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Inflamed Joints (inflamed + joint)

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Medical Sciences	96%

Selected Abstracts

Knockdown of Fc, receptor III in an arthritic temporomandibular joint reduces the nociceptive response in rats

ARTHRITIS & RHEUMATISM, Issue 10 2010
Phillip R. Kramer
Objective Fc, receptor III (Fc,RIII; CD16) is a receptor expressed on immune cells that selectively binds IgG molecules. IgG binding results in cellular activation and cytokine release. IgG is an important factor in arthritis and can be found in the arthritic temporomandibular joint (TMJ). We undertook this study to test the hypothesis that a reduction in Fc,RIII expression in TMJ tissues would reduce the nociceptive and inflammatory responses in an inflamed joint. Methods Small interfering RNA (siRNA), either naked or complexed with linear polyethyleneimine, was injected into the superior joint space of the TMJ in rats. After administration of siRNA the joint was injected with saline or with Freund's complete adjuvant to induce arthritis. Nociceptive responses were quantitated in the rat by measuring the animal's meal duration. Fc,RIII expression in the TMJ tissue was assayed by immunocytochemistry or Western blotting. Cleavage of Fc,RIII transcript was then assayed by 5, rapid amplification of complementary DNA ends. Interleukin-1, (IL-1,) and IgG content was measured in the TMJ tissue by enzyme-linked immunosorbent assay. Results Injection of Fc,RIII siRNA reduced the amount of Fc,RIII in the TMJ tissues, and the transcript was cleaved in a manner consistent with an RNA interference mechanism. Moreover, injection of Fc,RIII siRNA reduced the nociceptive response of rats with an arthritic TMJ and reduced the amount of the proinflammatory cytokine IL-1,. Conclusion Fc,RIII contributes to the pain resulting from inflammatory arthritis of the TMJ, and siRNA has the potential to be an effective treatment for this disorder. [source]

A randomized, double-blind, controlled study of ultrasound-guided corticosteroid injection into the joint of patients with inflammatory arthritis,

ARTHRITIS & RHEUMATISM, Issue 7 2010
Joanna Cunnington
Objective Most corticosteroid injections into the joint are guided by the clinical examination (CE), but up to 70% are inaccurately placed, which may contribute to an inadequate response. The aim of this study was to investigate whether ultrasound (US) guidance improves the accuracy and clinical outcome of joint injections as compared with CE guidance in patients with inflammatory arthritis. Methods A total of 184 patients with inflammatory arthritis and an inflamed joint (shoulder, elbow, wrist, knee, or ankle) were randomized to receive either US-guided or CE-guided corticosteroid injections. Visual analog scales (VAS) for assessment of function, pain, and stiffness of the target joint, a modified Health Assessment Questionnaire, and the EuroQol 5-domain questionnaire were obtained at baseline and at 2 weeks and 6 weeks postinjection. The erythrocyte sedimentation rate and C-reactive protein level were measured at baseline and 2 weeks. Contrast injected with the steroid was used to assess the accuracy of the joint injection. Results One-third of CE-guided injections were inaccurate. US-guided injections performed by a trainee rheumatologist were more accurate than the CE-guided injections performed by more senior rheumatologists (83% versus 66%; P = 0.010). There was no significant difference in clinical outcome between the group receiving US-guided injections and the group receiving CE-guided injections. Accurate injections led to greater improvement in joint function, as determined by VAS scores, at 6 weeks, as compared with inaccurate injections (30.6 mm versus 21.2 mm; P = 0.030). Clinicians who used US guidance reliably assessed the accuracy of joint injection (P < 0.001), whereas those who used CE guidance did not (P = 0.29). Conclusion US guidance significantly improves the accuracy of joint injection, allowing a trainee to rapidly achieve higher accuracy than more experienced rheumatologists. US guidance did not improve the short-term outcome of joint injection. [source]

Synovial fluid proteins differentiate between the subtypes of juvenile idiopathic arthritis

ARTHRITIS & RHEUMATISM, Issue 6 2010
Margalit E. Rosenkranz
Objective Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory diseases, and no clinically useful prognostic markers to predict disease outcome in children with JIA are currently available. Synovial fluid likely reflects the proteins present in the inflamed synovium. The purpose of this study was to delineate the synovial fluid proteome and determine whether protein expression differs in the different subtypes of JIA. Methods Synovial fluid samples obtained from children with oligoarticular JIA, polyarticular JIA, or systemic JIA were compared. Two-dimensional gel electrophoresis for protein separation and matrix-assisted laser desorption ionization,time-of-flight mass spectrometry and quadripole time-of-flight mass spectrometry for protein identification were used for this study. Synovial fluid cells were analyzed by polymerase chain reaction (PCR) for the presence of haptoglobin messenger RNA (mRNA). Results The synovial fluid proteome of the samples was delineated. The majority of proteins showed overexpression in JIA synovial fluid as compared with noninflammatory control samples. There were 24 statistically significantly differentially expressed spots (>2-fold change; P < 0.05) between the subtypes of JIA. PCR analysis revealed haptoglobin mRNA, suggesting that haptoglobin is locally produced in an inflamed joint in JIA. Conclusion Despite the similar histologic appearance of inflamed joints in patients with different subtypes of JIA, there are differences in protein expression according to the subtype of JIA. Haptoglobin is differentially expressed between the subtypes of JIA and is locally produced in an inflamed joint in JIA. Haptoglobin and other differentially expressed proteins may be potential biomarkers in JIA. [source]

Angiogenesis and blood vessel stability in inflammatory arthritis

ARTHRITIS & RHEUMATISM, Issue 3 2010
Aisling Kennedy
Objective To assess blood vessel stability in inflammatory synovial tissue (ST) and to examine neural cell adhesion molecule (NCAM), oxidative DNA damage, and hypoxia in vivo. Methods Macroscopic vascularity and ST oxygen levels were determined in vivo in patients with inflammatory arthritis who were undergoing arthroscopy. Vessel maturity/stability was quantified in matched ST samples by dual immunofluorescence staining for factor VIII (FVIII)/,-smooth muscle actin (,-SMA). NCAM and 8-oxo-7,8-dihydro-2,-deoxyguanosine (8-oxodG) were examined by immunohistochemistry. Angiogenesis was assessed in vitro, using human dermal endothelial cells (HDECs) in a Matrigel tube formation assay. Results A significant number of immature vessels (showing no pericyte recruitment) was observed in tissue from patients with inflammatory arthritis (P < 0.001), in contrast to osteoarthritic and normal tissue, which showed complete recruitment of pericytes. Low in vivo PO2 levels in the inflamed joint (median [range] 22.8 [3.2,54.1] mm Hg) were inversely related to increased macroscopic vascularity (P < 0.04) and increased microscopic expression of FVIII and ,-SMA (P < 0.04 and P < 0.03, respectively). A significant proportion of vessels showed focal expression of NCAM and strong nuclear 8-oxodG expression, implicating a loss of EC,pericyte contact and increased DNA damage, levels of which were inversely associated with low in vivo PO2 (P = 0.04 for each comparison). Circulating cells were completely negative for 8-oxodG. Exposure of HDEC to 3% O2 (reflecting mean ST in vivo measurements) significantly increased EC tube formation (P < 0.05). Conclusion Our findings indicate the presence of unstable vessels in inflamed joints associated with hypoxia, incomplete EC,pericyte interactions, and increased DNA damage. These changes may further contribute to persistent hypoxia in the inflamed joint to further drive this unstable microenvironment. [source]

Nitrite-mediated protection against hypochlorous acid,induced chondrocyte toxicity: A novel cytoprotective role of nitric oxide in the inflamed joint?

ARTHRITIS & RHEUMATISM, Issue 11 2003
Matthew Whiteman
Objective To examine the potential consequences of overproduction of nitric oxide (NO) and nitrite (NO) in the inflamed rheumatoid joint. Methods Human articular chondrocytes in culture were exposed to HOCl (hypochlorous acid, a physiologic oxidant formed in increased amounts at sites of chronic inflammation), and assays of cell viability, intracellular ATP and glutathione (GSH), and lactate dehydrogenase (LDH) were performed. HOCl-induced lipid peroxidation and activation of the MAP kinases ERK-1/2, JNK-1/2, and p38 were also measured. The modulatory effects of NO-derived nitrite (NO) and nitrate (NO) on HOCl-mediated chondrocyte toxicity were investigated. Results Exposure of human articular chondrocytes to HOCl resulted in a concentration- and time-dependent loss of viability, decrease in ATP and GSH levels, LDH leakage, and cell death. HOCl induced significant lipid peroxidation as well as activation of the MAP kinases ERK-1/2 and p38 but not JNK-1/2. However, the presence of NO but not NO substantially decreased HOCl-dependent cellular toxicity even when NO was added at low (,M) concentrations. In sharp contrast, NO (1 mM) did not inhibit superoxide-, hydroxyl radical,, H2O2 -, or peroxynitrite-mediated cytotoxicity. Furthermore, culture media from cells treated with interleukin-1, (to generate NO and NO) offered significantly more protection against HOCl-mediated cytotoxicity than culture media from untreated cells. Conclusion These data suggest that NO accumulation at chronically inflamed sites where both HOCl and NO are overproduced may be cytoprotective against damage induced by HOCl. Accumulation of NO could represent a novel cytoprotective role of NO in inflamed joints. A mechanism for this is suggested. [source]

Comparison of synovial tissues from the knee joints and the small joints of rheumatoid arthritis patients: Implications for pathogenesis and evaluation of treatment

ARTHRITIS & RHEUMATISM, Issue 8 2002
Maarten C. Kraan
Objective Serial synovial biopsy samples are increasingly being used for the evaluation of novel therapies for rheumatoid arthritis (RA). Most studies have used tissues from knee biopsies, but technical improvements have made serial small joint arthroscopy feasible as well. Theoretically, there could be differences in the features of synovial inflammation between various joints as a result of mechanical factors, differences in innervation, and other factors. We therefore undertook this study to compare the cell infiltrate in paired synovial biopsy samples from inflamed knee joints and paired inflamed small joints of patients with RA. Methods Nine RA patients with both an inflamed knee joint and an inflamed small joint (wrist or metacarpophalangeal joint) underwent an arthroscopic synovial biopsy of both joints on the same day. Multiple biopsy specimens were collected and stained for macrophages, T cells, plasma cells, fibroblast-like synoviocytes, and interleukin-6 (IL-6) by immunohistochemistry. Sections were evaluated by digital image analysis. Results There were no significant differences in mean cell numbers for all markers investigated in samples from the knee joint compared with samples from the small joints. We detected statistically significant correlations for the numbers of sublining macrophages, T cells, and plasma cells, as well as for IL-6 expression, between the knee joint and the small joints. However, there was no significant correlation between different joints for the numbers of intimal macrophages or fibroblast-like synoviocytes. Conclusion The results of this study show that the inflammation in one inflamed joint is generally representative of that in other inflamed joints. Therefore, it is possible to use serial samples from the same joint, selecting either large or small joints, for the evaluation of antirheumatic therapies. [source]

Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2004
Albert Hietala
Abstract To analyze the role of the classical and alternative pathways of complement activation in the effector phase of arthritis, we have induced arthritis in C3- and factor,B (FB)-deficient (C3,/, and FB,/,) DBA/1J mice using well-defined monoclonal IgG2b and IgG2a antibodies to type,II collagen. In control DBA/1J mice, severe swelling of the joints, destruction of cartilage and erosion of bone developed very rapidly with a 100% incidence and a peak on days,7,10. Although 75% of C3,/, mice developed arthritis, the clinical severity was very mild and the onset was delayed. Severity of arthritis in FB,/, mice ranked intermediate in comparison with C3,/, and control mice with an incidence of 100%. Immunohistochemical analysis of the inflamed joints demonstrated substantial reduction in macrophage and neutrophilic leukocyte infiltration in both C3,/, and FB,/, mice, thereby confirming the clinical findings. We conclude that both the classical and the alternative pathways of complement activation are involved in the effector phase of arthritis. [source]

Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2006
Allen P. Anandarajah
Abstract Focal bone loss around inflamed joints in patients with autoimmune disease, such as rheumatoid arthritis, remains a serious clinical problem. The recent elucidation of the RANK/RANK-ligand/OPG pathway and its role as the final effector of osteoclastogenesis and bone resorption has brought a tremendous understanding of the pathophysiology of inflammatory bone loss, and has heightened expectation of a novel intervention. Here, we review the etiology of inflammatory bone loss, the RANK/RANK-ligand/OPG pathway, and the clinical development of anti-RANK-ligand therapy. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source]

Efficacy of chitosan microspheres for controlled intra-articular delivery of celecoxib in inflamed joints

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2004
Hetal Thakkar
The use of polymeric carriers in formulations of therapeutic drug delivery systems has gained widespread application, due to their advantage of being biodegradable and biocompatible. In this study, we aimed to prepare celecoxib-loaded chitosan microspheres for intra-articular administration and to compare the retention of the celecoxib solution and chitosan microspheres in the joint cavity. The microspheres were characterized for entrapment efficiency, particle size and surface morphology by scanning electron microscopy. In-vitro drug release studies of microspheres revealed that the microspheres are able to control the release of celecoxib over a period of 96 h. Biodistribution studies of celecoxib and chitosan microspheres were performed by radiolabelling with 99mTc and injecting intra-articularly in rats. The study indicated that following intra-articular administration the distribution of the drug to the organs, like liver and spleen, is very rapid compared with that of the microspheres. Compared with the drug solution, a 10-fold increase in the concentration of the drug in the joint was observed 24 h post intra-articular injection (P < 0.005) when drug was encapsulated in microspheres. [source]

Synovial fluid proteins differentiate between the subtypes of juvenile idiopathic arthritis

Human single-chain variable fragment that specifically targets arthritic cartilage

ARTHRITIS & RHEUMATISM, Issue 4 2010
Chris Hughes
Objective To demonstrate that posttranslational modification of type II collagen (CII) by reactive oxygen species (ROS), which are known to be present in inflamed arthritic joints, can give rise to epitopes specific to damaged cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA) and to establish a proof of concept that antibodies specific to ROS-modified CII can be used to target therapeutics specifically to inflamed arthritic joints. Methods We used a semisynthetic phage display human antibody library to raise single-chain variable fragments (scFv) specific to ROS-modified CII. The specificity of anti,ROS-modified CII scFv to damaged arthritic cartilage was assessed in vitro by immunostaining articular cartilage from RA and OA patients and from normal controls. The in vivo targeting potential was tested using mice with antigen-induced arthritis, in which localization of anti,ROS-modified CII scFv in the joints was determined. The therapeutic effect of anti,ROS-modified CII scFv fused to soluble murine tumor necrosis factor receptor II,Fc fusion protein (mTNFRII-Fc) was also investigated. Results The anti,ROS-modified CII scFv bound to damaged arthritic cartilage from patients with RA and OA but not to normal preserved cartilage. When systemically administered to arthritic mice, the anti,ROS-modified CII accumulated selectively at the inflamed joints. Importantly, when fused to mTNFRII-Fc, it significantly reduced inflammation in arthritic mice, as compared with the effects of mTNFRII-Fc alone or of mTNFRII-Fc fused to an irrelevant scFv. Conclusion Our findings indicate that biologic therapeutics can be targeted specifically to arthritic joints and suggest a new approach for the development of novel treatments of arthritis. [source]

Angiogenesis and blood vessel stability in inflammatory arthritis

Adeno-associated virus type 5,mediated intraarticular administration of tumor necrosis factor small interfering RNA improves collagen-induced arthritis

ARTHRITIS & RHEUMATISM, Issue 3 2010
Maroun Khoury
Objective RNA interference (RNAi) is a powerful tool for sequence-specific gene silencing, and interest in its application in human diseases is growing. Given the success of recent strategies for administering gene therapy in rheumatoid arthritis using recombinant vectors such as adeno-associated virus type 5 (rAAV5) for optimized intraarticular gene transfer, we undertook the present study to determine the feasibility of using rAAV5-mediated RNAi-based therapy in arthritis. Methods We developed rAAV5 vectors expressing short hairpin small interfering RNA (shRNA) against tumor necrosis factor , (TNF,) under H1 promoter, and carrying the enhanced green fluorescent protein (eGFP) reporter gene under cytomegalovirus promoter (rAAV5-shTNF). TNF, gene silencing was validated in vitro with mouse macrophages. Mice with collagen-induced arthritis were injected in the ankle and knee joints, at disease onset, with either rAAV5-shTNF or control rAAV5-eGFP vectors (5 × 109 particles). Arthritis severity was assessed clinically and histologically, and immunologic response was examined. Local and systemic transgene expression was monitored using quantitative reverse transcriptase,polymerase chain reaction, immunohistochemical analysis, and enzyme-linked immunosorbent assay. Results After a single injection of rAAV5-shTNF into inflamed joints, local TNF, gene silencing provided rapid and long-term suppression of arthritis progression and reduced joint damage compared with that observed in control groups. Treatment with rAAV5-shTNF was associated with decreased proliferation and interferon-, production by antigen-stimulated T cells from draining lymph nodes, and the potency of this treatment was similar to that observed with other treatment strategies targeting TNF, at the protein level, either locally or systemically. Conclusion Our data present the first proof-of-concept for the application of rAAV5-mediated RNAi-based gene therapy for local blockade of inflammation in experimental arthritis. [source]

Thrombin-activatable carboxypeptidase B cleavage of osteopontin regulates neutrophil survival and synoviocyte binding in rheumatoid arthritis

ARTHRITIS & RHEUMATISM, Issue 10 2009
Shadi A. Sharif
Objective Osteopontin (OPN) is a proinflammatory cytokine that plays an important role in the pathogenesis of rheumatoid arthritis (RA). OPN can be cleaved by thrombin, resulting in OPN-R and exposing the cryptic C-terminal ,4,1 and ,9,1 integrin,binding motif (SVVYGLR). Thrombin-activatable carboxypeptidase B (CPB), also called thrombin-activatable fibrinolysis inhibitor, removes the C-terminal arginine from OPN-R, generating OPN-L and abrogating its enhanced cell binding. We undertook this study to investigate the roles of OPN-R and OPN-L in synoviocyte adhesion, which contributes to the formation of invasive pannus, and in neutrophil survival, which affects inflammatory infiltrates in RA. Methods Using specifically developed enzyme-linked immunosorbent assays, we tested the synovial fluid of patients with RA, osteoarthritis (OA), and psoriatic arthritis (PsA) to determine OPN-R, OPN-L, and full-length OPN (OPN-FL) levels. Results Elevated levels of OPN-R and OPN-L were found in synovial fluid samples from RA patients, but not in samples from OA or PsA patients. Increased levels of OPN-R and OPN-L correlated with increased levels of multiple inflammatory cytokines, including tumor necrosis factor , and interleukin-6. Immunohistochemical analyses revealed robust expression of OPN-FL, but only minimal expression of OPN-R, in RA synovium, suggesting that cleaved OPN is released into synovial fluid. In cellular assays, OPN-FL, and to a lesser extent OPN-R and OPN-L, had an antiapoptotic effect on neutrophils. OPN-R augmented RA fibroblast-like synoviocyte binding mediated by SVVYGLR binding to ,4,1, whereas OPN-L did not. Conclusion Thrombin activation of OPN (resulting in OPN-R) and its subsequent inactivation by thrombin-activatable CPB (generating OPN-L) occurs locally within inflamed joints in RA. Our data suggest that thrombin-activatable CPB plays a central homeostatic role in RA by regulating neutrophil viability and reducing synoviocyte adhesion. [source]

Elevated expression of interleukin-7 receptor in inflamed joints mediates interleukin-7,induced immune activation in rheumatoid arthritis

ARTHRITIS & RHEUMATISM, Issue 9 2009
Sarita A. Y. Hartgring
Objective To evaluate the expression and functional ability of the high-affinity interleukin-7 receptor (IL-7R,) in patients with rheumatoid arthritis (RA). Methods Expression of IL-7R, and IL-7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA). IL-7R, expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL-7R,bright and IL-7R,dim/, T cells was measured. In addition, we examined IL-7R blockade with soluble human IL-7R, (hIL-7R,) in the prevention of immune activation of peripheral blood mononuclear cells. Results We found significantly higher IL-7R, expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL-7R, expression correlated significantly with the levels of CD3 and IL-7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL-7R,. A substantial percentage of B cells and macrophages from RA synovial fluid and synovial tissue also expressed IL-7R,, although less prominently than T cells. We found that peripheral blood IL-7R,bright T cells that did not express FoxP3 were highly proliferative as compared with IL-7R,dim/, T cells that did express high levels of FoxP3. Soluble hIL-7R, inhibited IL-7,induced proliferation and interferon-, production by mononuclear cells from RA patients. Conclusion Our data suggest that enhanced expression of IL-7R, and IL-7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL-7R,mediated immune activation by soluble hIL-7R, further indicates an important role of IL-7R, in inflammatory responses in RA, suggesting IL-7R, as a therapeutic target for immunotherapy in RA. [source]

Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo

ARTHRITIS & RHEUMATISM, Issue 9 2009
Roland Axmann
Objective To investigate the efficacy of a murine anti,interleukin-6 receptor (anti,IL-6R) antibody in directly blocking tumor necrosis factor (TNF), and RANKL-mediated osteoclastogenesis in vitro and in vivo. Methods The efficacy of a murine antibody against IL-6R in blocking osteoclast differentiation of mononuclear cells stimulated with RANKL was tested. In addition, arthritic human TNF,,transgenic mice were treated with anti,IL-6R antibody, and osteoclast formation and bone erosion were assessed in arthritic paws. Results Blockade of IL-6R dose dependently reduced osteoclast differentiation and bone resorption in monocyte cultures stimulated with RANKL or RANKL plus TNF. In human TNF,,transgenic mice, IL-6R blockade did not inhibit joint inflammation, but it strongly reduced osteoclast formation in inflamed joints as well as bone erosion in vivo. Neither the cell influx into joints nor the synovial expression of IL-6 and RANKL changed with IL-6R blockade, while the synovial expression of IL-1 was significantly reduced. In contrast, TNF-mediated systemic bone loss was not inhibited by IL-6R blockade. Conclusion These data suggest that blockade of IL-6R directly affects osteoclast formation in vitro and in vivo, suggesting a direct and specific effect of anti,IL-6R therapy on osteoclasts independently of its antiinflammatory effects. This effect adds significantly to the structure-sparing potential of pharmacologic blockade of IL-6R in arthritis. [source]

Indoleamine 2,3 dioxygenase,mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis

ARTHRITIS & RHEUMATISM, Issue 5 2009
Gabriel Criado
Objective Indoleamine 2,3 dioxygenase (IDO) is a catabolic enzyme that initiates the kynurenine pathway of tryptophan degradation and has immunomodulatory properties. The aim of this study was to investigate the regulation of collagen-induced arthritis by tryptophan catabolism mediated by IDO. Methods Arthritis was induced by immunization with type II collagen. After induction of arthritis, the expression of IDO was analyzed by quantitative reverse transcription,polymerase chain reaction. The effect of IDO deficiency on collagen-induced arthritis was assessed in vivo by administration of 1-methyltryptophan and clinical and histologic evaluation of IDO-deficient mice. The requirement for IDO activation was bypassed by administration of L -kynurenine. Results IDO was induced in lymph node dendritic cells after collagen immunization. Systemic inhibition of tryptophan catabolism during active arthritis increased disease severity. Conversely, bypassing the requirement for tryptophan degradation by the administration of L -kynurenine resulted in amelioration of arthritis. Furthermore, IDO-deficient mice showed a higher incidence of arthritis and exacerbated disease severity compared with IDO-competent mice. Such increased disease activity in IDO-deficient mice correlated early with increased production of the proinflammatory cytokines interferon-, and interleukin-17 by lymph node T cells and later with increased infiltration of Th1 and Th17 cells in the inflamed joints. Conclusion Our data indicate that the induction of IDO controls the accumulation of Th1 and Th17 pathogenic T cells at the site of inflammation during collagen-induced arthritis. Therefore, manipulation of the kynurenine pathway of tryptophan degradation provides the potential for therapeutic intervention in rheumatoid arthritis. [source]

Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis

ARTHRITIS & RHEUMATISM, Issue 3 2009
Gaby Palmer
Objective Interleukin-33 (IL-33; or, IL-1F11) was recently identified as the ligand of the IL-1 family receptor T1/ST2. The aim of this study was to examine IL-33 production in human and mouse joints and to investigate the role of IL-33 and T1/ST2 in experimental arthritis. Methods IL-33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints. Mice with collagen-induced arthritis (CIA) were treated with blocking anti-ST2 antibody or control antibody beginning at the onset of disease. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (LN) cell responses were examined ex vivo, and joint messenger RNA (mRNA) was used for expression profiling. Results IL-33 was highly expressed in human RA synovium. In cultured synovial fibroblasts, IL-33 expression was strongly induced by IL-1, and/or tumor necrosis factor ,. Furthermore, IL-33 mRNA was detected in the joints of mice with CIA and increased during the early phase of the disease. Administration of a blocking anti-ST2 antibody at the onset of disease attenuated the severity of CIA and reduced joint destruction. Anti-ST2 antibody treatment was associated with a marked decrease in interferon-, production as well as with a more limited reduction in IL-17 production by ex vivo,stimulated draining LN cells. Finally, RANKL mRNA levels in the joint were reduced by anti-ST2 treatment. Conclusion IL-33 is produced locally in inflamed joints, and neutralization of IL-33 signaling has a therapeutic effect on the course of arthritis. These observations suggest that locally produced IL-33 may contribute to the pathogenesis of joint inflammation and destruction. [source]

Interleukin-1, and tumor necrosis factor , inhibit chondrogenesis by human mesenchymal stem cells through NF-,B,dependent pathways,

ARTHRITIS & RHEUMATISM, Issue 3 2009
N. Wehling
Objective The differentiation of mesenchymal stem cells (MSCs) into chondrocytes provides an attractive basis for the repair and regeneration of articular cartilage. Under clinical conditions, chondrogenesis will often need to occur in the presence of mediators of inflammation produced in response to injury or disease. The purpose of this study was to examine the effects of 2 important inflammatory cytokines, interleukin-1, (IL-1,) and tumor necrosis factor , (TNF,), on the chondrogenic behavior of human MSCs. Methods Aggregate cultures of MSCs recovered from the femoral intermedullary canal were used. Chondrogenesis was assessed by the expression of relevant transcripts by quantitative reverse transcription,polymerase chain reaction analysis and examination of aggregates by histologic and immunohistochemical analyses. The possible involvement of NF-,B in mediating the effects of IL-1, was examined by delivering a luciferase reporter construct and a dominant-negative inhibitor of NF-,B (suppressor-repressor form of I,B [srI,B]) with adenovirus vectors. Results Both IL-1, and TNF, inhibited chondrogenesis in a dose-dependent manner. This was associated with a marked activation of NF-,B. Delivery of srI,B abrogated the activation of NF-,B and rescued the chondrogenic response. Although expression of type X collagen followed this pattern, other markers of hypertrophic differentiation responded differently. Matrix metalloproteinase 13 was induced by IL-1, in a NF-,B,dependent manner. Alkaline phosphatase activity, in contrast, was inhibited by IL-1, regardless of srI,B delivery. Conclusion Cell-based repair of lesions in articular cartilage will be compromised in inflamed joints. Strategies for enabling repair under these conditions include the use of specific antagonists of individual pyrogens, such as IL-1, and TNF,, or the targeting of important intracellular mediators, such as NF-,B. [source]

Interactions of T helper cells with fibroblast-like synoviocytes: Up-regulation of matrix metalloproteinases by macrophage migration inhibitory factor from both Th1 and Th2 cells

ARTHRITIS & RHEUMATISM, Issue 10 2008
Uta Schurigt
Objective Interactions of immune cells, such as activated T helper cells, with fibroblast-like synoviocytes (FLS) play a crucial role in the joint destruction during human rheumatoid arthritis (RA). This study was undertaken to investigate the expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) by T helper cells, and to assess the role of MIF in overexpression of matrix metalloproteinases (MMPs) in cocultures of FLS from arthritic mice with either Th1 or Th2 cells. Methods MIF expression by in vitro,polarized murine Th1 and Th2 cells was determined using 2 different generation protocols. FLS were isolated from the inflamed joints of mice with antigen-induced arthritis. MMP expression was analyzed in cocultures of the FLS with T helper cell subsets. Effects of MIF were blocked by a neutralizing anti-MIF antibody. In addition, analyses were performed on cocultures of either Th1 or Th2 cells with FLS from MIF-deficient mice. Results Both Th1 and Th2 cells expressed high quantities of MIF. MMPs were overexpressed by FLS after coculture with both Th1 and Th2 cells. Activated T helper cells were more effective than resting cells. Neutralization of MIF by an anti-MIF antibody led to a marked reduction in MMP expression in Th1- and Th2-stimulated FLS. T helper cells generated from MIF-deficient mice exhibited a T helper cell,specific cytokine profile comparable with that in wild-type cells, except in the expression of MIF, but showed an impaired ability to stimulate MMP expression in FLS. Conclusion MIF is an important Th1 and Th2 cell,derived proinflammatory cytokine that stimulates MMP expression in FLS from arthritic mice, and therefore inhibition of MIF might be a promising target for novel therapeutic strategies in human RA. [source]

Nitrite-mediated protection against hypochlorous acid,induced chondrocyte toxicity: A novel cytoprotective role of nitric oxide in the inflamed joint?

CD13/aminopeptidase N,induced lymphocyte involvement in inflamed joints of patients with rheumatoid arthritis

ARTHRITIS & RHEUMATISM, Issue 9 2002
Teruki Shimizu
Objective We previously showed that CD13/aminopeptidase N (EC 3.4.11.2) induces chemotactic migration of T lymphocytes by its enzymatic activity. In this study, we examined the role of CD13/aminopeptidase N in lymphocyte involvement in rheumatoid arthritis (RA). Methods Synovial fluids were obtained from 27 RA patients and 6 osteoarthritis (OA) patients. Synovial tissue specimens were obtained from 3 RA patients and 3 OA patients. Protease activity of aminopeptidase in synovial fluids and synovial fibroblasts was assayed fluorometrically using the specific substrate. Expression of CD13/aminopeptidase N in synovial fibroblasts was determined by flow cytometry analyses, Western blotting, and reverse transcriptase,polymerase chain reaction (RT-PCR). Results The mean value of aminopeptidase activity in synovial fluid samples from RA patients was significantly higher than that in samples from OA patients. Increased enzymatic activity of aminopeptidase was detected on synovial fibroblasts from RA patients compared with those from OA patients. Flow cytometry showed that the expression of CD13/aminopeptidase N on synovial fibroblasts from RA patients was higher than the expression on synovial fibroblasts from OA patients, and Western blots and RT-PCR showed that synovial fibroblasts from RA patients contained a greater amount of CD13/aminopeptidase N. The activity of CD13/aminopeptidase N correlated significantly with lymphocyte counts in synovial fluids from RA patients. Synovial fluids from RA patients in which high aminopeptidase activity was detected contained considerable chemotactic activity for lymphocytes, and bestatin, a specific inhibitor of aminopeptidases, partially inhibited the chemotactic activity. Conclusion CD13/aminopeptidase N may participate in the mechanism of lymphocyte involvement in inflamed joints of RA patients as a lymphocyte chemoattractant. [source]

Comparison of synovial tissues from the knee joints and the small joints of rheumatoid arthritis patients: Implications for pathogenesis and evaluation of treatment

A subset of natural killer cells is greatly expanded within inflamed joints

ARTHRITIS & RHEUMATISM, Issue 7 2002
Nicola Dalbeth
Objective To determine whether natural killer (NK) cells are present within inflamed joints and whether they might play a role in amplifying the inflammatory process. Methods Paired samples of peripheral blood and synovial fluid were obtained from 22 patients with inflammatory arthritis. The frequency and phenotype of the peripheral and synovial NK cells were analyzed using a panel of monoclonal antibodies. Further experiments were performed to investigate the functional capacity of the synovial NK cells. Results The study showed that the CD3,, CD56bright subset of NK cells was greatly expanded within inflamed joints. Our experiments suggested that this subset of cells was preferentially recruited from the periphery and that NK cells may be further activated by cytokines present within the joint. Furthermore, synovial NK cells responded to a combination of interleukin-12 (IL-12) and IL-15, cytokines that are secreted by cells of the monocyte/macrophage lineage, by rapidly secreting interferon-,, a cytokine that can, in turn, activate macrophages. Conclusion A subset of NK cells was expanded within inflamed joints. The functional properties of these NK cells rendered them good candidates for a role in interacting with the macrophage/monocyte population within the joint, thus amplifying the production of proinflammatory cytokines. [source]

Cloricromene, a coumarine derivative, protects against collagen-induced arthritis in Lewis rats

BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2000
Salvatore Cuzzocrea
The aim of the present study was to investigate the effects of cloricromene, a coumarine derivative, in rats subjected to collagen-induced arthritis. Collagen-induced arthritis (CIA) was induced in Lewis rats by an intradermal injection of 100 ,l of the emulsion (containing 100 ,g of bovine type II collagen) (CII) and complete Freund's adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. Lewis rats developed an erosive hind paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA first appeared as peri-articular erythema and oedema in the hind paws. The incidence of CIA was 100% by day 27 in the CII challenged rats and the severity of CIA progressed over a 35-day period with radiographic evaluation revealing focal resorption of bone together with osteophyte formation in the tibiotarsal joint and soft tissue swelling. The histopathology of CIA included erosion of the cartilage at the joint margins. Treatment of rats with cloricromene (10 mg kg,1 i.p. daily) starting at the onset of arthritis (day 23), delayed the development of the clinical signs at days 24,35 and improved histological status in the knee and paw. Immunohistochemical analysis for iNOS, COX-2, nitrotyrosine and for poly (ADP-ribose) synthetase (PARS) revealed a positive staining in inflamed joints from collagen-treated rats. The degree of staining for iNOS, COX-2, nitrotyrosine and PARS were markedly reduced in tissue sections obtained from collagen-treated rats, which had received cloricromene. Radiographic signs of protection against bone resorption and osteophyte formation were present in the joints of cloricromene-treated rat. This study provides the first evidence that cloricromene, a coumarine derivative, attenuates the degree of chronic inflammation and tissue damage associated with collagen-induced arthritis in the rat. British Journal of Pharmacology (2000) 131, 1399,1407; doi:10.1038/sj.bjp.0703695 [source]