Home About us Contact
|
Home About us Contact | ||
|
|
||
Inflammatory Arthritis (inflammatory + arthritis)
Kinds of Inflammatory Arthritis Selected AbstractsOsteoblast Function Is Compromised at Sites of Focal Bone Erosion in Inflammatory Arthritis,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2009Nicole C Walsh PhD Abstract In rheumatoid arthritis (RA), synovial inflammation results in focal erosion of articular bone. Despite treatment attenuating inflammation, repair of erosions with adequate formation of new bone is uncommon in RA, suggesting that bone formation may be compromised at these sites. Dynamic bone histomorphometry was used in a murine model of RA to determine the impact of inflammation on osteoblast function within eroded arthritic bone. Bone formation rates at bone surfaces adjacent to inflammation were similar to those observed in nonarthritic bone; therefore, osteoblast activity is unlikely to compensate for the increased bone resorption at these sites. Within arthritic bone, the extent of actively mineralizing surface was reduced at bone surfaces adjacent to inflammation compared with bone surfaces adjacent to normal marrow. Consistent with the reduction in mineralized bone formation, there was a notable paucity of cells expressing the mid- to late stage osteoblast lineage marker alkaline phosphatase, despite a clear presence of cells expressing the early osteoblast lineage marker Runx2. In addition, several members of the Dickkopf and secreted Frizzled-related protein families of Wnt signaling antagonists were upregulated in arthritic synovial tissues, suggesting that inhibition of Wnt signaling could be one mechanism contributing to impaired osteoblast function within arthritic bone. Together, these data indicate that the presence of inflammation within arthritic bone impairs osteoblast capacity to form adequate mineralized bone, thus contributing to the net loss of bone and failure of bone repair at sites of focal bone erosion in RA. [source] Inflammatory arthritis in caspase 1 gene,deficient mice: Contribution of proteinase 3 to caspase 1,independent production of bioactive interleukin-1,ARTHRITIS & RHEUMATISM, Issue 12 2009Leo A. B. Joosten Objective Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro,interleukin-1, (proIL-1,), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. Methods Acute and chronic arthritis were induced in caspase 1,/, mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. Results Surprisingly, caspase 1,/, mice, in a model of acute (neutrophil-dominated) arthritis, developed joint swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1, were comparable in caspase 1,/, mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1,/, mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1,dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1, concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. Conclusion Caspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1, production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present. [source] Is it possible to identify early predictors of the future cost of chronic arthritis?FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2009The VErA project Abstract This study was conducted to identify early predictors of the total cost of inflammatory arthritis (IA). One hundred and eighty patients affected by undifferentiated arthritis (UA) or rheumatoid arthritis (RA) were included in the French Very Early rheumatoid Arthritis (VErA) cohort between 1998 and 2001. Health economic data for 2003 were collected using a patient self-questionnaire. Results were analysed in terms of direct, indirect and total costs in 2003 euros (2003,) for the population as a whole and in diagnostic subgroups. A payor perspective (the French National Health Insurance, in this case) was adopted. Multiple linear regression models were used to identify predictors of total cost from among the criteria assessed on recruitment. Results of the study showed that for the study population as a whole, the mean total cost was ,4700 per patient. The costs attributable to the RA and UA sub-groups were ,5928 and ,2424 per patient, respectively. In a univariate analysis, certain parameters were significantly correlated with a higher cost of illness. In the multivariate analysis, some of these parameters were further identified as being predictive of higher cost. Two strong significant, early predictors of total cost were identified: higher pain (P = 0.002) and the presence of rheumatoid factor (P = 0.004). In the RA sub-group, lower grip strength of the dominant hand (P = 0.039) was another predictor of the illness's subsequent economic impact. In conclusion, our data show that simple clinical and laboratory parameters can be used early in the course of IA to predict the condition's impact on healthcare budgets. [source] Synovial mast cells: role in acute and chronic arthritisIMMUNOLOGICAL REVIEWS, Issue 1 2007Peter A. Nigrovic Summary:, Mast cells reside in the normal synovium and increase strikingly in number in rheumatoid arthritis and other joint diseases. Given the broad spectrum of activity of this lineage, it has for decades been considered probable that mast cells are involved in the pathophysiology of synovitis. Recent work in murine arthritis has substantiated this suspicion, showing that mast cells can contribute importantly to the initiation of inflammatory arthritis. However, the role of the greatly expanded population of synovial mast cells in established arthritis remains unknown. Here we review the current understanding of mast cell function in acute arthritis and consider the potentially important influence of this cell on key processes within the chronically inflamed synovium, including leukocyte recruitment and activation, fibroblast proliferation, angiogenesis, matrix remodeling, and injury to collagen and bone. We also consider recent evidence supporting an immunomodulatory or anti-inflammatory role for mast cells as well as pharmacologic approaches to the mast cell as a therapeutic target in inflammatory arthritis. [source] The genetic and immunopathological processes underlying collagen-induced arthritisIMMUNOLOGY, Issue 4 2001JEFF A. Luross Summary Animal models of rheumatoid arthritis (RA) have provided substantial insights into basic pathogenic mechanisms of chronic inflammatory arthritis and autoimmune disease in general. Of the variety of models reported, collagen-induced arthritis (CIA) has been the most characterized in terms of both its pathogenesis and its underlying immunological basis. Collagen-induced arthritis has also been the model of choice in terms of testing potential new therapeutic agents for the treatment of human RA. Nevertheless, the complex nature of the balance between T-cell cytokines and the chronic inflammatory processes is only recently becoming clear. This review focuses on these developments, highlighting their implications for our understanding of RA and for the use of CIA as a suitable animal model. [source] Normal ultrasound anatomy of the triangular fibrocartilage of the wrist: A study on cadavers and on healthy subjectsJOURNAL OF CLINICAL ULTRASOUND, Issue 4 2009Lionel Pesquer MD Abstract Purpose. To report the normal sonographic anatomy of the triangular fibrocartilage (TFC) of the wrist in cadavers and volunteers. Method. Five hands from cadavers were examined sonographically before and after wrist dissection, during which the TFC was marked with surgical wires. Twenty volunteers without wrist limitation or pain, and without any history of wrist disease or inflammatory arthritis (mean age, 26 years (range,19,45 years) were also examined. Results. Sonograms showed that the meniscus and the TFC were clearly separated. The meniscus appeared as a triangular structure that was homogeneous and slightly hyperechoic. Compared with the meniscus, the TFC appeared hypoechoic. The same patterns were observed for cadavers and volunteers. In 3 volunteers (15%), the TFC was not visualized. Conclusions. Using high-resolution ultrasound systems, the TFC can be separated from meniscus. However, vizualization of the TFC remains limited due to its deep location and the presence of acoustic shadowing from bony structures. © 2008 Wiley Periodicals, Inc. J Clin Ultrasound 2009 [source] The lectin-like domain of thrombomodulin interferes with complement activation and protects against arthritisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2006M. VAN DE WOUWER Summary.,Background: Thrombomodulin (TM) is predominantly a vascular endothelial cell plasma membrane glycoprotein that, via distinct structural domains, interacts with multiple ligands, thereby modulating coagulation, fibrinolysis, complement activation, inflammation and cell proliferation. We previously reported that by mediating signals that interfere with mitogen-activated protein kinase and nuclear factor ,B pathways, the amino-terminal C-type lectin-like domain of TM has direct anti-inflammatory properties. Methods: In the current study, we use murine models of acute inflammatory arthritis and biochemical approaches to assess the mechanism by which the lectin-like domain of TM modifies disease progression. Results: Mice lacking the lectin-like domain of TM (TMLeD/LeDmice) develop inflammatory arthritis that is more rapid in onset and more severe than that developed in their wildtype counterparts. In two models of arthritis, treatment of mice with recombinant soluble lectin-like domain of TM significantly suppresses clinical evidence of disease and diminishes monocyte/macrophage infiltration into the synovium, with weaker expression of the pro-inflammatory high mobility group box chromosomal protein 1. While thrombin-TM mediated activation of thrombin activatable fibrinolysis inhibitor inactivates complement factors C3a and C5a, we show that TM has a second independent mechanism to regulate complement: the lectin-like domain of TM directly interferes with complement activation via the classical and lectin pathways. Conclusions: These data extend previous insights into the mechanisms by which TM modulates innate immunity, and highlight its potential as a therapeutic target for inflammatory diseases. [source] Knockdown of Fc, receptor III in an arthritic temporomandibular joint reduces the nociceptive response in ratsARTHRITIS & RHEUMATISM, Issue 10 2010Phillip 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] The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological reportARTHRITIS & RHEUMATISM, Issue 9 2010Tuhina Neogi Objective The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set. Methods Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of "developing RA," complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis. Results The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach. Conclusion The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set. [source] Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 8 2010Daniel Cejka Objective Activation of the mammalian target of rapamycin (mTOR) pathway is important for immune cell activation and bone metabolism. To date, the contribution of mTOR signaling to joint inflammation and structural bone and cartilage damage is unknown. The aim of this study was to investigate the potential of inhibiting mTOR as a treatment of inflammatory arthritis. Methods Human tumor necrosis factor,transgenic mice in which inflammatory arthritis was developing were treated with 2 different mTOR inhibitors, sirolimus or everolimus. The effects of treatment on clinical disease activity, inflammation, and localized joint and cartilage destruction were studied. In addition, the effects of mTOR inhibition on osteoclast survival and expression of key molecules of osteoclast function were analyzed in vitro. Moreover, synovial tissue from patients with rheumatoid arthritis (RA) was assessed for activation of the mTOR pathway. Results Inhibition of mTOR by sirolimus or everolimus reduced synovial osteoclast formation and protected against local bone erosions and cartilage loss. Clinical signs of arthritis improved after mTOR inhibition, and histologic evaluation showed a decrease in synovitis. In vitro, mTOR inhibition down-regulated the expression of digestive enzymes and led to osteoclast apoptosis. Moreover, mTOR signaling was shown to be active in the synovial membrane of patients with RA, particularly in synovial osteoclasts. Conclusion Signaling through mTOR is an important link between synovitis and structural damage in inflammatory arthritis. Current pharmacologic inhibitors of mTOR could be effective in protecting joints against structural damage. [source] R-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathwayARTHRITIS & RHEUMATISM, Issue 8 2010Gerhard Krönke Objective During the course of different musculoskeletal diseases, joints are progressively damaged by inflammatory, infectious, or mechanical stressors, leading to joint destruction and disability. While effective strategies to inhibit joint inflammation, such as targeted cytokine-blocking therapy, have been developed during the last decade, the molecular mechanisms of joint damage are still poorly understood. This study was undertaken to investigate the role of the Wnt pathway modulator R-Spondin 1 (RSpo1) in protecting bone and cartilage in a mouse model of arthritis. Methods Tumor necrosis factor , (TNF,),transgenic mice were treated with vehicle or Rspo1. Mice were evaluated for signs of arthritis, and histologic analysis of the hind paws was performed. Moreover, we determined the effect of Rspo1 on Wnt signaling activity and osteoprotegerin (OPG) expression in murine primary osteoblasts. Results The secreted Wnt pathway modulator RSpo1 was highly effective in preserving the structural integrity of joints in a TNF,-transgenic mouse model of arthritis by protecting bone and cartilage from inflammation-related damage. RSpo1 antagonized the Wnt inhibitor Dkk-1 and modulated Wnt signaling in mouse mesenchymal cells. In osteoblasts, RSpo1 induced differentiation and expression of OPG, thereby inhibiting osteoclastogenesis in vitro. In vivo, RSpo1 promoted osteoblast differentiation and bone formation while blocking osteoclast development, thereby contributing to the integrity of joints during inflammatory arthritis. Conclusion Our results demonstrate the therapeutic potential of RSpo1 as an anabolic agent for the preservation of joint architecture. [source] Targeted tumor necrosis factor receptor I preligand assembly domain improves skin lesions in MRL/lpr miceARTHRITIS & RHEUMATISM, Issue 8 2010Guo-Min Deng Objective Skin disease is the second most common manifestation in patients with systemic lupus erythematosus (SLE). Tumor necrosis factor receptor (TNFR) preligand assembly domain (PLAD) has been found to block the effect of TNF,, and TNFRI PLAD (p60 PLAD) inhibits inflammatory arthritis. This study was undertaken to investigate whether TNFR PLAD limits inflammatory skin injury in a mouse model of SLE. Methods Female MRL/lpr mice received p60 PLAD (100 ,g/mouse intraperitoneally), p80 PLAD (100 ,g/mouse intraperitoneally), or phosphate buffered saline (100 ,l/mouse intraperitoneally) 3 times a week for 26 weeks, starting at age 6 weeks. Results Immunohistochemistry studies demonstrated that TNFRI but not TNFRII was dominantly expressed in skin lesions in MRL/lpr mice. We found that TNFRI PLAD (p60 PLAD) but not TNFRII PLAD (p80 PLAD) protein significantly inhibited skin injury in the MRL/lpr mouse model of lupus. NF-,B, monocyte chemotactic protein 1, and inducible nitric oxide synthase expression in skin lesions were significantly inhibited by p60 PLAD. Lupus serum,induced monocyte differentiation into dendritic cells was reduced by p60 PLAD, but p60 PLAD did not reduce IgG deposition in the skin or improve the progression of kidney damage in MRL/lpr mice. Conclusion Our results indicate that TNFRI is involved in the expression of skin injury in MRL/lpr mice with lupus and that p60 PLAD or similar biologics may be of clinical value if applied locally. [source] A randomized, double-blind, controlled study of ultrasound-guided corticosteroid injection into the joint of patients with inflammatory arthritis,ARTHRITIS & RHEUMATISM, Issue 7 2010Joanna 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] Near-infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute versus chronic phases of arthritis in miceARTHRITIS & RHEUMATISM, Issue 7 2010Quan Zhou Objective To develop an in vivo imaging method to assess lymphatic draining function in the K/BxN mouse model of inflammatory arthritis. Methods Indocyanine green, a near-infrared fluorescent dye, was injected intradermally into the footpads of wild-type mice, mouse limbs were illuminated with an 806-nm near-infrared laser, and the movement of indocyanine green from the injection site to the draining popliteal lymph node (LN) was recorded with a CCD camera. Indocyanine green near-infrared images were analyzed to obtain 5 measures of lymphatic function across time. Images of K/BxN arthritic mice and control nonarthritic littermates were obtained at 1 month of age, when acute joint inflammation commenced, and again at 3 months of age, when joint inflammation became chronic. Lymphangiogenesis in popliteal LNs was assessed by immunochemistry. Results Indocyanine green and its transport within lymphatic vessels were readily visualized, and quantitative measures were derived. During the acute phase of arthritis, the lymphatic vessels were dilated, with increased indocyanine green signal intensity and lymphatic pulses, and popliteal LNs became fluorescent quickly. During the chronic phase, new lymphatic vessels were present near the foot. However, the appearance of indocyanine green in lymphatic vessels was delayed. The size and area of popliteal LN lymphatic sinuses progressively increased in the K/BxN mice. Conclusion Our findings indicate that indocyanine green near-infrared lymphatic imaging is a valuable method for assessing the lymphatic draining function in mice with inflammatory arthritis. Indocyanine green,near-infrared imaging of K/BxN mice identified 2 distinct lymphatic phenotypes during the acute and chronic phase of inflammation. This technique can be used to assess new therapies for lymphatic disorders. [source] Endogenous estrogen regulation of inflammatory arthritis and cytokine expression in male mice, predominantly via estrogen receptor ,ARTHRITIS & RHEUMATISM, Issue 4 2010Y. H. Yang Objective A number of experimental observations have associated elevated estrogen levels with amelioration of inflammation. The involvement of estrogen and estrogen receptor (ER) isotypes in the regulation of inflammation in males is not well understood. In this study, we used specific ER, and ER, agonists in male mice deficient in estrogen because of a deletion of aromatase (aromatase-knockout [ArKO] mice) to investigate ER isotype utilization in estrogen regulation of inflammation. Methods Lipopolysaccharide (LPS)-induced cytokine expression and antigen-induced arthritis (AIA) were investigated in male ArKO and WT littermate mice, as well as in response to selective agonists of ER, (16,-LE2) and ER, (8,-VE2). The therapeutic effect of selective ER agonists was also examined in mice with collagen-induced arthritis (CIA). Results Estrogen deficiency in ArKO mice was associated with significant increases in LPS-induced serum interleukin-6 (IL-6), tumor necrosis factor, monocyte chemotactic protein 1, and interferon-, levels, which were significantly abrogated by administration of 16,-LE2, but not 8,-VE2. In contrast, both 16,-LE2 and 8,-VE2 significantly increased LPS-induced IL-10 levels. Estrogen deficiency was also associated with significant exacerbation of AIA and antigen-specific T cell proliferation, which was reversed by administration of either 16,-LE2 or 8,-VE2. ArKO mice showed increased antigen-specific T cell proliferation in response to immunization with type II collagen (CII). Administration of 16,-LE2, but not 8,-VE2, significantly reduced the severity of CIA, which was associated with inhibition of anti-CII,specific IgG. Conclusion These data indicate that endogenous estrogen plays an essential inhibitory role in inflammation in male mice and that ER, is the dominant receptor that mediates these effects. [source] Angiogenesis and blood vessel stability in inflammatory arthritisARTHRITIS & RHEUMATISM, Issue 3 2010Aisling 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] Bim,Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosisARTHRITIS & RHEUMATISM, Issue 2 2010John C. Scatizzi Objective Rheumatoid arthritis (RA) is a destructive autoimmune disease characterized by an increased inflammation in the joint. Therapies that activate the apoptotic cascade may have potential for use in RA; however, few therapeutic agents fit this category. The purpose of this study was to examine the potential of Bim, an agent that mimics the action of Bcl-2 homology 3 (BH3) domain,only proteins that have shown success in preclinical studies of cancer, in the treatment of autoimmune disease. Methods Synovial tissues from RA and osteoarthritis patients were analyzed for the expression of Bim and CD68 using immunohistochemistry. Macrophages from Bim,/, mice were examined for their response to lipopolysaccharide (LPS) using flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and immunoblotting. Bim,/, mice were stimulated with thioglycollate or LPS and examined for macrophage activation and cytokine production. Experimental arthritis was induced using the K/BxN serum,transfer model. A mimetic peptide corresponding to the BH3 domain of Bim (TAT-BH3) was administered as a prophylactic agent and as a therapeutic agent. Edema of the ankles and histopathologic analysis of ankle tissue sections were used to determine the severity of arthritis, its cellular composition, and the degree of apoptosis. Results The expression of Bim was reduced in RA synovial tissue as compared with controls, particularly in macrophages. Bim,/, macrophages displayed elevated expression of markers of inflammation and secreted more interleukin-1, following stimulation with LPS or thioglycollate. TAT-BH3 ameliorated arthritis development, reduced the number of myeloid cells in the joint, and enhanced apoptosis without inducing cytotoxicity. Conclusion These data demonstrate that BH3 mimetic therapy may have significant potential for the treatment of RA. [source] Multiple interleukin-1,,converting enzymes contribute to inflammatory arthritisARTHRITIS & RHEUMATISM, Issue 12 2009Christian Stehlik First page of article [source] Caspase 1,independent activation of interleukin-1, in neutrophil-predominant inflammationARTHRITIS & RHEUMATISM, Issue 12 2009Monica Guma Objective Interleukin-1, (IL-1,) is a key cytokine linked to the pathogenesis of acute arthritis. Caspase 1, neutrophil elastase, and chymase all process proIL-1, to its biologically active form. This study was undertaken to examine the potential contributions of each of these proteases in experimental models of inflammatory arthritis. Methods Caspase 1,deficient (Casp1,/,) and wild-type (WT) mice were tested for their response to arthritogenic K/BxN serum transfer for induction of arthritis or injection of monosodium urate monohydrate (MSU) crystals for induction of peritonitis. All mice were prophylactically treated with inhibitors of neutrophil elastase or chymase. Arthritic paws were tested for the presence of IL-1, protein by enzyme-linked immunosorbent assay and Western blotting. Neutrophils and mast cells from WT and mutant mice were tested for their ability to secrete IL-1, after in vitro stimulation, in the presence of protease inhibitors. Results Casp1,/, and WT mice developed paw swelling to the same extent in the K/BxN serum transfer,induced arthritis model. MSU crystal injection into Casp1,/, mice also resulted in neutrophil influx and production of measurable peritoneal IL-1, protein. Both of these responses were attenuated with neutrophil elastase inhibitors. K/BxN serum transfer,induced arthritis was also reduced by treatment with a chymase inhibitor. Casp1,/, neutrophils and mast cells, when exposed to MSU crystals, secreted similar amounts of IL-1, protein upon in vitro stimulation with lipopolysaccharide, albeit at lower levels than that secreted by WT cells. Elastase and chymase inhibitors reduced the amount of IL-1, released by these cells. Conclusion The production of IL-1, by neutrophils and mast cells is not exclusively dependent on caspase 1, and other proteases can compensate for the loss of caspase 1 in vivo. These pathways might therefore compromise the caspase 1,targeted therapies in neutrophil-predominant arthritis. [source] Inflammatory arthritis in caspase 1 gene,deficient mice: Contribution of proteinase 3 to caspase 1,independent production of bioactive interleukin-1,ARTHRITIS & RHEUMATISM, Issue 12 2009Leo A. B. Joosten Objective Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro,interleukin-1, (proIL-1,), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. Methods Acute and chronic arthritis were induced in caspase 1,/, mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. Results Surprisingly, caspase 1,/, mice, in a model of acute (neutrophil-dominated) arthritis, developed joint swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1, were comparable in caspase 1,/, mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1,/, mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1,dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1, concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. Conclusion Caspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1, production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present. [source] Gadd45, deficiency in rheumatoid arthritis: Enhanced synovitis through JNK signalingARTHRITIS & RHEUMATISM, Issue 11 2009Camilla I. Svensson Objective JNK-mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45,, which is an NF-,B,regulated gene, was recently identified as an endogenous negative regulator of the JNK pathway, since it could block the upstream kinase MKK-7. This study was carried out to evaluate whether low Gadd45, expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45, deficiency increases arthritis severity in passive K/BxN murine arthritis. Methods Activation of the NF-,B and JNK pathways and Gadd45, expression were analyzed in human synovium and fibroblast-like synoviocytes (FLS) using quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, electrophoretic mobility shift assay, and luciferase reporter constructs. Gadd45,,/, and wild-type mice were evaluated in the K/BxN serum transfer model of inflammatory arthritis, and clinical signs of arthritis, osteoclast formation, and bone erosion were assessed. Results Expression levels of the Gadd45, gene and protein were unexpectedly low in human RA synovium despite abundant NF-,B activity. Forced Gadd45, expression in human FLS attenuated tumor necrosis factor,induced signaling through the JNK pathway, reduced the activation of activator protein 1, and decreased the expression of MMP genes. Furthermore, Gadd45, deficiency exacerbated K/BxN serum,induced arthritis in mice, dramatically increased signaling through the JNK pathway, elevated MMP3 and MMP13 gene expression in the mouse joints, and increased the synovial inflammation and number of osteoclasts. Conclusion Deficient Gadd45, expression in RA can contribute to activation of JNK, exacerbate clinical arthritis, and augment joint destruction. This process can be mitigated by enhancing Gadd45, expression or by inhibiting the activity of JNK or its upstream regulator, MKK-7. [source] Tumor necrosis factor , and RANKL blockade cannot halt bony spur formation in experimental inflammatory arthritisARTHRITIS & RHEUMATISM, Issue 9 2009Georg Schett Objective To investigate the kinetics of bony spur formation and the relationship of bony spur formation to synovial inflammation and bone erosion in 2 rat arthritis models, and to address whether bony spur formation depends on the expression of tumor necrosis factor , (TNF,) or RANKL. Methods Analysis of the kinetics of synovial inflammation, bone erosion, osteoclast formation, and growth of bony spurs was performed in rat collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA). In addition, inhibition experiments were performed to assess whether inhibition of TNF, and RANKL by pegylated soluble TNF receptor type I (pegTNFRI) and osteoprotegerin (OPG), respectively, affected bony spur formation. Results Bony spurs emerged from the periosteal surface close to joints, and initial proliferation of mesenchymal cells was noted as early as 3 days and 5 days after onset of CIA and AIA, respectively. Initiation of bony spur formation occurred shortly after the onset of inflammation and bone erosion. Neither pegTNFRI nor OPG could significantly halt the osteophytic responses in CIA and AIA. Conclusion These results suggest that bony spur formation is triggered by inflammation and initial structural damage in these rat models of inflammatory arthritis. Moreover, emergence of bony spurs depends on periosteal proliferation and is not affected by inhibition of either TNF, or RANKL. Bony spur formation can thus be considered a process that occurs independent of TNF, and RANKL and is triggered by destructive arthritis. [source] Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritisARTHRITIS & RHEUMATISM, Issue 9 2009Ruolin Guo Objective This study was undertaken to investigate the effect of lymphatic inhibition on joint and draining lymph node (LN) pathology during the course of arthritis progression in mice. Methods Tumor necrosis factor (TNF),transgenic mice were used as a model of chronic inflammatory arthritis. Mice were subjected to contrast-enhanced magnetic resonance imaging to obtain ankle and knee joint synovial volumes and draining popliteal LN volumes before and after 8 weeks of treatment with vascular endothelial growth factor receptor 3 (VEGFR-3) neutralizing antibody, VEGFR-2 neutralizing antibody, or isotype IgG. Animals were subjected to near-infrared lymphatic imaging to determine the effect of VEGFR-3 neutralization on lymph transport from paws to draining popliteal LNs. Histologic, immunohistochemical, and reverse transcriptase,polymerase chain reaction analyses were used to examine lymphatic vessel formation and the morphology of joints and popliteal LNs. Results Compared with IgG treatment, VEGFR-3 neutralizing antibody treatment significantly decreased the size of popliteal LNs, the number of lymphatic vessels in joints and popliteal LNs, lymphatic drainage from paws to popliteal LNs, and the number of VEGF-C,expressing CD11b+ myeloid cells in popliteal LNs. However, it increased the synovial volume and area of inflammation in ankle and knee joints. VEGFR-2 neutralizing antibody, in contrast, inhibited both lymphangiogenesis and joint inflammation. Conclusion These findings indicate that lymphangiogenesis and lymphatic drainage are reciprocally related to the severity of joint lesions during the development of chronic arthritis. Lymphatic drainage plays a beneficial role in controlling the progression of chronic inflammation. [source] Abrogation of antibody-induced arthritis in mice by a self-activating viridin prodrug and association with impaired neutrophil and endothelial cell functionARTHRITIS & RHEUMATISM, Issue 8 2009Lars Stangenberg Objective To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis. Methods The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin,selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil,endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay. Results SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor , was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration. Conclusion A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions. [source] Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 6 2009Hui Shen Objective To analyze the frequency, surface phenotype, and cytokine secretion of CD4+ T cells in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS) compared with both healthy control subjects and patients with rheumatoid arthritis (RA). Methods Eight-color flow cytometry was used to analyze the surface phenotype and cytokine production of PBMCs from 20 patients with AS, 12 patients with RA, and 16 healthy control subjects, following stimulation ex vivo with phorbol myristate acetate and ionomycin for 5 hours. Secretion of interleukin-17 (IL-17) by PBMCs was measured by enzyme-linked immunosorbent assay, following stimulation with anti-CD3/CD28 for 4 days. Results The percentages of IL-17,positive CD4+ T cells and IL-22,positive CD4+ T cells were increased in the PBMCs of both patients with AS and patients with RA compared with healthy control subjects, whereas there were no differences in the percentages of interferon-, (IFN,),positive or IL-10,positive CD4+ T cells. Likewise, concentrations of IL-17 in supernatants from patients with AS were significantly higher compared with those from healthy control subjects. In patients with RA, the concentrations of IL-17 were increased but not significantly. There was a correlation between the percentages of IL-17,positive CD4+ T cells detected in PBMCs and the amounts of IL-17 in culture supernatants (r = 0.414, P = 0.0034). All IL-17,producing cells were CD4+CD45RO+; most expressed both CCR6 and CCR4, but only 50% expressed the IL-23 receptor (IL-23R). Nevertheless, there was a positive relationship between the percentage of IL-23R,positive CD4+ T cells and the frequency of IL-17,positive CD4+ T cells or IL-22,positive CD4+ T cells (r = 0.57, P < 0.0001 and r = 0.46, P = 0.001, respectively). A significant proportion of cells that produced IL-17 also produced IL-22 and IFN,, but none produced IL-10. Conclusion The frequencies of IL-17,positive and IL-22,positive CD4+ T cells were increased in PBMCs from patients with AS and patients with RA, resulting in secretion of higher quantities of IL-17 by PBMCs following stimulation. These data support the hypothesis that Th17 cells, particularly when present in excess of IL-10,producing cells, are involved in the pathogenesis of inflammatory arthritis. [source] Microanatomic studies to define predictive factors for the topography of periarticular erosion formation in inflammatory arthritisARTHRITIS & RHEUMATISM, Issue 4 2009Dennis McGonagle Objective The microanatomic basis for formation of erosions in inflammatory arthritis is incompletely understood but is thought to be related to bare areas and the associated cartilage,synovium junction. The purpose of this study was to test the hypothesis that erosion-prone sites are associated with microdamage in macroscopically normal joints. Methods Histologic evaluation of erosion-prone sites was performed on 20 collateral ligaments (CLs) from the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of 5 normal cadavers. In addition, the MCP joints (n = 17) and PIP joints (n = 3) of 20 patients with rheumatoid arthritis (RA) were assessed by computed tomography (CT) to ascertain whether the topography of erosion formation in patients with RA corresponded to the cadaveric findings. Results Absence of a bare area was noted in cadaveric tissue at the periligamentous erosion-prone regions, especially in the distal MCP joints and both distal and proximal PIP joints. Nevertheless, these sites exhibited soft-tissue pathologic features and bony microdamage/cyst formation. Other significant findings included the presence of pannus without inflammatory changes in the regions in which a bare area was absent, and the replacement of bare area regions with fibrovascular synovial tissue in joints without inflammatory changes. The sites of cadaveric tissue microdamage corresponded to CT-determined erosion formation in the MCP and PIP joints of patients with RA, in whom erosions adjacent to the CLs were more common than dorsal or volar erosions. Conclusion Periarticular erosion formation may not necessarily depend on the presence of a bare area and has a propensity to occur adjacent to ligaments in which bone microdamage is common. These findings suggest that periligamentous locations prone to microdamage may critically influence the topography of erosion formation in inflammatory arthritis. [source] HLA type and immune response to Borrelia burgdorferi outer surface protein a in people in whom arthritis developed after Lyme disease vaccinationARTHRITIS & RHEUMATISM, Issue 4 2009Robert Ball Objective To investigate whether persons with treatment-resistant Lyme arthritis,associated HLA alleles might develop arthritis as a result of an autoimmune reaction triggered by Borrelia burgdorferi outer surface protein A (OspA), the Lyme disease vaccine antigen. Methods Persons in whom inflammatory arthritis had developed after Lyme disease vaccine (cases) were compared with 3 control groups: 1) inflammatory arthritis but not Lyme disease vaccine (arthritis controls), 2) Lyme disease vaccine but not inflammatory arthritis (vaccine controls), and 3) neither Lyme disease vaccine nor inflammatory arthritis (normal controls). HLA,DRB1 allele typing, Western blotting for Lyme antigen, and T cell reactivity testing were performed. Results Twenty-seven cases were matched with 162 controls (54 in each control group). Odds ratios (ORs) for the presence of 1 or 2 treatment-resistant Lyme arthritis alleles were 0.8 (95% confidence interval [95% CI] 0.3-2.1), 1.6 (95% CI 0.5,4.4), and 1.75 (95% CI 0.6,5.3) in cases versus arthritis controls, vaccine controls, and normal controls, respectively. There were no significant differences in the frequency of DRB1 alleles. T cell response to OspA was similar between cases and vaccine controls, as measured using the stimulation index (OR 1.6 [95% CI 0.5,5.1]) or change in uptake of tritiated thymidine (counts per minute) (OR 0.7 [95% CI 0.2,2.3]), but cases were less likely to have IgG antibodies to OspA (OR 0.3 [95% CI 0.1,0.8]). Cases were sampled closer to the time of vaccination (median 3.59 years versus 5.48 years), and fewer cases had received 3 doses of vaccine (37% versus 93%). Conclusion Treatment-resistant Lyme arthritis alleles were not found more commonly in persons who developed arthritis after Lyme disease vaccination, and immune responses to OspA were not significantly more common in arthritis cases. These results suggest that Lyme disease vaccine is not a major factor in the development of arthritis in these cases. [source] CCAAT/ENHANCER binding protein , mediates expression of matrix metalloproteinase 13 in human articular chondrocytes in inflammatory arthritisARTHRITIS & RHEUMATISM, Issue 3 2009Mitsumasa Hayashida Objective To determine the function of CCAAT/enhancer binding protein , (C/EBP,) in the expression of matrix metalloproteinase 13 (MMP-13) in chondrocytes in inflammatory arthritis. Methods Cartilage obtained from patients with rheumatoid arthritis and osteoarthritis was immunostained for expression of C/EBP, or MMP-13. Interleukin-1,, or tumor necrosis factor , (TNF,),stimulated chondrocytes were subjected to Western blotting and real-time reverse transcriptase,polymerase chain reaction (RT-PCR). MMP-13 promoter assays were conducted, and the C/EBP, response element was characterized by deletion and mutation analysis. C-28/I2 cells were treated with TNF, and subjected to chromatin immunoprecipitation (ChIP) assays. Finally, C/EBP,,liver-enriched activator protein (LAP) was overexpressed in C-28/I2 cells or cartilage tissues, and MMP-13 expression was analyzed. Results C/EBP, and MMP-13 expression was colocalized in chondrocytes in arthritic cartilage. MMP-13 promoter activity was stimulated by C/EBP, overexpression in a dose-dependent manner. Luciferase assays revealed that a ,981-bp promoter had the greatest activity, while deletion to ,936 bp strongly diminished promoter activity. Luciferase activity was repressed to basal levels by mutations in potential C/EBP binding sites. The stimulatory effects of C/EBP, overexpression were diminished by mutation. ChIP assays revealed that TNF, treatment enhanced the binding of C/EBP, to the MMP-13 promoter. When C/EBP,-LAP was overexpressed in C-28/I2 cells, endogenous MMP-13 expression was stimulated up to 32-fold as detected by real-time RT-PCR. Furthermore, following adenoviral overexpression of C/EBP,-LAP in organ culture of articular cartilage, stimulation of MMP-13 was also detected by immunohistochemistry. Conclusion C/EBP, directly binds to the MMP-13 promoter region and stimulates the expression of MMP-13 in chondrocytes in inflammatory arthritis. [source] Promotion of the local differentiation of murine Th17 cells by synovial macrophages during acute inflammatory arthritisARTHRITIS & RHEUMATISM, Issue 12 2008Paul J. Egan Objective To examine the generation of proinflammatory Th17 cells at the site of tissue inflammation and in draining lymph nodes using an interleukin-17 (IL-17),dependent model of acute inflammatory arthritis. Methods Arthritis was elicited in mice by intraarticular injection of methylated bovine serum albumin (mBSA) into the knee and subcutaneous injection of IL-1,. Anti,IL-17 or control antibodies were administered during arthritis induction. Cytokine expression was evaluated by intracellular cytokine staining of synovial lymphocytes, by polymerase chain reaction analysis of RNA extracted from lymph node cells, and by enzyme-linked immunosorbent assay of cell culture supernatants. Th17 differentiation of naive CD4+ T cells was assessed in cocultures with macrophages from arthritic mice. Results Anti,IL-17 antibody administered during acute arthritis markedly reduced disease, indicating that the model is IL-17 dependent. IL-17 messenger RNA (mRNA), but not protein, was detected in draining lymph node CD4+ T cells and preceded joint inflammation. In addition, mRNA for Th17 cell,stimulatory cytokines (transforming growth factor ,, IL-6) and Th17 cell,inhibitory cytokines (interferon-,, IL-4) was detected in lymph nodes following injection of mBSA and IL-1,. Th17 cells were clearly identified in the inflamed synovium at the peak of disease. Synovial macrophages supported Th17 cell generation from naive CD4+ T cell precursors stimulated via CD3 in vitro and produced high levels of IL-6. In contrast, peritoneal macrophages failed to induce Th17 cell differentiation and produced less IL-6. Conclusion These results suggest that Th17 cell differentiation is initiated in draining lymph nodes but that IL-17,producing cells are restricted to the inflamed synovium, being generated in response to local cytokines produced by inflammatory macrophages. [source] Arthritis develops but fails to resolve during inhibition of cyclooxygenase 2 in a murine model of lyme diseaseARTHRITIS & RHEUMATISM, Issue 5 2008Victoria A. Blaho Objective Recent studies have implicated products of cyclooxygenase 2 (COX-2) in not only induction but also resolution of the inflammatory response; however, the contribution of COX-2 products to the in vivo response to infection is unknown. The aim of this study was to determine the contribution of COX-2 to temporal regulation of the inflammatory response to infection in a murine model of Lyme arthritis. Methods Experimental Lyme disease was induced in both arthritis-resistant DBA/2J and arthritis-susceptible C3H/HeJ mice by inoculation in the hind footpads with Borrelia burgdorferi. COX-2 inhibitors were administered daily, and their effect on arthritis pathology was assessed at various time points postinfection. The COX-2 deficiency was also backcrossed onto both DBA and C3H backgrounds to confirm the findings from COX-2 inhibitor,treated mice. Results In COX-2 inhibitor,treated or COX-2,/, C3H mice, arthritis developed normally but did not resolve. Cessation of COX-2 inhibitor treatment on day 14 postinfection did not induce resolution of arthritis, indicating an early onset for the molecular mechanisms governing resolution. The lack of resolution of arthritis correlated with altered COX-2 and cytosolic phospholipase A2 messenger RNA levels in the joints of C3H mice. In addition, the proresolution lipid molecule 15-deoxy-,12,14 -prostaglandin J2 was produced in response to B burgdorferi infection, and its production was attenuated by the inhibition of COX-2. Conclusion Our results demonstrate that early production of COX-2 products is necessary for resolution of the inflammatory arthritis induced by Borrelia infection, and that COX-2 inhibition may result in prolonged inflammatory states, possibly by inhibition of proresolution eicosanoids. [source] | ||||||||||