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Inflamed Synovium (inflamed + synovium)
Selected AbstractsSynovial ablation in a rabbit rheumatoid arthritis model using photodynamic therapyANZ JOURNAL OF SURGERY, Issue 7 2002Andrew D. Beischer Background: At present there is no ideal minimally invasive method for ablating inflamed synovium in joints that has been unresponsive to optimal medical management in patients with rheumatoid arthritis. The aim of this study was to determine whether photodynamic therapy could be used for this purpose. Methods: In a rabbit knee model of rheumatoid arthritis the pharmacokinetics of the photosensitizer Haematoporphyrin Derivative (HpD) into periarticular tissues and blood was measured following intravenous injection of HpD. The second phase of the study was to determine the histological effect of HpD activation by 63 nm light delivered via an intra-articular optic fibre using a dye pumped KTP-YAG laser. The light dose was varied from 0,200 joule/cm2. Results: Pharmacokinetic studies determined that inflamed synovium rapidly accumulated HpD, with peak levels being reached 12 h following intravenous injection. The ratio of HpD uptake into inflamed synovium versus peri-articular quadriceps muscle was found to be 22.8. Histological examination of the treated knees indicated that selective destruction of inflamed synovium was achieved at light doses 100 joules/cm2 and above. No significant effect was observed on normal intra-articular tissues. Conclusion: We have demonstrated that the first generation photosensitizer HpD selectively accumulates within inflamed synovium. Activation of HpD by intra-articular light administration resulted in selective ablation of the inflamed synovium. These findings indicate that PDT offers potential as a new selective, minimally invasive synovectomy technique. [source] Adiponectin-mediated changes in effector cells involved in the pathophysiology of rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 10 2010Klaus W. Frommer Objective Rheumatoid arthritis (RA) is associated with increased production of adipokines, which are cytokine-like mediators that are produced mainly in adipose tissue but also in synovial cells. Since RA synovial fibroblasts (RASFs), lymphocytes, endothelial cells, and chondrocytes are key players in the pathophysiology of RA, this study was undertaken to analyze the effects of the key adipokine adiponectin on proinflammatory and prodestructive synovial effector cells. Methods Lymphocytes were activated in part prior to stimulation. All cells were stimulated with adiponectin, and changes in gene and protein expression were determined by Affymetrix and protein arrays. Messenger RNA and protein levels were confirmed using semiquantitative reverse transcription,polymerase chain reaction (PCR), real-time PCR, and immunoassays. Intracellular signal transduction was evaluated using chemical signaling inhibitors. Results Adiponectin stimulation of human RASFs predominantly induced the secretion of chemokines, as well as proinflammatory cytokines, prostaglandin synthases, growth factors, and factors of bone metabolism and matrix remodeling. Lymphocytes, endothelial cells, and chondrocytes responded to adiponectin stimulation with enhanced synthesis of cytokines and various chemokines. Additionally, chondrocytes released increased amounts of matrix metalloproteinases. In RASFs, adiponectin-mediated effects were p38 MAPK and protein kinase C dependent. Conclusion Our previous findings indicated that adiponectin was present in inflamed synovium, at sites of cartilage invasion, in lymphocyte infiltrates, and in perivascular areas. The findings of the present study indicate that adiponectin induces gene expression and protein synthesis in human RASFs, lymphocytes, endothelial cells, and chondrocytes, supporting the concept of adiponectin being involved in the pathophysiologic modulation of RA effector cells. Adiponectin promotes inflammation through cytokine synthesis, attraction of inflammatory cells to the synovium, and recruitment of prodestructive cells via chemokines, thus promoting matrix destruction at sites of cartilage invasion. [source] Synovial fluid proteins differentiate between the subtypes of juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 6 2010Margalit 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] Scavenger receptor class A type I/II determines matrix metalloproteinase,mediated cartilage destruction and chondrocyte death in antigen-induced arthritisARTHRITIS & RHEUMATISM, Issue 10 2009P. L. E. M. van Lent Objective Scavenger receptor class A type I (SR-AI) and SR-AII are expressed by macrophages in particular and bind and internalize a broad range of molecules (including endotoxins, apoptotic bodies, and oxidized low-density lipoprotein). This study was undertaken to investigate the role of SR-AI/II in mediating severe cartilage destruction in antigen-induced arthritis (AIA). Methods AIA was induced in the knee joints of SR-AI/II,/, mice and wild-type (WT) controls. Joint inflammation and cartilage destruction (chondrocyte death) were measured by examining the histology of total knee joints. Matrix metalloproteinase (MMP),mediated neoepitopes were measured by immunolocalization using anti-VDIPEN antibodies and chondrocyte activation with anti-S100A8 antibodies. Messenger RNA (mRNA) levels were determined in inflamed synovium using microarray analysis and quantitative reverse transcriptase,polymerase chain reaction. In synovial washouts, cytokines (interleukin-1, [IL-1,], IL-10, and tumor necrosis factor ,) and S100A8/S100A9 were measured using Luminex and enzyme-linked immunosorbent assay. Results Levels of SR-AI/II mRNA were strongly elevated in inflamed synovium in AIA. On days 2, 8, and 14 after AIA induction, joint inflammation (exudates/infiltrate) was similar between the 2 groups. In WT mice, severe cartilage destruction was found in multiple cartilage surfaces of the inflamed knee joint on day 14 after AIA induction. MMP-mediated matrix destruction ranged between 40% and 60%, and chondrocyte death was prominent in 40,75% of the cartilage surfaces. In striking contrast, in SR-AI/II,/, mice, despite comparable joint inflammation, pronounced cartilage destruction was almost completely absent. Levels of IL-1, and S100A8/S100A9 were significantly lower on days 7 and 14 after AIA induction, but levels of mRNA for various MMPs (MMP-2, MMP-3, MMP-9, and MMP-13) were comparable. Conclusion Our findings indicate that SR-AI and SR-AII are crucial receptors involved in mediating severe cartilage destruction in AIA. [source] The ,7 nicotinic acetylcholine receptor on fibroblast-like synoviocytes and in synovial tissue from rheumatoid arthritis patients: A possible role for a key neurotransmitter in synovial inflammationARTHRITIS & RHEUMATISM, Issue 5 2009Marjolein A. Van Maanen Objective Recent studies have suggested an important role for neurotransmitters as modulators of inflammation. Therefore, we undertook this study to investigate the expression of the ,7 subunit of the nicotinic acetylcholine receptor (,7nAChR) and its function in rheumatoid arthritis (RA). Methods The potential role of the ,7nAChR in modulating proinflammatory cytokine expression in fibroblast-like synoviocytes (FLS) was identified by screening an adenoviral short hairpin RNA (Ad.shRNA) library. An ,7-specific antibody was used for immunohistochemistry, and fluorescein isothiocyanate,labeled ,-bungarotoxin, which binds specifically to the ,7nAChR, was used for immunofluorescence. Gene expression in FLS was determined by quantitative polymerase chain reaction with primers specific for the ,7nAChR. In addition, we analyzed messenger RNA (mRNA) expression of dup,7, a variant ,7 transcript. Next, we studied the functional role of the ,7nAChR in RA FLS by examining the effects of ,7-specific agonists on the production of interleukin-6 (IL-6) and IL-8 by activated FLS. Results A screen using an Ad.shRNA library against 807 transcripts revealed that a specific ,7nAChR shRNA potently modulated IL-8 and matrix metalloproteinase expression in FLS. The ,7nAChR was expressed in the inflamed synovium from RA patients, predominantly in the intimal lining layer. We found ,7nAChR expression at both the mRNA and protein level in cultured RA FLS. FLS also constitutively expressed dup,7 mRNA. Specific ,7nAChR agonists reduced tumor necrosis factor ,,induced IL-6 and IL-8 production by FLS. Conclusion The ,7nAChR and its dup,7 variant are expressed in RA synovium, where they may play a critical role in regulating inflammation. Targeting the ,7nAChR could provide a novel antiinflammatory approach to the treatment of RA. [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] Antibodies against citrullinated vimentin in rheumatoid arthritis: Higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides,ARTHRITIS & RHEUMATISM, Issue 1 2008Linda Mathsson Objective The Sa autoantigen can be found in inflamed synovium of patients with rheumatoid arthritis (RA), and at least part of the humoral RA-specific anti-Sa response is directed against citrullinated vimentin. This study was undertaken to evaluate the sensitivity, specificity, and prognostic value of determination of levels of antibodies against modified citrullinated vimentin (anti-MCV) as compared with antibodies against cyclic citrullinated peptides (anti-CCP) in an inception cohort of patients with early RA. Methods Clinical data, radiographs, and measurements of levels of anti-MCV and anti-CCP antibodies were obtained in 273 patients with early RA at baseline, after 3 months, and after 1, 2, 3, and 5 years. Autoantibodies were also analyzed in 100 healthy controls. Results Of the 273 patients, 193 (70.7%) were anti-MCV positive and 158 (57.9%) were anti-CCP positive at the time of diagnosis, with nearly equal specificities (95% and 96%, respectively). Forty (14.7%) were anti-MCV positive only, and 5 (1.8%) were anti-CCP positive only. Anti-MCV,positive and anti-MCV,negative patients had similar disease activity at baseline, but presence of anti-MCV was predictive of subsequent high disease activity and continued radiographic progression. Changes in anti-MCV level showed stronger correlation with changes in clinical parameters than did changes in anti-CCP level. The subgroup of patients who were anti-MCV positive and anti-CCP negative showed a higher rate of radiographic destruction than did patients who were negative for both anti-MCV and anti-CCP. Conclusion These findings show that when patients with early RA are compared with healthy controls, analysis of anti-MCV yields greater sensitivity and unchanged specificity as compared with analysis of anti-CCP. Anti-MCV also appears to perform better than anti-CCP in identifying poor radiographic prognosis in patients with early RA. [source] Inflammation and angiogenesis in osteoarthritisARTHRITIS & RHEUMATISM, Issue 8 2003L. Haywood Objective To quantify the relationship between inflammation and angiogenesis in synovial tissue from patients with osteoarthritis (OA). Methods Hematoxylin and eosin staining and histologic grading for inflammation were performed for 104 patients who met the American College of Rheumatology criteria for OA and had undergone total joint replacement or arthroscopy. A purposive sample of synovial specimens obtained from 70 patients was used for further analysis. Vascular endothelium, endothelial cell (EC) proliferating nuclei, macrophages, and vascular endothelial growth factor (VEGF) were detected by immunohistochemical analysis. Angiogenesis (EC proliferation, EC fractional area), macrophage fractional area, and VEGF immunoreactivity were measured using computer-assisted image analysis. Double immunofluorescence histochemical analysis was used to determine the cellular localization of VEGF. Radiographic scores for joint space narrowing and osteophyte formation in the knee were also assessed. Results Synovial tissue samples from 32 (31%) of 104 patients with OA showed severe inflammation; thickened intimal lining and associated lymphoid aggregates were often observed. The EC fractional area, EC proliferation, and VEGF immunoreactivity all increased with increasing histologic inflammation grade and increasing macrophage fractional area. In the synovial intimal lining, VEGF immunoreactivity was localized to macrophages and increased with increasing EC fractional area and angiogenesis. No inflammation or angiogenic indices were significantly correlated with radiographic scores. Conclusion Inflammation and angiogenesis in the synovium are associated with OA. The angiogenic growth factor VEGF generated by the inflamed synovium may promote angiogenesis, thereby contributing to inflammation in OA. [source] | ||||||||||