bluuebunny/crossref_metadata_2025_split huggingface dataset:
The arthritis severity locusCia5dis a novel genetic regulator of the invasive properties of synovial fibroblasts
Authors: Laragione Teresina , Brenner Max , Mello Adriana , Symons Marc , Gulko Pércio S. 
Published: August 2008

AbstractObjectiveThe synovial fibroblast, or fibroblast‐like synoviocyte (FLS), has a central role in pannus invasion and destruction of cartilage and bone in rheumatoid arthritis (RA). However, regulation of the FLS remains incompletely understood. The aim of this study was to determine whether the invasive properties of FLS are genetically regulated by arthritis severity loci.MethodsDA rats (arthritis susceptible) and rat strains congenic for arthritis‐protective intervals were studied. Primary FLS cell lines were generated from each strain and used in a well‐established FLS invasion model through a collagen‐rich barrier. Cells or culture supernatants were analyzed for gene expression, activity of different matrix metalloproteinases (MMPs), cytoskeleton integrity, and cell proliferation.ResultsThe median number of FLS from DA.F344(Cia5d) rats that invaded through the collagen‐rich barrier was reduced 86.5% compared with the median number of invading FLS from DA rats. Histologic examination showed that DA.F344(Cia5d) rats preserved a normal joint without pannus, hyperplasia, or erosions. FLS from DA.F344(Cia5d) rats produced significantly lower levels of active MMP‐2 compared with FLS from DA rats, but the levels of proMMP‐2 and MMP‐2 messenger RNA in DA.F344(Cia5d) rats were similar to those in DA rats. Treatment of FLS from DA rats with an MMP‐2 inhibitor reduced cell invasion to a level similar to that in DA.F344(Cia5d) rats, demonstrating that MMP‐2 activity accounted for the difference between FLS from these 2 strains. Analysis of MMP‐2–activating pathways revealed increased levels of soluble membrane type 1 (MT1)–MMP in DA rats compared with DA.F344(Cia5d) rats.ConclusionThese data represent the first evidence for a genetic component in the regulation of FLS invasion. A gene located within theCia5dinterval accounts for this effect and operates via the regulation of soluble MT1‐MMP production and MMP‐2 activation. These observations suggest novel potential pathways for prognostication and therapy.
Association of the IRF5 risk haplotype with high serum interferon‐α activity in systemic lupus erythematosus patients
Authors: Niewold Timothy B. , Kelly Jennifer A. , Flesch Marie H. , Espinoza Luis R. , Harley John B. , Crow Mary K. 
Published: August 2008

AbstractObjectiveA haplotype of the interferon regulatory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon‐α (IFNα) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNα activity.MethodsIFNα levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single‐nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data.ResultsSLE patients with risk/risk and risk/neutral IRF5 genotypes had higher serum IFNα activity than did those with protective/protective and neutral/protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNα levels was driven largely by SLE patients who were positive for either anti–RNA binding protein (anti‐RBP) or anti–double‐stranded DNA (anti‐dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was independently associated with high serum IFNα in this autoantibody group. We found no difference in IFNα activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody.ConclusionThe IRF5 SLE risk haplotype is associated with higher serum IFNα activity in SLE patients, and this effect is most prominent in patients positive for either anti‐RBP or anti‐dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.
Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis
Authors: Kinloch Andrew , Lundberg Karin , Wait Robin , Wegner Natalia , Lim Ngee Han , Zendman Albert J. W. , Saxne Tore , Malmstr Vivianne , Venables Patrick J. 
Published: August 2008

AbstractObjectiveTo examine synovial fluid as a site for generating citrullinated antigens, including the candidate autoantigen citrullinated α‐enolase, in rheumatoid arthritis (RA).MethodsSynovial fluid was obtained from 20 patients with RA, 20 patients with spondylarthritides (SpA), and 20 patients with osteoarthritis (OA). Samples were resolved using sodium dodecyl sulfate–polyacrylamide gel electrophoresis, followed by staining with Coomassie blue and immunoblotting for citrullinated proteins, α‐enolase, and the deiminating enzymes peptidylarginine deiminase type 2 (PAD‐2) and PAD‐4. Proteins from an RA synovial fluid sample were separated by 2‐dimensional electrophoresis, and each protein was identified by immunoblotting and mass spectrometry. Antibodies to citrullinated α‐enolase peptide 1 (CEP‐1) and cyclic citrullinated peptide 2 were measured by enzyme‐linked immunosorbent assay.ResultsCitrullinated polypeptides were detected in the synovial fluid from patients with RA and patients with SpA, but not in OA samples. Alpha‐enolase was detected in all of the samples, with mean levels of 6.4 ng/μl in RA samples, 4.3 ng/μl in SpA samples, and <0.9 ng/μl in OA samples. Two‐dimensional electrophoresis provided evidence that the α‐enolase was citrullinated in RA synovial fluid. The citrullinating enzyme PAD‐4 was detected in samples from all 3 disease groups. PAD‐2 was detected in 18 of the RA samples, in 16 of the SpA samples, and in none of the OA samples. Antibodies to CEP‐1 were found in 12 of the RA samples (60%), in none of the SpA samples, and in 1 OA sample.ConclusionThese results highlight the importance of synovial fluid for the expression of citrullinated autoantigens in inflammatory arthritis. Whereas the expression of citrullinated proteins is a product of inflammation, the antibody response remains specific for RA.
A pilot study to evaluate the safety and efficacy of the long‐acting interleukin‐1 inhibitor rilonacept (interleukin‐1 trap) in patients with familial cold autoinflammatory syndrome
Authors: Goldbach‐Mansky Raphaela , Shroff Sharukh D. , Wilson Mildred , Snyder Christopher , Plehn Sara , Barham Beverly , Pham Tuyet‐Hang , Pucino Frank , Wesley Robert A. , Papadopoulos Joanne H. , Weinstein Steven P. , Mellis Scott J. , Kastner Daniel L. 
Published: August 2008

AbstractObjectiveFamilial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1 gene, leading to excessive secretion of interleukin‐1β (IL‐1β), which is associated with cold‐induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL‐1 Trap), a long‐acting IL‐1 receptor fusion protein, in patients with FCAS.MethodsFive patients with FCAS were studied in an open‐label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage‐escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high‐sensitivity C‐reactive protein [hsCRP], serum amyloid A [SAA], and IL‐6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values.ResultsIn all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute‐phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well‐tolerated. Weight gain in 2 patients was noted. No study drug–related serious adverse events were seen.ConclusionIn this study, we present 2‐year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.
The chemokine receptors CXCR1/CXCR2 modulate antigen‐induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature
Authors: Coelho Fernanda M. , Pinho Vanessa , Amaral Flávio A. , Sachs Daniela , Costa Vívian V. , Rodrigues David H. , Vieira Angélica T. , Silva Tarcília A. , Souza Daniele G. , Bertini Riccardo , Teixeira Antônio L. , Teixeira Mauro M. 
Published: August 2008

AbstractObjectiveThe chemokine receptors CXCR1 and CXCR2 play a role in mediating neutrophil recruitment and neutrophil‐dependent injury in several models of inflammation. We undertook this study to investigate the role of these receptors in mediating neutrophil adhesion, subsequent migration, and neutrophil‐dependent hypernociception in a murine model of monarticular antigen‐induced arthritis (AIA).MethodsAIA was induced by administration of antigen into the knee joint of previously immunized mice. Intravital microscopy studies were performed to assess leukocyte rolling and adhesion. Mechanical hypernociception was investigated using an electronic pressure meter. Neutrophil accumulation in the tissue was measured by counting neutrophils in the synovial cavity and assaying myeloperoxidase activity. Levels of tumor necrosis factor α (TNFα) and the chemokines CXCL1 and CXCL2 were quantified by enzyme‐linked immunosorbent assay. Histologic analysis was performed to evaluate the severity of arthritis and leukocyte infiltration.ResultsAntigen challenge in immunized mice induced production of TNFα, CXCL1, and CXCL2 and also resulted in neutrophil recruitment, leukocyte rolling and adhesion, and hypernociception. Treatment with reparixin or DF2162 (allosteric inhibitors of CXCR1/CXCR2) decreased neutrophil recruitment, an effect that was associated with marked inhibition of neutrophil adhesion. Drug treatment also inhibited TNFα production, hypernociception, and the overall severity of the disease in the tissue.ConclusionBlockade of CXCR1/CXCR2 receptors inhibits neutrophil recruitment by inhibiting the adhesion of neutrophils to synovial microvessels. As a consequence, there is decreased local cytokine production and reduced hypernociception, as well as ameloriation of overall disease in the tissue. These studies suggest a potential therapeutic role for the modulation of CXCR1/CXCR2 receptor signaling in the treatment of arthritis.
Genome‐wide association study of rheumatoid arthritis in the Spanish population: KLF12 as a risk locus for rheumatoid arthritis susceptibility
Authors: Julià Antonio , Ballina Javier , Cañete Juan D. , Balsa Alejandro , Tornero‐Molina Jesus , Naranjo Antonio , Alperi‐López Mercedes , Erra Alba , Pascual‐Salcedo Dora , Barceló Pere , Camps Jordi , Marsal Sara 
Published: August 2008

AbstractObjectiveTo identify new genes associated with susceptibility to rheumatoid arthritis (RA), using a 2‐stage genome‐wide association study.MethodsFollowing a liability‐based study design, we analyzed 317,503 single‐nucleotide polymorphisms (SNPs) in 400 patients with RA and 400 control subjects. We selected a group of candidate SNPs for replication in an independent group of 410 patients with RA and 394 control subjects. Using data from the 3 previous genome‐wide association studies in RA, we also looked for genomic regions showing evidence of common association signals. Finally, we analyzed the presence of genome‐wide epistasis using the binary test implemented in the PLINK program.ResultsWe identified several genomic regions showing evidence of genome‐wide association (P < 1 × 10 −5). In the replication analysis, we identified KLF12 SNP rs1324913 as the most strongly associated SNP (P = 0.01). In our study, we observed that this SNP showed higher significance than PTPN22 SNP rs2476601, in both the genome‐wide association studies and the replication analyses. Furthermore, the integration of our data with those from previous genome‐wide association studies showed that KLF12 and PTPRT are the unique loci that are commonly associated in 3 different studies (P = 0.004 and P = 0.002 for KLF12 in the Wellcome Trust Case Control Consortium study and the Brigham and Women's Rheumatoid Arthritis Sequential Study genome‐wide association study, respectively). The genome‐wide epistasis analysis identified several SNP pairs close to significance after multiple test correction.ConclusionThe present genome‐wide association study identified KLF12 as a new susceptibility gene for RA. The joint analysis of our results and those from previous genome‐wide association studies showed genomic regions with a higher probability of being genuine susceptibility loci for RA.
An early sympathetic nervous system influence exacerbates collagen‐induced arthritis via CD4+CD25+ cells
Authors: Härle Peter , Pongratz Georg , Albrecht Julia , Tarner Ingo H. , Straub Rainer H. 
Published: August 2008

AbstractObjectiveActivation of the sympathetic nervous system (SNS) ameliorates collagen‐induced arthritis (CIA) in the late phase of the disease but aggravates it in the presymptomatic phase. The aim of the present study was to determine whether CD4+CD25+ T cells are influenced by the SNS of mice and play a disease‐modifying role in the early symptomatic phase of the disease.MethodsWe tested the effects of the SNS on arthritis by transferring CD4+CD25+ T cells from sympathectomized mice immunized with type II collagen and from immunized, SNS‐intact animals (controls). We further characterized transferred cells by studying forkhead box P3 (FoxP3) expression, cell proliferation, and cytokine secretion.ResultsUsing anti–dopamine‐β‐hydroxylase antibodies for systemic sympathectomy, we noticed a time‐dependent disease amelioration (strongest when sympathectomy was performed 7 days before immunization, with no effect 30 days after immunization). When CD4+CD25+ T cells from immunized and sympathectomized animals were transferred into mice with CIA (on day 32), disease severity was reduced compared with that in controls. However, the number of CD4+CD25+FoxP3+ cells and the FoxP3 expression level in CD4+CD25+ cells were not changed by sympathectomy. In a mixed assay of donor CD4+CD25− and CD4+CD25+ cells, proliferation was reduced when cells from sympathectomized animals were studied. In the same assay, secretion of tumor necrosis factor, interleukin‐17 (IL‐17), IL‐10, and IL‐4 (not interferon‐γ) was markedly reduced when cells were taken from sympathectomized animals. Culture of CD4+CD25+ cells with norepinephrine (10−5M) for 24 hours before transfer worsened the arthritis.ConclusionThe SNS increases disease severity in the early phase of symptomatic CIA by stimulating several proinflammatory aspects of CD4+CD25+ T cells.
Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis
Authors: Kadri A. , Ea H. K. , Bazille C. , Hannouche D. , Lioté F. , Cohen‐Solal M. E. 
Published: August 2008

AbstractObjectiveTo characterize bone microarchitectural changes and to test the hypothesis that disrupting local cytokine equilibrium could modify cartilage degradation in a murine model of experimental osteoarthritis (OA).MethodsTen‐week‐old male C57BL/6 mice underwent medial meniscectomy of their right knees and a sham operation of their left knees. The mice received intraperitoneal injections of osteoprotegerin (OPG) (10 mg/kg), interleukin‐1 receptor antagonist (IL‐1Ra) (100 mg/kg), or phosphate buffered saline for 6 weeks. The microarchitecture of the trabecular bone, the OA score, and expression of ADAMTS‐4 and ADAMTS‐5 were assessed. Proteoglycan release was measured in cartilage explant cultures in the presence of IL‐1Ra and OPG.ResultsIn the meniscectomized knees, bone volume/tissue volume (BV/TV) was lower, whereas trabecular separation, the OA score, and aggrecanase expression were higher than in the sham‐operated knees. After treatment with OPG, BV/TV was significantly increased and trabecular separation was reduced in the knees that underwent meniscectomy. The OA score and the number of ADAMTS‐positive cells were significantly decreased by treatment with OPG but were not affected by IL‐1Ra. Moreover, OPG did not directly reduce the release of proteoglycans from cartilage explant cultures.ConclusionIn an experimental model of OA, meniscectomy induced bone loss and cartilage degradation at 6 weeks. Systemic administration of OPG prevented bone and cartilage degradation in vivo but had no effect on cartilage in vitro. These data collectively indicate that bone could be a contributor in the early stages of OA pathogenesis. They further suggest that disruption of RANKL/OPG balance might result in the degradation of cartilage subjected to mechanical loading. Specific targeting of the bone cytokine network might help to prevent OA.
The mouse mast cell–restricted tetramer‐forming tryptases mouse mast cell protease 6 and mouse mast cell protease 7 are critical mediators in inflammatory arthritis
Authors: McNeil H. Patrick , Shin Kichul , Campbell Ian K. , Wicks Ian P. , Adachi Roberto , Lee David M. , Stevens Richard L. 
Published: August 2008

AbstractObjectiveIncreased numbers of mast cells (MCs) that express β tryptases bound to heparin have been detected in the synovium of patients with rheumatoid arthritis (RA). The corresponding tryptases in mice are mouse MC protease 6 (mMCP‐6) and mMCP‐7. Although MCs have been implicated in RA and some animal models of arthritis, no direct evidence for a MC‐restricted tryptase in the pathogenesis of inflammatory arthritis has been shown. We created transgenic mice that lack heparin and different combinations of mMCP‐6 and mMCP‐7, to evaluate the roles of MC‐restricted tryptase–heparin complexes in an experimental model of arthritis.MethodsThe methylated bovine serum albumin/interleukin‐1β (mBSA/IL‐1β) experimental protocol was used to induce inflammatory monarthritis in different mouse strains. Mice were killed at the time of peak disease on day 7, and histochemical methods were used to assess joint pathology.ResultsArthritis was induced in the knee joints of mBSA/IL‐1β–treated mMCP‐6+/mMCP‐7− and mMCP‐6−/mMCP‐7+ C57BL/6 mice, and numerous activated MCs that had exocytosed the contents of their secretory granules were observed in the diseased mice. In contrast, arthritis was markedly reduced in heparin‐deficient mice and in mMCP‐6−/mMCP‐7− C57BL/6 mice.ConclusionMC‐derived tryptase–heparin complexes play important roles in mBSA/IL‐1β–induced arthritis. Because mMCP‐6 and mMCP‐7 can compensate for each other in this disease model, the elimination of both tryptases is necessary to reveal the prominent roles of these serine proteases in joint inflammation and destruction. Our data suggest that the inhibition of MC‐restricted tryptases could have therapeutic potential in the treatment of RA.
Mitochondrial dysfunction activates cyclooxygenase 2 expression in cultured normal human chondrocytes
Authors: Cillero‐Pastor Berta , Caramés Beatriz , Lires‐Deán Marcos , Vaamonde‐García Carlos , Blanco Francisco J. , López‐Armada María J. 
Published: August 2008

AbstractObjectiveMitochondrial alterations play a key role in the pathogenesis of osteoarthritis (OA). This study evaluated a potential role of mitochondrial respiratory chain (MRC) dysfunction in the inflammatory response of normal human chondrocytes.MethodsCommonly used inhibitors of the MRC were utilized to induce mitochondrial dysfunction in normal human chondrocytes. Levels of prostaglandin E2 (PGE2) protein and expression of cyclooxygenase 2 (COX‐2) and COX‐1 messenger RNA (mRNA) and protein were analyzed. To identify the underlying mechanisms responsible for PGE2 liberation, reactive oxygen species (ROS) were measured. Inhibitors of ROS, including vitamin E, and inhibitors of mitochondrial Ca2+ and NF‐κB were used to test their effects on the MRC.ResultsAntimycin A and oligomycin (inhibitors of mitochondrial complexes III and V, respectively) significantly increased the levels of PGE2 (mean ± SEM 505 ± 132 pg/50,000 cells and 288 ± 104 pg/50,000 cells, respectively, at 24 hours versus a basal level of 29 ± 9 pg/50,000 cells; P < 0.05) and increased the expression of COX‐2 at both the mRNA and protein levels. Expression of COX‐1 did not show any modulation with either inhibitor. Further experiments revealed that antimycin A and oligomycin induced a marked increase in the levels of ROS. Production of PGE2 and expression of COX‐2 protein were inhibited by antioxidants, vitamin E, and mitochondrial Ca2+ and NF‐κB inhibitors. The response to blockers of mitochondrial Ca2+ movement showed that ROS production was dependent on mitochondrial Ca2+ accumulation.ConclusionThese results strongly suggest that, in human chondrocytes, the inhibition of complexes III and V of the MRC induces an inflammatory response, which could be especially relevant in relation to PGE2 production via mitochondrial Ca2+ exchange, ROS production, and NF‐κB activation. These data may prove valuable for a better understanding of the participation of mitochondria in the pathogenesis of OA.
Is imatinib mesylate a promising drug in systemic sclerosis?
Authors: van Daele P. L. A. , Dik W. A. , Thio H. B. , van Hal P. Th. W. , van Laar J. A. M. , Hooijkaas H. , van Hagen P. M. 
Published: August 2008

AbstractA patient with therapy‐resistant and progressive systemic sclerosis (SSc) with pulmonary involvement who was treated with imatinib mesylate is described herein. Prior to treatment, pulmonary fibroblasts obtained from the patient were cultured and incubated with imatinib mesylate. Preincubation of the fibroblasts for 16 hours with 2.5 μg/ml imatinib mesylate efficiently abrogated platelet‐derived growth factor BB–induced fibroblast proliferation. Furthermore, transforming growth factor β1–induced type I collagen gene transcription was blocked. During treatment, the patient's pulmonary involvement stabilized and her skin tightness improved. To our knowledge, this is the first report of a patient with therapy‐refractory SSc responding to treatment with imatinib mesylate.