice model induced significantly higher expression of IL-1b, TNF-a, IL18 and IFNg, as well as higher expression of IL-17, IL-21 and IL-23 in relation to controls [69]. IL-32 is produced by T lymphocytes, natural killer cells, epithelial cells and blood monocytes [70,71]. Of particular importance, IL-32 is prominently induced by IFN-g in epithelial cells and monocytes [70]. Human recombinant IL-32 exhibits several properties typical of a proinflammatory cytokine [70]. For example, the cytokine induces other proinflammatory cytokines and chemokines such as TNF-a, IL-1b, IL-6, and IL-8 by means of the activation of NF-kB and p38-MAPK [71]. An unexpected property of IL-32 is its ability to augment by 10-fold production of IL-1b and IL-6 induced by muramyl dipeptides by means of the nucleotide oligomerization domains 1 and 2 (NOD1 and NOD2) through a caspase1-dependent mechanism [71,72]. A single mutation in NOD2 plays a role in a subgroup of patients with Cohn’s inflammatory bowel disease. Together, these studies suggest that IL-32 has an important role in inflammation, both during host defenses against microorganisms and in autoimmune diseases. Furthermore, treatment with IL-32 highly increased thymic stromal lymphopoietin (TSLP) production in monocytic cell line (THP-1) cells and human blood monocytes via activation of caspase-1 and NF-kB [68]. While in human peripheral blood mononuclear cells (PBMC), IL-32 treatment stimulated the synthesis of prostaglandin E2 (PGE2), an important

Therapeutic targets for RA

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mediator of cartilage and bone destruction in RA [73]. Together, all these findings suggest that IL-32 is crucial in regulating the generation of autoimmune-related components of RA. However, further studies are required, especially in human systems to explore the therapeutic potential of IL-32 comprehensively in RA.

Adipokines Great strides have been made towards understanding the molecules linking obesity, inflammation and immunity and understanding why obesity leads to chronic inflammation. It is now evident that there are prototypic adipokines (also known as adipocytokines), that are synthesized mainly in the WAT, circulate at high concentrations, function in a hormonelike manner and have many of the features of classical cytokines, which play a critical role in the development and progression of RA [13]. Leptin, adiponectin, resistin and visfatin are adipokines and are thought to provide an important link between obesity, and related inflammatory disorders [13,74]. The role of WAT in the progression of inflammatory arthritis has been summarized in Figure 2. Obese WAT under pathological conditions elevates the synthesis of leptin, adiponectin, resistin and visfatin and various other proinflammatory mediators, these factors are causing stimulation of synovial cells and chondrocytes which further promote loss of cartilage and bone. This could play a role I arthritis [13,75–78]. Here, we provide an overview

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of currently available adipokines for RA therapy that in our opinion offer several potential therapeutic opportunities for RA. Leptin A remarkable aspect of the effects of leptin on the immune system is its action as a proinflammatory cytokine and its structural similarity to other proinflammatory cytokines such as IL-6, IL-12 and granulocyte colony-stimulating factor [79]. Recently, it is demonstrated that leptin acts as a proinflammatory adipokine with a catabolic role on cartilage metabolism via the upregulation of proteolytic enzymes and acts synergistically with other proinflammatory stimuli [80]. This suggests that the intrapatellar fat pad and other WAT in arthritis joints are local producers of leptin, which may contribute to the inflammatory and degenerative processes in cartilage catabolism, providing a mechanistic link between obesity and arthritis. Leptin-deficient mice are less prone than non-leptin-deficient mice to develop inflammatory diseases, regardless of whether these involve innate or adaptive immunity; leptin seems to play a role in autoimmune diseases such as RA, but whether leptin can harm or protect joint structures in RA is still unclear [74]. In patients with RA, circulating leptin levels have been described as either higher or unmodified in comparison to healthy controls [81,82]. Experimental antigen-induced arthritis is less severe in leptindeficient ob/ob mice than in wild-type mice, whereas leptin

Figure 2. White adipose tissue in RA therapy. The multiple functions of joints obese/white adipose tissue (WAT) including the synthesis and secretion of adipokines. Adipose tissue, the main energy store of the body, is also a source of proinflammatory factors that modulate the inflammatory response and promote inflammatory arthritis. Inflammatory or immune diseases to which the major adipokines contribute by action or omission are depicted in boxes. Upper left diagram is an enlarged view of the rheumatoid joint showing the adipokines mediated events occur within the synovial pannus. Blue arrows (all arrows in right diagram) indicate activation and red squares (small squares) denote therapeutic targets. Abbreviations: RA, rheumatoid arthritis; OA, osteoarthritis; CCL, CC-chemokine ligand; CXCL, CXC-chemokine ligand; MMP, matrix metalloproteinase; IL, interleukin, IFN, interferon, RASF, RA synovial fibroblast.

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deficient mice and leptin-receptor-deficient mice exhibited a delayed resolution of the inflammatory process in zymosaninduced experimental arthritis. Notably, leptin decreased the severity of septic arthritis in wild type mice [83]. Therefore, in the light of the present results it seems difficult to make an unambiguous conclusion about a potential role of leptin in RA. In osteoarthritis (OA), leptin production is much higher in osteoarthritic human cartilage than in normal cartilage. The finding that administration of exogenous leptin increases IGF1 and TGFb1 production by rat knee-joint cartilage has suggested that high circulating leptin levels in obese individuals might protect cartilage from osteoarthritic degeneration [84]. Under pathological conditions, however, control of matrix homeostasis by chondrocytes in the joint is lost, and most of the evidence points the other way. Activation of human chondrocytes by the combination of leptin plus IFNg stimulates the production of inducible nitric oxide synthase (iNOS) [85]. Not only this it is also reported that iNOS activation by IL-1 is increased by leptin via a mechanism involving JAK2, PI3K, MEK1 and p38-MAPK [85]. Relevant to arthritis, leptin receptor (LR) activation stimulates the transcription factor NF-kB involving in the regulation of proinflammatory gene expression [86,87]. It has been also well established that leptin induces the synthesis of cartilage degradation enzymes MMPs such as MMP-9 and MMP-13 [88]. However, the impact of leptin on RA development and progression is unclear [86]. Some clinical studies found no correlation between leptin levels and disease activity or inflammation in RA patients [89,90]. Other reports noted significantly elevated leptin levels in RA patients relative to controls [91]. Interestingly, studies also found a significant inverse correlation between inflammation and leptin concentrations in patients with active RA [92,93]. Because of the increasing prevalence of obesity and a potential link between obesity and RA, a better understanding of the impact of leptin on RA onset and progression is needed. Adiponectin Adiponectin has a wide range of effects in pathologies with immune and inflammatory components, such as RA [77]. In contrast to its ‘‘protective’’ role against obesity and vascular diseases, it seems that in skeletal joints adiponectin might be proinflammatory and involved in matrix degradation and now it is considered to be a biomarker for RA therapy [77,94]. Serum adiponectin levels in RA patients are higher than in healthy controls [95], and adiponectin levels in synovial fluid are higher in patients with RA than in patients with OA [96]. In human synovial fibroblasts, adiponectin induces two of the main mediators of RA via the p38MAPK pathway: IL-6 and MMP-1 [97]. Chondrocytes also present functional adiponectin receptors, activation of which leads to the induction of iNOS via a signaling pathway that involves PI3 kinase; and adiponectin treated chondrocytes similarly increase IL-6, TNF and MCP1 (monocyte chemotactic protein 1) synthesis [74]. On the other hand, the high adiponectin levels of patients with RA can also be interpreted as an attempt to overcome the well-known proinflammatory effect of leptin, for example by counteracting the pro-inflammatory effects of TNF and reducing the production of IL-6 and C-reactive

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protein in RA [74,98]. Taken together, these results suggest that it might be worth considering adiponectin as a potential target of treatment for degenerative joint diseases. Resistin Resistin is involved in the pathogenesis of RA as it has been found in the plasma and the synovial fluid of RA patients, and injection of resistin into mice joints induces an arthritislike condition, with leukocyte infiltration of synovial tissues, hypertrophy of the synovial layer and pannus formation [99,100]. Resistin levels were found to be higher in the serum and synovial fluid of RA patients than in those with OA [76]. This clearly indicating its role in inflammatory rheumatologic diseases such as RA, however, plasma resistin levels in RA patients seem to be similar to those found in healthy controls; and although in some studies RA patients’ resistin levels were higher in synovial fluid than in serum, the discrepancy might be due simply to the increased permeability of inflamed synovial membrane, or could simply be an epiphenomenon [100]. However, resistin strongly upregulated the expression of TNF-a and IL-6 by human PBMCs and induces arthritis after injection into the joints of healthy mice [79,100]. These proinflammatory properties of resistin were abrogated by NF-kB inhibitor, showing the important role of NF-kB in resistin-controlled inflammatory reactions. Resistin has also been shown to accumulate in the inflamed joints of patients with RA and its levels correlate with markers of inflammation [101]. Human resistin stimulates synthesis of the pro-inflammatory cytokines TNF-a, IL-1b, IL-6 and IL-12 by various cell types through NF-kB-dependent pathway [102]. We have also shown these effects of resistin in Figure 2. In further support of its proinflammatory profile, resistin also upregulate the expression of vascular cell-adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1) and CCL2 by human endothelial cells and induces these cells to release endothelin-1 [103]. Therefore, this adipokine in humans has many features of proinflammatory cytokine and could have a role in RA. These proinflammatory effects, however, are based on a limited number of studies and much more information is needed to characterize resistin more fillies in both mice and human. Despite of all these resistin may also be considered as a potential future therapeutic target for RA therapy. Visfatin Visfatin, also known as pre-B cell colony-enhancing factor (PBCEF), is a cytokine like protein originally cloned from PBMC as a factor that enhances differentiation of pre-B cells in synergy with IL-7 and stem cell factor [104]. Visfatin is produced by peripheral blood neutrophils upon stimulation by inflammatory factors such as lipopolysaccharide and TNF-a [105]. It is also reported that IL-6 regulated visfatin has been shown to induce inflammation in synovial fibroblast [106]. Furthermore, visfatin has been shown to induce chemotaxis and the production of potent proinflammatory cytokines IL-1b, TNF-a, IL-6 and costimulatory molecules by CD14þ monocytes, and to increase their ability to induce allow proliferative responses in lymphocytes, effects which are mediated intracellularly by p38 and MEK1 [107]. In addition,

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circulating visfatin is higher in patients with RA than in healthy controls [81] and recently it has been proposed to be a novel marker in RA patients for generating metabolic disturbances [75]. The physiological role or relevance of visfatin in the context of RA is currently unclear; it might involve modulation of the inflammatory or immune response by visfatin, or it might be part of a compensatory mechanism, or the increased levels could simply be an epiphenomenon. What is also not clear is whether inhibition of visfatin in-vivo will be safe, or whether long-term inhibition will increase the risk of infection. The success of this approach in animal models of autoimmune disease, however, clearly warrants further study.

Multi-ligand RAGE RAGE is a multi-ligand receptor that belongs to the immunoglobulin (IgG) superfamily of transmembrane proteins. RAGE binds AGEs (advanced glycation end products), HMGB1 (high-mobility group box-1; also designated as amphoterin), members of the S100 protein family, glycosaminoglycans and amyloid b peptides [15]. The RAGE has been implicated in the pathogenesis of RA through its ability to amplify inflammatory pathways [17,108,109]. A member of the IgG superfamily of cell surface receptors, RAGE binds AGEs, which are non-enzymatically glycated or oxidized proteins, lipids and nucleic acids formed under conditions of oxidative stress and hyperglycemia [110]. In addition to these, RAGE binds some proinflammatory ligands, including members of the S100/calgranulin family, and HMGB-1, which is implicated in cell signaling by synergizing with DNA CpG motifs [110]. Several RAGE ligands are characteristically over expressed in serum and synovial fluid of RA patients and also in RA synoviocytes and chondrocytes [111]. RAGE is expressed by many of the cells that participate in the development of RA, including macrophages, neutrophils and T cells. RAGE is expressed on macrophages and T cells within synovial tissues of RA patients as well as on synovial fluid macrophages [16]. Ligation of RAGE on the cellular surface triggers a series of cellular signaling events, dependent on the ligand, environment and cell type and cover Rasextracellular signal-regulated kinase 1/2 (ERK1/2), Cdc42/ Rac, stress-activated protein kinase/c-Jun-NH2-terminal kinase (SAPK/JNK) and p38 mitogen-activated protein (MAP) kinase pathways resulting in the activation of transcription factors like nuclear factor (NF)-kB, activator protein-1 (AP-1) or a member of the signal transducers and activators of transcription family (STAT3) [112], leading to the production of pro-inflammatory cytokine, chemokines, adhesion molecules and oxidative stress and causing inflammation in RA [16]. Future therapeutic approaches therefore might aim to disrupt these cell signaling loops by blocking the receptor–ligand interaction. Such an intervention will require detailed knowledge of the molecular mechanism of RAGEligand interactions. Moreover, in murine type II collageninduced arthritis, in which RAGE expression is increased, synovial tissue inflammation and cartilage and bone destruction are decreased by treatment with soluble RAGE, the extracellular ligand-binding domain of the receptor, in parallel with diminished generation of TNF-a, IL-6, and

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MMPs [113]. In addition, HMGB-1-mediated TNF-a production in macrophages derived from RA synovial fluid were shown to be significantly inhibited by sRAGE [111]. These findings suggest that cellular RAGE plays an important role in the activation of inflammatory effector cells such as macrophages by recognizing its pathogenic ligands in the joint. In view of these recently investigations, RAGE and its associated signaling events may represent future therapeutic targets for the treatment of RA. RAGE mediated signaling events and their possible therapeutic targets have been summarized in Figure 3.

Mitogen activated protein kinases MAPKs have been implicated as playing key regulatory roles in the production of inflammatory cytokines (TNF-a, IL-1, IL-6, IL-17, etc.) and downstream signaling events leading to inflammation and joint destruction by providing the essential link between receptor signals and nuclear gene transcription [4,21]. Recently, it has been shown that pharmacologic inhibition of MAPKs that mediate pathogenic signal transduction heralds a new era for RA therapeutics [114,115]. MAPKs comprise a family of highly conserved serine/ threonine protein kinases that have been implicated in the regulation of key cellular processes including gene induction, cell survival/apoptosis, proliferation and differentiation as well as cellular stress and inflammatory responses [20]. There are three major classes of MAPKs in mammals, p38-MAPK, c-jun N-terminal kinase (JNK) and the extracellular signalregulated kinases (ERKs). MAPKs are activated via a signaling cascade as stimulation of MAPKs requires the upstream activation of a MAPK kinase (termed MAPKK, MEK or MKK) and an MAPK kinase kinase (termed MAPKKK, MEKK or MKKK) (Figure 4). Clearly, MAPKs play important roles in transducing inflammation and joint destruction and therefore received considerable attention as potential therapeutic targets in RA [114–116]. However, several recent clinical trials have concluded in a disappointing manner [22]. Why is this so, if p38-MAPK or other MAPKS contributes to the excessive production of inflammatory mediators, the destruction of bone and cartilage? We argue that, to explain the apparent failure of p38 or other MAPKs inhibitors in arthritis, we need to understand better the complexities of the p38 pathways and its many levels of combination with other cellular signaling pathways. In this regards, here we discuss the multiple isoforms of MAPKs (p38a,b,g and , JNK1-3, ERK-1-8) that have been implicated in the regulation of a plethora of essential cellular responses [20], dictating that inhibitors that simply ablate p38-, JNK- or ERK-MAPKs activities are likely to have serious side effects [22]. Moreover, most of the current inhibitor compounds under trial are competitors for the ATP-binding site of p38MAPK and hence are likely to induce side effects due to cross inhibition of other classes of kinases [20]. Interestingly, the ERK/MEK inhibitors are not ATP competitive but rather act to prevent the MAPKKK, Raf1 from activating MEK and thus their observed relative lack of side effects probably reflects that they do not non-specifically inhibit other kinases in-vivo [20]. Similarly, peptide-based approaches to disrupting JNK signaling by targeting scaffold protein interactions show

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Figure 3. RAGE and its associated signaling events in RA therapy. RAGE is known to interact with a broad spectrum of extracellular ligands (L) and multiple signal transduction pathways. PI3K, different MAPKs, JAK are involved in functions of RAGE which further activate the transcriptional regulations NF-kB, AP-1 and Stat3 which promotes induction of proinflammatory mediators. On the level of transcriptional regulation, NF-kB, AP-1 and Stat3 have emerged as crucial targets of RAGE signaling, nevertheless other transcription factors (B) might be involved in regulation and function of RAGE as well. Upper left diagram is an enlarged view of the rheumatoid joint, where major RAGE signaling events occur in the synovial pannus. Blue arrows (downwards arrows) indicate activation and red squares (small squares) denote therapeutic targets. Abbreviations: RA, rheumatoid arthritis; RAGE, receptor for advanced glycation end products; MMP, matrix metalloproteinase; IL, interleukin, ER, endoplasmic reticulum; JAK, Janus kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated kinase; NF-kB, nuclear factor kappa B; PI3K, phosphoinositide 3-kinase; Stat3, signal transducer and activator of transcription; AP-1, activator protein-1.

promise but as yet have not been tested in in-vivo models of inflammation [20]. Of note, inhibition of the p38a-MAPK isoform seems to be particularly effective with regard to cartilage and bone destruction, since a selective p38a-MAPK inhibitor reduced bone loss, numbers of osteoclasts and serum levels of cartilage breakdown metabolites in arthritic model of mice [21]. Therefore, in our opinion the future strategies should target in the development of inhibitors that target inflammation-restricted MAPK signaling and, in particular, the aberrant inflammation related to chronic disease whilst leaving intact the ‘‘healthy’’ inflammation that is essential for fighting infection. The recent explosion in identifying isoforms of the major components (MAPKs, MAPKKs, MAPKKKs) of MAPK cascades [20] and the delineation of their specific roles in coupling individual receptors to particular p38-, JNK- and ERK- MAPK signals and their functional outcomes will ultimately lead to the unraveling of their role in disease pathogenesis and the development of specific inhibitors that will provide novel, safe small molecule therapeutics for RA.

Nuclear factor-iB pathway as a therapeutic target Nuclear transcription factor (NF)-kB plays crucial roles in the regulation of inflammation and immune responses, and inappropriate NF-kB activity has been linked with many autoimmune and inflammatory diseases, including RA [117]. Cells employ a multilayered control system to keep NF-kB

signaling in check, including a repertoire of negative feedback regulators ensuring termination of NF-kB responses [118]. NF-kB is induced by many stimuli including TNF-a and IL-1b, forming a positive regulatory cycle that may amplify and maintain RA disease process. NF-kB and enzymes involved in its activation can be a target for anti-arthritic treatment [4]. NF-kB proteins include RelA (p65), RelB, c-Rel, p50/p105, and p52/p100, which normally bind to IkB in the cytoplasm. Stress, inflammatory cytokines, and microbial products result in IkB phosphorylation and degradation, allowing NF-kB to translocate to the nucleus and regulate gene transcription. IkB kinases (IKK) are the primary enzymes that phosphorylate IkB [118]. NF-kB is expressed in rheumatoid synovium, and the p50 and p65 subunits have been localized to cell nuclei in the synovial intimal lining tissue [4,21]. Previous studies implicated IKKb (IKK-2) as a central pathway for NF-kB activation in cytokine-stimulated fibroblast-like syoviocytes [119]. Thus, blockade of IKKb in-vitro with a dominant negative IKKb adenoviral construct inhibited IL-6, IL-8, and intercellular adhesion molecule 1 (ICAM-1) induction after cytokine stimulation with IL-1 or TNF-a [120]. Additionally, intra-articular gene therapy with the same construct or with decoy oligonucleotides effectively suppressed adjuvant arthritis and TNF-a production by RA synovial membrane cells does not appear to require IKKb, although IL-1, IL-6, and MMP expression is dependent on this pathway [121]. Additional proof of concept regarding the role of IKKb comes from studies using small molecule

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Figure 4. Mitogen activated protein kinases are potential intracellular targets for RA therapy. MAPKs are a group of signaling enzymes that include many different members (or submembers); of these p38-MAPKs (a,b,g,), ERK-MAPKs (1-8) and JNK-MAPKs (1-3) have received particular attention. The MAPKs relay proinflammatory signals to the nucleus by sequential phosphorylation. Specific small molecule inhibitors have been developed to intercept signal transduction by these kinases. Upper left diagram is an enlarged view of the rheumatoid joint, where major MAPKs signaling events occur in the synovial pannus. Blue arrows (downwards arrows) indicate activation, black arrow (upwards arrow with tip rightwards) indicates initiation of transcription in the nucleus, and red squares (small squares) denote therapeutic targets. Abbreviations: RA, rheumatoid arthritis; MAPKKKs: MAPK kinase kinase, MAPKK (MKK): MAPK kinase, p38-MAPKs: p38 mitogen activated protein kinases, JNK: c-Jun-N-terminal kinase, ERK: extracellular signal-related kinase.

inhibitors of IkB. One of these, SC-514, inhibited IL-1 induced IkB degradation and NF-kB activation in fibroblastlike synoviocytes [122]. Other subunits of the IKK complex were also characterized by biochemical analysis and molecular cloning and they include NF-kB-inducing kinase (NIK), IKK-g and IKK-complex-associated protein (IKAP). These subunits were shown to play roles in the transmission of upstream signals to IKKa (IKK-1) and IKKb by direct phosphorylating them or by acting as scaffold protein that aid association of various IKK components [123]. Activation of NF-kB has also been suggested to play an important role in the regulation of hyperplasia in the RA synovium by blocking apoptosis of synovial cells. In contrast to the normal synovium, the rheumatoid synovium is characterized by massive infiltration of inflammatory cells accompanied with hyperplasia and fibrotic changes in synovial tissues [124]. This process of disease progression results in the formation of tumor-like structure called pannus, which destroys joint bone and cartilage. In-vitro studies show that NF-kB activation leads to expression of several survival genes that prevent apoptosis in a number of cell types [125]. Inhibition of NF-kB by expression of IkBa in RA synovial fibroblast potentiated potent TNF-a and Fas ligand-induced cytotoxicity, and invivo suppression of NF-kB enhanced apoptosis in the synovium of experimentally-induced arthritis of rats [124]. Pharmacologic inhibition of the IkB-phosphorylating kinase IKK subsequently prevents NF-kB activation and has proven to be a successful approach for the reduction of inflammatory

disease activity and bone destruction in mice with CIA. Other kinases associated with the NFkB system might also represent future therapeutic targets [4,21]. Figure 5 describes the NF-kB associated possible intracellular targets for RA therapy.

JAK-STAT pathways as a therapeutic target The JAK- STAT pathways play a critical role in cytokine signal transduction. JAK is recruited and activated by surface receptor ligation followed by phosphorylation and translocation of STAT protein to the nucleus (Figure 6). With the concerns of JAK-STAT pathways and suppressors of cytokine signaling (SOCS) proteins could represent a therapeutic target for RA therapy. Activation of the JAK-STAT pathway induces expression of its naturally occurring regulators, the SOCS proteins, in an autoregulatory fashion, this makes SOCS proteins an attractive target for specific control of individual JAK-STAT pathways (Figure 6). Lack of SOCS1 or SOCS3 results in enhanced severity of experimental arthritis and increased bone destruction [126,127]. Furthermore, overexpression of SOCS3 inhibited the arthritic symptoms in RA mice model [128]. Therapeutic over-expression of SOCS molecules requires elaborate manipulative techniques (such as gene therapy approaches) and is less likely to be achieved with small-molecule or protein-molecule biologics [21]. In addition, the compound CP-690550, a small molecule inhibitor of JAK3 that is also being tested in transplant medicine

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Figure 5. NF-kB as a potential therapeutic target in RA therapy. A broad range of stimuli including the cytokines, TNF-a, IL-1b, chemokines, AGEs, bacterial and viral products, UV radiation, free radicals activate the NF-kB dimers by triggering a signaling pathway that leads to the phosphorylation of IkB, its ubiquitination, and its consequent degradation by 26S proteasome. The IKK complex consists of at least three subunits, including the kinases IKKa and IKKb and the associated regulatory subunit IKK-/NF-kB essential modulator (NEMO). IKKb is the dominant kinase involved in the activation of NF-kB proteins, whereas IKK plays a partially redundant role of NF-kB activation in bone and cartilage destruction. In addition, NIK and IKK regulate the phosphorylation and processing of NF-kB2 (p100) to produce p52, which translocates to the nuclease. Upper left diagram is an enlarged view of the rheumatoid joint, where major NF-kB signaling events occur in the synovial pannus. Blue arrows (downwards arrows) indicate activation, black arrow (upwards arrow with tip rightwards) indicates initiation of transcription in the nucleus, and red squares (small squares) denote therapeutic targets. Abbreviations: RA, rheumatoid arthritis; AGEs, advanced glycation end products; IKK, IkB kinases; ATP, adenosine triphosphate; P, phosphorylation; Ub, ubiquitination.

and was found that JAK3 relays the signals of several cytokines including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 [129], therefore, a potent anti-inflammatory effect could be anticipated from these types compounds. In view of these, we proposed that similar strategies will be made that target the specific JAK-STATs/SOCSs signaling proteins which definitely show the promise outputs for RA therapy and might have a clinical application in the future.

Innate immunity and adaptive immunity as targets for therapy in RA Innate immunity is the first line of defense against infectious organisms. The many factors involved in innate immunity include anti-bacterial peptides, the alternate pathway of complement activation, mannose-binding lectin, and a number of cytokine [130]. Macrophages, dendritic cells, neutrophils, natural killer cells and Tg lymphocytes contribute to innate immune responses. Specific adaptive immunity, in contrast, involves humoral immunity (mediated by antibodies produced by B cells) and cell-mediated immunity (mediated by T cells) that specifically recognizes nonself-antigens and can distinguish between self and non-self.

Although innate and adaptive immunities have opposite characteristics, they are linked by a rich web of interactions, most notably in the rheumatoid synovium [131]. Investigations into these interactions can help to understand RA and to identify new therapeutic approaches. Innate immunity, with macrophages playing a central role, is critically important in the pathogenesis of RA [132]. Arthritis models document the importance in innate immune cells in the initiation of many experimental models of joint diseases, promoting the onset of adaptive immunity, which results in autoantibody production [133]. In RA patients, the presence of rheumatoid factors and anti-cyclic citrullinated peptide antibodies supports the importance of innate or adaptive immunity in the initiation of RA [134]. In addition, in the joints of RA patients, there is abundant evidence for the presence of immune complexes and the activation of complement, which directly contributes to the pathogenesis of RA. Furthermore, immune complexes bind to Fcg receptors (FcgRs), which are capable of activating macrophages and dendritic cells (DC). The importance of this process is supported by the preliminary observations demonstrating that suppression of the FcgR activation pathway may be effective in treating RA patients [133]. Finally, synovial macrophages

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Figure 6. JAK-STAT pathway as a potential therapeutic target for RA therapy. The JAK-STAT pathway seems to be a selective target for therapeutic intervention since the tissue distribution of this pathway is restricted and different JAKs transfer the signals of different cytokines. JAK-STAT signaling induces an auto-regulatory loop that leads to expression of SOCS protein, which could also represent attractive targets. Upper left diagram is an enlarged view of the rheumatoid joint, where JAK-STAT signaling events occur in the synovial pannus. Blue arrows (downwards arrows) indicate activation, black arrow (rightwards thick arrows) indicates initiation of transcription in the nucleus, red arrows (upwards arrows) indicate negative regulation, red and green squares denote therapeutic targets. Red squares (squares on downwards arrows) for inhibition and green squares (squares on upwards arrows) for stimulation. Abbreviations: RA, rheumatoid arthritis; JAK-STAT, Janus kinase-signal transducer and activator of transcription pathways; P, phosphorylation; SOCS, suppressor of cytokine signaling.

have clearly been demonstrated to be critically important in the RA pathogenesis, and effective therapies result in a reduction in the number of synovial macrophages, regardless of the biologic pathways targeted [132,133]. The mechanisms contributing to the persistent activation of macrophages may be a result of the expression of endogenous toll-like receptor (TLR) ligands such as gp96 and tenascin-C, which are upregulated in RA and are capable of activating macrophages through TLR signaling [135], thus creating of self-perpetuating, progressive chronic inflammatory process. Thus, targeting innate or adaptive immunity has a already proved beneficial in RA, and targeting additional pathways such as complement, the FcgR, and TLR signaling pathways hold promise for further therapeutic advances.

Selective biological agents for RA therapy A growing knowledge of the pathogenesis of an autoimmune inflammatory process has expanded the spectrum of new molecules and some of these may become the therapeutic targets of RA [195]. The therapeutic possibilities have been expanded by novel monoclonal antibodies, fusion protein or antagonist against several proinflammatory cytokines, cytokine receptors, adipokines, multi-ligand RAGE or agents targeting cell surface markers. Most encouraging therapeutic strategies of recent years are small molecules; mostly inhibitors of intracellular signaling pathways. There are many other targets with potential therapeutic utility

approaching such as various components innate immunity, regulatory T cells, B cells. We have selected various targets and number of biologic agents for RA therapy that in our opinion offer several potential therapeutic opportunities for RA. These selected targets and their respective biologic agents (or small inhibitors) have been summarized in Table 1. Advances in the current knowledge of RA pathogenesis have contributed to the development of biological therapy, and translated research findings into clinical practice. TNF-a, IL-1 and IL-6 inhibitors, a B-cell depleting agents and drugs blocking T-cell costimulation have been approved for RA. The progress in manufacturing biotechnology has contributed to the development of several other prospective agents that may form the basis for the therapy of RA in the near future. New or modified TNF-a inhibitors, new monoclonal antibodies against other cytokines (e.g. IL-7, IL-15, IL-17, IL-23, IL-19, IL-18, etc.), and other agents targeting B-cell depletion (e.g. ocrelizumab and ofatumumab) are in various stages of development. Many pharmaceutical companies have focused on developing small molecule inhibitors, which are considered promising drugs for RA. In most cases, these small molecules inhibit cellular kinases that mediate the signaling and transcription of proinflammatory genes. Now many kinases (e.g. p38a-MAPK, JNK-1 MAPK, MEK 1/2, JAK 1/2/3 or IKK-2) have been convincingly implicated in the pathogenesis of RA, and many kinase inhibitors have proved efficacious in the treatment of inflammatory arthritis in animals. Few kinase inhibitors, however, have so far made it

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Table 1. Selected therapeutic targets and their respective biological agents for RA therapy. S No.

Targets

Agents

Agents properties

Reference(s)

1. (a)

Cytokines TNF

(b)

IL-1

(c)

IL-6

(d)

IL-15

(e)

IL-17

(f)

IL-23/IL-19

(g) (h)

IL-7 IL-18

Anti-IL-7Ra IL-18BP

TNF-specific monoclonal antibodies, DMARD. TNF-specific monoclonal antibodies, DMARD. TNF-R-Fc fusion protein, DMARD. TNF-specific monoclonal antibodies, DMARD. TNF-specific monoclonal antibodies, DMARD. Recombinant IL-1R antagonist, DMARD. IL-1-specific monoclonal antibodies. Construct of two IL-1Rchains with an IgG-Fc domain, DMARD. IL-6R-specific monoclonal antibodies, DMARD. Soluble IL-6R fusion protein IL-15-specific monoclonal antibodies, DMARD. Antibody specific for gc subunit of IL-15R, DMARD. IL-15 fusion protein specific for IL-15R IL-17A-specific monoclonal antibodies IL-17 receptor/human IgG1 Fc fusion protein Inhibitor of nuclear translocation of c-Rel. Down-regulator of IL-12p35 and IL-12/IL-23p40 at the transcriptional level. IL-6R-specific antibodies IL-18 fusion protein with the Fc portion of murine IgG1

2.

Adipokines

Allo-aca

Leptin R antagonist peptide

[152]

3.

RAGE

RAP sRAGE Anti-RAGE

S100-P derived RAGE antagonist peptide Analog of RAGE, a decoy for RAGE ligands Antibodies specific for RAGE

[153] [154,155] [156]

4.

Innate immunity

Celecoxib TFM-C DCB 3503

COX-2 inhibitor, immunomodulator, DMARD. 4-trifluoromethyl analogue of celecoxib Tylophorine analog, suppressor of innate immune response.

[157] [158] [159]

5. (a)

Adaptive immunity T-cells

(b)

B-cells

Alemtuzumab Keliximab Clenoliximab Ocrelizumab Ofatumumab (HUMax-CD20)

Anti-CD52, Campath-1H, DMARD. Anti-CD4 monoclonal antibody, DMARD. IgG4 of CD4 antibody, DMARD. Anti-CD20 monoclonal antibody (humarized), DMARD. Anti-CD20 monoclonal antibody (fully), DMARD.

[160] [161] [162] [163] [164]

7. (a)

p38-MAPK

TRU-015 RWJ-67657 KR-003048 FRI167653

anti-CD20 IgG fusion protein, DMARD. Inhibitor of p38a and p38b p38a inhibitor p38 inhibitor (subunits not defined), which blocks CIA onset. Inhibitor of p38a, p38b and p38g p38a inhibitor Inhibitor of p38a and p38b Inhibitor of p38a and p38b Inhibitor of all p38MAPK: p38a/b/g/ p38a inhibitor p38a inhibitor p38a inhibitor Inhibitor of all JNKs: JNK1/2/3 Pan-JNK inhibitor JNK-interacting protein 1 peptide, JNK 1 inhibitor ERK-I and ERK-II inhibitor MEK-1 inhibitor MEK-1 and MEK-II inhibitor MEK-1 and MEK-II inhibitor MEK-1 and MEK-II inhibitor

[165] [166,167] [168] [169]

(b)

JNK-MAPKs

(c)

MEK/ERK-MAPKs

8.

NF-kB

Infliximab (Remicade) Adalimumab (Humira) Etanercept (Enbrel) Golimumab Certolizumab pegal (CDP870) Anakinra (Kineret) Canakinumab (ACZ885) Rilonacept (IL-1 trap) Tocilizumab IL-6RFP AMG714 HuMax IL-15 antibody IL-15-Fcg2a AIN457 muIL-17R:Fc Apilimod STA-5326

VX-745 VX-702 SB-203580 SB-731445 BIRB-796 SCIO-323 AMG-548 Pamapimond SP600125 AS601245 pepJIP1 FR180204 PD98059 PD184352 U0126 ARRY-162 BMS-205820 BMS-345541 BMS-066 SPC839 Staurosporin TPCA-1 PHA-408 ML120B IMD-0560

Synthetic D-amino acid peptide, inhibitor of nuclear localization IKK2 inhibitor IKK2 inhibitor IKK2 inhibitor IKK2 inhibitor IKK2 inhibitor IKK2 inhibitor IKK2 inhibitor IKK2 inhibitor

[4–6,136] [4–6,137] [4–6,136] [4–6,136] [138] [139] [140] [141] [142] [4,143] [144,145] [145] [146] [147] [148] [149] [150] [151] [40]

[170] [171,172] [173] [173] [173] [173] [172] [172] [172,174] [172] [172,175] [172,176] [177] [178] [179] [172] [180] [181] [182] [183] [184] [185] [186] [187] [188] (continued )

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Table 1. Continued

S No.

9.

Targets

Janus kinases

Agents

Agents properties

Reference(s)

NSAIDs (asprin, salycilate, inbuprofen, sulindac, etc.) Sulfasalazine SC-514 Cyclosporin A Tacrolimus (FK-506) Bortezomib (PS-341)

IKK2 inhibitors

[125]

IKK2 inhibitor IKK2 inhibitor Inhibitor of 20S proteasomal degradation Inhibitor of nuclear translocation of c-Rel Proteasome inhibitor

[189] [190] [191] [192] [193]

CP-690550 INCB18424

JAK3 inhibitor JAK1 and JAK2 inhibitor

[129,194] [194]

RA, rheumatoid arthritis; TNF, tumor necrosis factor; DMARD, disease modifying anti-arthritic drug; R, receptor; IL, interleukin; IgG, immunoglobulin G; IL-18BP, IL-18 binding protein; RAGE, receptor for advanced glycation end products; RAP, RAGE antagonist peptide; sRAGE, soluble RAGE; COX-2, cyclooxygenase-2; CD, cluster of differentiation; MAPKs, mitogen activated protein kinases; CIA, collagen induced arthritis; JNK, c-jun N-terminal kinases; ERK, extracellular receptor kinases; MEK, MAP kinase ERK ; NF-kB, nuclear factor-kappa B; IKK, IkB kinase; NSAIDS, non-sterodial anti-inflammatory drugs; JAK; janus kinase.

into clinical development, let alone survived the rigors of a phase II RA clinical trial [172]. For instance, the experience with p38a-MAPK or IKK-2 inhibitors highlights the importance of appraising the potential effects of kinase inhibition on feedback loops. Finally, caution should be exerted in assigning culpability to a specific kinase on the basis of the effects of small-molecule inhibitors, most of which lack specificity. Finally, the up-and-coming efforts at biomarker discovery in RA may one day mean that even those kinase inhibitors now relegated to the scrap heap can be used as effective and safe therapy in specific patient subsets.

[198]. Now it is well clear that inhibition of a single proinflammatory cytokine or any other single proinflammatory mediators is insufficient to arrest the OA process. Although a rationale exists, the available evidence does not support the current use of biologic therapy in OA, but there is still some hope for biologic agents in the future treatment of OA. As the molecular pathogenesis of OA clarifies, and now clinical development programs for disease-modifying OA drugs development become more efficient [197,198], it is likely that biological will be among the interesting candidate agents evaluated for structural modification in OA.

Targeted therapy for osteoarthritis: relevance to RA

Challenges and opportunities

The two most common diseases affecting human articulating joints are RA and OA. The debilitating joint destruction associated with RA has long been attributed to ongoing chronic inflammation of the synovial lining. The infiltration of this tissue with immunocompetent cells and the proliferation of synovial fibroblasts lead to the formation of pannus tissue, which invades and degrades the articular cartilage and subchondral bone. In comparison, the major pathological feature of OA is the gradual destruction and loss of the articular cartilage, which has been linked to a combination of mechanical and biochemical factors. Synovial inflammation in OA is thought to be a secondary process driven by the degradation of articular cartilage and the release of potentially immunogenic molecules during this process [196]. Despite the obvious differences in their pathologies, both diseases share a number of molecular targets that have been considered key control points for therapeutic intervention. These include the cytokines IL-b and TNF-a; extracellular matrix degrading enzymes such as the MMPs; prostaglandins and nitric oxide synthase [197]. The success of targeted biological therapy in RA has taught that the blockade of a single dominant cytokine can lead to remarkable clinical benefit, even in complex disease. The effectiveness of biological in inflammatory arthritis as disease modifying agents has increased the likelihood that similar strategies can be developed to target specific molecular mechanisms in OA. But the future of therapies targeting cytokines, nitric oxide synthesis and growth factors in OA is questionable as recent results from clinical trials have been repeatedly negative

The emerging biologic agents show that a new era has started in the treatment of RA. Recent advances in our understanding of cellular and molecular mechanisms of RA has identified numerous pathogenetic pathways that represent potential targets for biologic therapy beyond the already successful anti-TNF inhibitors; however, a significant proportion of patients show only partial responses or fail to respond [199]. Present clinical data suggest that inhibition of IL-1, IL-6, IL-15 and IL-17 are emerging as suitable therapeutic targets for effective amelioration of inflammation and bone destruction and perhaps IL-7, IL-18, IL-32 and IL-10 family of cytokines, could offer therapeutic potentials. Choosing the correct target is always challenging. The hierarchical relationship within synovial cytokine network remains unclear. In addition, adipokines are fascinating novel mediators of proinflammatory intercellular communicators. Understanding the mechanisms that lead from obesity to inflammation will have important implications for the design of new therapies to reduce the morbidity and mortality of obesity and RA. Therefore it is very exciting to consider adipokines as future therapeutic targets for RA therapeutics. Furthermore, multiligands receptor RAGE and its associated signaling events are involved in the production of proinflammatory cytokine, chemokines, adhesion molecules and oxidative stress and causing inflammation in RA. Recent therapeutic strategies show that RAGE is an important target for RA therapy. Finally, intracellular signaling and transcription pathways represent attractive therapeutic targets, provided that potential therapeutic modulators are carefully selected and have high

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molecular specificities. Understanding intracellular signaling cascades may offer opportunities to target cytokine pathways, transcription factors with small molecule inhibitors to replace the current trend to biological interventions. But a careful dissection of a targeted pathway is needed so that novel therapeutic interventions designed to specifically block inflammatory signaling may be developed. Further as these signaling pathways evolved for host defense, questions about the risks of signal transduction blockade using small molecule inhibitors will need to be carefully addressed. Preliminary clinical data on p38a-MAPK and JAK3 inhibition seems promising so far, but further understanding of these and other arthritic mechanisms has the potential to provide effective, and importantly, safe therapeutic options for RA therapy in the coming years. In short, novel proinflammatory activities of cytokines and other inflammatory mediators are emerging on an ongoing basis. There remain difficulties in ascribing regulatory hierarchy for given moieties on the basis of existing preclinical model systems. This in turn poses novel challenges in determining which targets represent the best therapeutic targets.

Key messages   

Preclinical evidences suggest that IL-7, IL-18, IL-22 and IL-32 offer novel therapeutic potential for RA. Multi-ligand receptor RAGE and adipokines are intriguing targets for new biologics. p38a-MAPK, IKK(a/b) or JAK3 are intracellular mediators for joint destruction, therefore are powerful targets.

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11. 12. 13. 14. 15. 16. 17. 18.

19.

20. 21. 22. 23.

Declaration of interest The authors report no conflicts of interests. The authors are responsible for the content and the writing of this article. This work was supported by National Science Technology Innovation Plan/KACST grant 11-BIO1885-09.

24.

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Therapeutic targets for rheumatoid arthritis: Progress and promises.

Recent therapeutic advancements in understanding of molecular and cellular mechanisms of rheumatoid arthritis (RA) have highlighted the strategies tha...
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