bluuebunny/crossref_metadata_2025_split huggingface dataset:
Junctional adhesion molecule C mediates leukocyte adhesion to rheumatoid arthritis synovium
Authors: Rabquer Bradley J. , Pakozdi Angela , Michel James E. , Gujar Bansari S. , Haines G. Kenneth , Imhof Beat A. , Koch Alisa E. 
Published: September 2008

AbstractObjectiveLeukocyte infiltration into the rheumatoid arthritis (RA) synovium is a multistep process in which leukocytes leave the bloodstream and invade the synovial tissue (ST). Leukocyte transendothelial migration and adhesion to RA ST requires adhesion molecules on the surface of endothelial cells and RA ST fibroblasts. This study was undertaken to investigate the role of junctional adhesion molecule C (JAM‐C) in mediating leukocyte recruitment and retention in the RA joint.MethodsImmunohistologic analysis was performed on RA, osteoarthritis (OA), and normal ST samples to quantify JAM‐C expression. Fibroblast JAM‐C expression was also analyzed using Western blotting, cell surface enzyme‐linked immunosorbent assay, and immunofluorescence. To determine the role of JAM‐C in leukocyte retention in the RA synovium, in vitro and in situ adhesion assays and RA ST fibroblast transmigration assays were performed.ResultsJAM‐C was highly expressed by RA ST lining cells, and its expression was increased in OA ST and RA ST endothelial cells compared with normal ST endothelial cells. JAM‐C was also expressed on the surface of OA ST and RA ST fibroblasts. Furthermore, we demonstrated that myeloid U937 cell adhesion to both OA ST and RA ST fibroblasts and to RA ST was dependent on JAM‐C. U937 cell migration through an RA ST fibroblast monolayer was enhanced in the presence of neutralizing antibodies against JAM‐C.ConclusionOur results highlight the novel role of JAM‐C in recruiting and retaining leukocytes in the RA synovium and suggest that targeting JAM‐C may be important in combating inflammatory diseases such as RA.
Disrupted brain–immune system–joint communication during experimental arthritis
Authors: del Rey Adriana , Wolff Christine , Wildmann Johannes , Randolf Anke , Hahnel Anja , Besedovsky Hugo O. , Straub Rainer H. 
Published: September 2008

AbstractObjectiveTo explore the hypothesis that, in parallel with alterations in the hypothalamus–pituitary–adrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the course of arthritis development induced by type II collagen. This hypothesis was based on evidence that acute inflammatory processes induce cytokine expression in the brain and affect neuronal activity. We also studied whether depletion of hypothalamic noradrenaline can affect peripheral joint disease.MethodsHypothalamic cytokine gene expression and neurotransmitter concentration, parameters of inflammation, and joint innervation were evaluated during arthritis development in rats induced by injection of type II collagen in Freund's incomplete adjuvant. Noradrenergic neurons in the brain were depleted with 6‐hydroxydopamine.ResultsTransiently increased corticosterone levels, followed by increased adrenaline levels and hypothalamic interleukin‐1β (IL‐1β) and IL‐6 overexpression were observed only during the induction phase of the disease. Hypothalamic noradrenaline content was increased during the symptomatic phase and was paralleled by a gradual loss of noradrenergic fibers in the joints. The positive correlation between hypothalamic IL‐1β expression and noradrenaline content in control groups was not observed in rats in which arthritis developed. Depletion of hypothalamic noradrenergic neurons when arthritis was established did not affect the course of the disease.ConclusionThe dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate a disruption in communication between afferent immune messages to the central nervous system and 2 main efferent antiinflammatory pathways under control of the brain during collagen‐induced arthritis.
Regulation of pain sensitivity in experimental osteoarthritis by the endogenous peripheral opioid system
Authors: Inglis Julia J. , McNamee Kay E. , Chia Shi‐Lu , Essex David , Feldmann Marc , Williams Richard O. , Hunt Stephen P. , Vincent Tonia 
Published: September 2008

AbstractObjectiveOA is the most common joint disease, affecting 10–15% of people over 60 years of age. However, up to 40% of individuals with radiologic damage are asymptomatic. The purpose of this study was to assess the role of the endogenous opioid system in delaying the onset of pain in a murine model of osteoarthritis (OA).MethodsOsteoarthritis was induced by transection of the medial meniscotibial ligament. Pain was assessed by monitoring weight distribution and activity. At various times postsurgery, the opioid receptor antagonists naloxone or peripherally restricted naloxone methiodide were administered, and pain was assessed. Levels of the μ‐opioid receptor were assessed in the nerves innervating the joint by real‐time reverse transcription–polymerase chain reaction analysis.ResultsAs in human disease, significant joint damage occurred in mice before the onset of pain. To assess whether delayed pain was partly the result of increased endogenous opioid function, naloxone or naloxone methiodide was administered. Both opioid receptor antagonists led to pain onset 4 weeks earlier than in vehicle‐treated mice, indicating a role of the peripheral opioid system in masking OA pain. The expression of the μ‐opioid receptor in the peripheral nerves supplying the joint was transiently increased in naloxone‐responsive mice.ConclusionThese findings indicate that a temporal induction of μ‐opioid receptors in the early stages of OA delays the onset of pain. This is of clinical relevance and may contribute to the assessment of patients presenting with pain late in the disease. Furthermore, it may point to a mechanism by which the body blocks pain perception in moderate states of tissue damage, allowing an increased chance of survival.
Feasibility of a tetracycline‐binding method for detecting synovial fluid basic calcium phosphate crystals
Authors: Rosenthal Ann K. , Fahey Mark , Gohr Claudia , Burner Todd , Konon Irina , Daft Laureen , Mattson Eric , Hirschmugl Carol , Ryan Lawrence M. , Simkin Peter 
Published: September 2008

AbstractObjectiveBasic calcium phosphate (BCP) crystals are common components of osteoarthritis (OA) synovial fluid. Progress in understanding the role of these bioactive particles in clinical OA has been hampered by difficulties in their identification. Tetracyclines stain calcium phosphate mineral in bone. The aim of this study was to investigate whether tetracycline staining might be an additional or alternative method for identifying BCP crystals in synovial fluid.MethodsA drop of oxytetracycline was mixed with a drop of fluid containing synthetic or native BCP, calcium pyrophosphate dihydrate (CPPD), or monosodium urate (MSU) crystals and placed on a microscope slide. Stained and unstained crystals were examined by light microscopy, with and without a portable broad‐spectrum ultraviolet (UV) pen light. A small set of characterized synovial fluid samples were compared by staining with alizarin red S and oxytetracycline. Synthetic BCP crystals in synovial fluid were quantified fluorimetrically using oxytetracycline.ResultsAfter oxytetracycline staining, synthetic and native BCP crystals appeared as fluorescent amorphous aggregates under UV light. Oxytetracycline did not stain CPPD or MSU crystals or other particulates. Oxytetracycline staining had fewer false‐positive test results than did alizarin red S staining and could provide estimates of the quantities of synthetic BCP crystals in synovial fluid.ConclusionWith further validation, oxytetracycline staining may prove to be a useful adjunct or alternative to currently available methods for identifying BCP crystals in synovial fluid.
Immunoglobulin gene polymorphisms are susceptibility factors in clinical and autoantibody subgroups of the idiopathic inflammatory myopathies
Authors: O'Hanlon Terrance P. , Rider Lisa G. , Schiffenbauer Adam , Targoff Ira N. , Malley Karen , Pandey Janardan P. , Miller Frederick W. 
Published: September 2008

AbstractObjectiveTo investigate possible associations of GM and KM markers with adult and juvenile forms of the idiopathic inflammatory myopathies (IIMs) in Caucasian and African American patients.MethodsWe performed serologic analyses of polymorphic determinants associated with immunoglobulin gamma heavy chains (GM) and kappa light chains (KM) in large populations of Caucasian patients (n= 514 [297 adults and 217 children]) and African American patients (n = 123 [73 adults and 50 children]) with IIM representing the major clinical and autoantibody groups.ResultsFor Caucasian patients with dermatomyositis (DM), the Gm 3 23 5,13 phenotype was a risk factor in both adults (odds ratio [OR] 2.2, corrected P [Pcorr] = 0.020) and children (OR 2.2, Pcorr = 0.0013). Of interest, the GM 13 allotype was a risk factor for juvenile DM in both Caucasian subjects (OR 3.9, Pcorr < 0.0001) and African American subjects (OR 4.8, Pcorr = 0.033). However, the Gm 1,3,17 5,13,21 phenotype was a risk factor for juvenile DM in Caucasian subjects but not African American subjects. Among the IIM autoantibody groups, Gm 3 23 5,13 was a risk factor in Caucasian adults with anti–Jo‐1 autoantibodies (OR 3.4, Pcorr = 0.0031), while the GM 3 allotype was protective in adults with anti–threonyl–transfer RNA synthetase or anti–U RNP autoantibodies (OR 0.1, Pcorr = 0.047 and OR 0.2, Pcorr = 0.034, respectively). In contrast, GM 6 was a risk factor in African American adults with anti–signal recognition particle autoantibodies (OR 7.5, Pcorr = 0.041).ConclusionThese data suggest that polymorphic alleles of GM and KM loci are differentially associated with IIM subgroups defined by age, ethnicity, clinical features, and autoantibody status, and expand the list of immune response genes that are possibly important in the pathogenesis of myositis.
The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients
Authors: Chinoy H. , Platt H. , Lamb J. A. , Betteridge Z. , Gunawardena H. , Fertig N. , Varsani H. , Davidson J. , Oddis C. V. , McHugh N. J. , Wedderburn L. R. , Ollier W. E. R. , Cooper R. G. 
Published: September 2008

AbstractObjectiveTo examine single‐nucleotide polymorphisms (SNPs) of the protein tyrosine phosphatase N22 gene (PTPN22) and to study the relationship between PTPN22 and the HLA region in patients with idiopathic inflammatory myopathies (IIMs).MethodsPTPN22 SNPs were assessed in a large, cross‐sectional, case–control study from the UK involving patients with adult or juvenile IIM, comprising patients with polymyositis (PM) (n = 114), dermatomyositis (DM) (n = 102), myositis associated with another connective tissue disease (myositis–CTD overlap syndrome) (n = 64), or juvenile DM (n = 101), in comparison with 748 control subjects. Seventeen PTPN22 SNPs were genotyped using the Sequenom MassArray iPLEX platform. Serotyping for myositis‐specific/myositis‐associated autoantibodies (MSAs/MAAs) was performed by radioimmunoprecipitation.ResultsA significant association was noted between the R620W variant (rs2476601) and IIM (corrected P [Pcorr] = 0.0009 versus controls), and specifically with the clinical subgroup of PM (Pcorr = 0.003 versus controls). A weaker association was noted with juvenile DM (Pcorr = 0.009 versus controls). No significant associations were noted after stratification by serologic subgroups. The association with the R620W variant was independent of alleles forming the HLA 8.1 haplotype. No other PTPN22 SNPs were associated with IIM. The PTPN22 haplotype containing the R620W T allele was the only haplotype significantly associated with IIM.ConclusionThe R620W variant is a significant risk factor for IIM, independent of the HLA 8.1 haplotype. Unlike that in the HLA region, risk is not increased in individuals possessing MSAs/MAAs. These results are further evidence that the PTPN22 gene confers autoimmune susceptibility.
Reactivation of rheumatoid arthritis after pregnancy: Increased phagocyte and recurring lymphocyte gene activity
Authors: Häupl Thomas , ØStensen Monika , Grützkau Andreas , Radbruch Andreas , Burmester Gerd‐R. , Villiger Peter M. 
Published: September 2008

AbstractObjectivePregnancy is associated with reduced disease activity in rheumatoid arthritis (RA) and frequently with disease exacerbation after delivery. This study was undertaken to generate a systematic overview of the molecular mechanisms related to disease remission and postpartum reactivation.MethodsTranscriptomes of peripheral blood mononuclear cells (PBMCs) were generated from RA patients and healthy women by transcription profiling during the third trimester and 24 weeks after delivery. For functional interpretation, signatures of highly purified immune cells as well as Kyoto Encyclopedia of Genes and Genomes pathway annotations were used as a reference.ResultsOnly minor differences in gene expression in PBMCs during pregnancy were found between RA patients and controls. In contrast, RA postpartum profiles presented the most dominant changes. Systematic comparison with expression signatures of monocytes, T cells, and B cells in healthy donors revealed reduced lymphocyte and elevated monocyte gene activity during pregnancy in patients with RA and in controls. Monocyte activity decreased after delivery in controls but persisted in RA patients. Furthermore, analysis of 32 immunologically relevant cellular pathways demonstrated a significant additional activation of genes related to adhesion, migration, defense of pathogens, and cell activation, including Notch, phosphatidylinositol, mTOR, Wnt, and MAPK signaling, in RA patients postpartum.ConclusionOur findings indicate that innate immune functions play an important role in postpartum reactivation of arthritis. However, this may depend not only on the monocyte itself, but also on the recurrence of lymphocyte functions postpartum and thus on a critical interaction between both arms of the immune system.
Epigallocatechin‐3‐gallate diminishes CCL2 expression in human osteoblastic cells via up‐regulation of phosphatidylinositol 3‐Kinase/Akt/Raf‐1 interaction: A potential therapeutic benefit for arthritis
Authors: Lin Sze‐Kwan , Chang Hao‐Hueng , Chen Yunn‐Jy , Wang Chih‐Chiang , Galson Deborah L. , Hong Chi‐Yuan , Kok Sang‐Heng 
Published: September 2008

AbstractObjectiveTo assess the effects of epigallocatechin‐3‐gallate (EGCG) on oncostatin M (OSM)–induced CCL2 synthesis and the associated signaling pathways in human osteoblastic cells. The therapeutic effect of EGCG on collagen‐induced arthritis (CIA) in rats was also studied.MethodsCCL2 and c‐Fos messenger RNA expression was analyzed by Northern blotting. The modulating effects of EGCG on the activation of Raf‐1, Akt, and phosphatidylinositol 3‐kinase (PI 3‐kinase) were examined by coimmunoprecipitation, Western blotting, and PI 3‐kinase activity assay. Interactions between c‐Fos and CCL2 promoter were evaluated by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. The effect of EGCG on CIA in rats was examined clinically and immunohistochemically.ResultsEGCG inhibited OSM‐stimulated CCL2 expression in primary human osteoblasts and MG‐63 cells. In MG‐63 cells, EGCG alleviated the OSM‐induced phosphorylation of Raf‐1 at Ser338 but restored the dephosphorylation of Raf‐1 at Ser259. EGCG increased the activity of PI 3‐kinase, the level of phosphorylated Akt (Ser473), and binding between Raf‐1 and active Akt. EMSA and ChIP assay revealed that EGCG attenuated activator protein 1 (AP‐1)–CCL2 promoter interaction, possibly by reducing c‐Fos synthesis. Codistribution of CD68+ macrophages and CCL2+ osteoblasts in osteolytic areas was obvious in the CIA model. Administration of EGCG markedly diminished the severity of CIA, macrophage infiltration, and the amount of CCL2‐synthesizing osteoblasts.ConclusionBy stimulating PI 3‐kinase activity, EGCG promoted Akt/Raf‐1 crosstalk, resulting in decreased AP‐1 binding to CCL2 promoter, and finally reduced CCL2 production in osteoblasts. EGCG alleviated the severity of CIA, probably by suppressing CCL2 synthesis in osteoblasts to diminish macrophage infiltration. Our data support the therapeutic potential of EGCG on arthritis.
Neutrophil dysfunction in a family with a SAPHO syndrome–like phenotype
Authors: Ferguson Polly J. , Lokuta Mary A. , El‐Shanti Hatem I. , Muhle Leah , Bing Xinyu , Huttenlocher Anna 
Published: September 2008

AbstractSAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) is an inflammatory disorder of the bone, skin, and joints. We describe a family with multiple affected members who segregate a SAPHO syndrome–like phenotype, and we report the results of neutrophil studies and candidate gene analysis. We obtained written informed consent and a family history and reviewed medical records. We collected DNA and sequenced candidate genes, and we performed functional studies on neutrophils isolated from the proband and her mother. The pedigree segregated chronic osteomyelitis and cutaneous inflammation in a pattern that suggested an autosomal‐dominant disorder. No coding sequence mutations were detected in PSTPIP1, PSTPIP2, LPIN2, SH3BP2, or NCF4. Analysis of neutrophil function in the proband, including nitroblue tetrazolium tests, myeloperoxidase assays, neutrophil chemotaxis, and neutrophil chemotaxis assays, revealed no identifiable abnormalities. However, an abnormality in the luminol, but not the isoluminol, respiratory burst assays following stimulation with phorbol myristate acetate (PMA) was detected in neutrophils isolated from the affected proband. Internal oxidant production was also reduced in the proband and her mother when neutrophils were treated with fMLP with or without platelet‐activating factor, PMA alone, or tumor necrosis factor α alone. This family segregates a disorder characterized by chronic inflammation of the skin and bone. Functional differences in neutrophils exist between affected individuals and controls. The biologic significance of this defect remains unknown. Identification of the gene defect will help identify an immunologic pathway that, when dysregulated, causes inflammation of the skin and bone.
Induction of osteoclast‐associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis
Authors: Herman Sonja , Müller Ruediger B. , Krönke Gerhard , Zwerina Jochen , Redlich Kurt , Hueber Axel J. , Gelse Holger , Neumann Elena , Müller‐Ladner Ulf , Schett Georg 
Published: September 2008

AbstractObjectiveOsteoclast‐associated receptor (OSCAR) is a newly identified osteoclast‐specific receptor and is of key importance in the process of osteoclast costimulation. This study was undertaken to define the role of costimulation in osteoclast differentiation during inflammatory arthritis.MethodsOSCAR expression was assessed in the synovium and peripheral blood monocytes of patients with rheumatoid arthritis (RA), and associations with disease activity were assessed. Serum levels of OSCAR were determined by enzyme‐linked immunosorbent assay. In vitro osteoclast assays were performed to characterize the role of OSCAR in human osteoclastogenesis. Cytokine regulation of OSCAR was investigated by reverse transcriptase–polymerase chain reaction.ResultsOSCAR was expressed by osteoclasts at the erosion front and by mononuclear cells around synovial microvessels. Flow cytometry revealed enhanced expression of OSCAR in peripheral blood monocytes of RA patients as compared with healthy controls. OSCAR expression was correlated with disease activity and acute‐phase reactant concentrations. Serum levels of soluble OSCAR were lower in RA patients than in healthy controls. Monocytes with high OSCAR expression exhibited an enhanced potential to differentiate into osteoclasts. Tumor necrosis factor α was identified as the main inducer of OSCAR expression in monocytes.ConclusionThese data suggest that the osteoclast costimulation pathway is activated in RA. OSCAR is induced in monocytes of RA patients, facilitating their differentiation into osteoclasts and bone resorption.
Induction of an osteoarthritis‐like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice
Authors: Wu Qiuqian , Kim Kyung‐Ok , Sampson Erik R. , Chen Di , Awad Hani , O'Brien Todd , Puzas J. Edward , Drissi Hicham , Schwarz Edward M. , O'Keefe Regis J. , Zuscik Michael J. , Rosier Randy N. 
Published: September 2008

AbstractObjectiveTo determine whether Smurf2, an E3 ubiquitin ligase known to inhibit transforming growth factor β (TGFβ) signaling, is expressed in human osteoarthritic (OA) cartilage and can initiate OA in mice.MethodsHuman OA cartilage was obtained from patients undergoing knee arthroplasty. Samples were graded histologically using the Mankin scale and were examined immunohistochemically for Smurf2 expression. A transgene driven by the collagen 2α1 promoter was used to overexpress Smurf2 in mice. Smurf2 overexpression in mouse sternal chondrocytes was confirmed by reverse transcription–polymerase chain reaction and Western blotting. Changes in articular cartilage area, chondrocyte number, and chondrocyte diameter were assessed histomorphometrically using OsteoMeasure software. Alterations in type X collagen and matrix metalloproteinase 13 (MMP‐13) in articular chondrocytes were examined by in situ hybridization and immunohistochemistry, respectively. Joint bone phenotypes were evaluated by microfocal computed tomography. The effects of Smurf2 overexpression on TGFβ signaling were examined using a luciferase‐based reporter and immunoprecipitation/Western blotting.ResultsHuman OA cartilage strongly expressed Smurf2 as compared with nonarthritic human cartilage. By 8 months of age, Smurf2‐transgenic mice exhibited decreased articular cartilage area, fibrillation, clefting, eburnation, subchondral sclerosis, and osteophytes. Increased expression of type X collagen and MMP‐13 were also detected in articular cartilage from transgenic mice. Transgenic sternal chondrocytes showed reduced TGFβ signaling as well as decreased expression and increased ubiquitination of pSmad3.ConclusionSmurf2 is up‐regulated during OA in humans, and Smurf2‐transgenic mice spontaneously develop an OA‐like phenotype that correlates with decreased TGFβ signaling and increased pSmad3 degradation. Overall, these results suggest a role of Smurf2 in the pathogenesis of OA.