bluuebunny/crossref_metadata_2025_split huggingface dataset:
A potential role of thymic stromal lymphopoietin in the recruitment of macrophages to mouse intervertebral disc cells via monocyte chemotactic protein 1 induction: Implications for herniated discs
Authors: Ohba Tetsuro , Haro Hirotaka , Ando Takashi , Koyama Kensuke , Hatsushika Kyosuke , Suenaga Fumiko , Ohnuma Yuko , Nakamura Yuki , Katoh Ryohei , Ogawa Hideoki , Hamada Yoshiki , Nakao Atsuhito 
Published: October 2008

AbstractObjectiveTo determine whether thymic stromal lymphopoietin (TSLP) plays a role in the resorption of herniated disc tissue.MethodsThe expression of TSLP messenger RNA (mRNA) and protein in mouse intervertebral disc cells was assessed by quantitative real‐time polymerase chain reaction, enzyme‐linked immunosorbent assay (ELISA), and immunohistochemical analysis. The ability of mouse intervertebral disc cells to respond to TSLP stimulation was examined by Western blot analysis, ELISA, and protein array analysis. Intracellular signaling pathways involved in TSLP signaling in mouse intervertebral disc cells were investigated using several chemical inhibitors. The role of TSLP in macrophage migration into the intervertebral disc was assessed by in vitro migration assay. Finally, TSLP expression in clinical specimens derived from patients with a herniated disc was examined by immunohistochemistry.ResultsMouse intervertebral disc cells expressed TSLP mRNA and protein upon stimulation with NF‐κB–activating ligands such as tumor necrosis factor α. In addition, the mouse intervertebral disc cells expressed the TSLP receptor and produced monocyte chemotactic protein 1 (MCP‐1; CCL2) and macrophage colony‐stimulating factor in response to TSLP stimulation. Both anulus fibrosus and nucleus pulposus intervertebral disc cells expressed MCP‐1 upon TSLP stimulation, which was mediated via the phosphatidylinositol 3‐kinase/Akt pathway. Consistently, the supernatants of TSLP‐activated intervertebral disc cultures had the capacity to induce macrophage migration in an MCP‐1–dependent manner. Finally, TSLP and MCP‐1 were coexpressed in human herniated disc specimens in which macrophage infiltration into the tissue was observed.ConclusionTSLP induced by NF‐κB–activating ligands in intervertebral discs may contribute to the recruitment of macrophages to the intervertebral disc by stimulating MCP‐1 production and may be involved in the resorption of herniated disc tissue.
Mature antigen‐experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint
Authors: Manzo Antonio , Vitolo Barbara , Humby Frances , Caporali Roberto , Jarrossay David , Dell'Accio Francesco , Ciardelli Laura , Uguccioni Mariagrazia , Montecucco Carlomaurizio , Pitzalis Costantino 
Published: October 2008

AbstractObjectiveSynovial B cells play a critical role in rheumatoid arthritis (RA), being involved in autoantibody synthesis, T cell activation, and cytokine production. CXCL13 is a B cell chemoattractant that is instrumental in synovial B cell organization; the regulatory determinants of CXCL13 in inflammation are poorly characterized. This study was undertaken to investigate the functional involvement of synovial T cells in the ectopic expression of CXCL13 in RA.MethodsCXCL13 production and regulation were addressed using immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction, multicolor flow cytometry, and enzyme‐linked immunosorbent assay, by in situ–ex vivo analysis and in vitro functional assays with rheumatoid synovial tissue and primary cells.ResultsCXCL13 messenger RNA and protein expression and spontaneous CXCL13 secretion were detected in RA synovial fluid T cells but were not detected (or were detected only occasionally) in peripheral blood T cells. Analysis of tissue expression confirmed cytoplasm localization of CXCL13 in T lymphocytes infiltrating B cell follicles and small perivascular aggregates. Multicolor characterizations in synovial fluid demonstrated CXCL13 expression in antigen‐experienced T helper cells, frequently characterized by terminal differentiation and the lack of the follicular helper T cell markers CXCR5 and BCL6 protein. In vitro functional assays revealed the enhancing effect of T cell receptor–CD28 engagement on CXCL13 production and secretion in primary cells.ConclusionOur findings define a new functional property of synovial T cells, demonstrating their active involvement in the local production of B cell chemoattractants, and support a direct contribution of the adaptive immune system and antigen‐dependent signals in the mechanisms of B cell localization in RA.
Toll‐like receptor 2 variants are associated with acute reactive arthritis
Authors: Tsui Florence W. L. , Xi Nancy , Rohekar Sherry , Riarh Reena , Bilotta Rose , Tsui Hing Wo , Inman Robert D. 
Published: October 2008

AbstractObjectiveWe previously reported a recent outbreak of salmonellosis in which some individuals developed complications of the enteric infection. The objective of this study was to identify genetic variants that might predispose infected individuals to develop articular and/or extraarticular sequelae after Salmonella enteritidis infection.MethodsThe entire exposed cohort was invited to participate in the study by sending a saliva sample for DNA analysis. Seventy‐five Salmonella‐infected subjects for whom there was clinical information agreed to participate and were stratified into 4 groups. Group 1 patients had arthritis and extraarticular features, group 2 patients had arthritis alone, group 3 patients had extraarticular features alone, and group 4 patients had neither. DNA samples from an uninfected cohort of 91 normal subjects were also genotyped. Genotyping was performed using 2 Toll‐like receptor 2 (TLR‐2) (rs5743708 and rs5743704) and 2 TLR‐4 (rs4986790 and rs4986791) single‐nucleotide polymorphisms (SNPs). Statistical analyses were carried out using chi‐square tests.ResultsThere was no association of TLR‐4 exonic variants with any clinical events that were reported as accompanying the Salmonella infection. In contrast, compared with normal controls, one of the rare TLR‐2 SNPs (rs5743708, R753Q) was associated with the development of arthritis and extraarticular features (P = 0.015 by chi‐square test). The TLR‐2 variant 753Q was not detected in any of the infected individuals with an uncomplicated course. Another TLR‐2 variant, 631H, was associated with articular symptoms in infected males (P = 0.03 by chi‐square test).ConclusionIn this outbreak, genetic variants of TLR‐2, but not TLR‐4, were associated with acute reactive arthritis following infection with S enteritidis.
Angiogenesis in systemic sclerosis: Impaired expression of vascular endothelial growth factor receptor 1 in endothelial progenitor–derived cells under hypoxic conditions
Authors: Avouac J. , Wipff J. , Goldman O. , Ruiz B. , Couraud P. O. , Chiocchia G. , Kahan A. , Boileau C. , Uzan G. , Allanore Y. 
Published: October 2008

AbstractObjectiveTo assess angiogenesis and explore the expression and regulation of vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR‐1), and VEGFR‐2, the leading mediators of angiogenesis, in SSc patients and controls.MethodsLate‐outgrowth endothelial progenitor cells (EPCs), isolated from the peripheral blood of systemic sclerosis (SSc) patients and controls, and human umbilical vein endothelial cells (HUVECs) were assessed under normal and hypoxic conditions. Genomic background was evaluated in a large case–control study (including 659 patients with SSc and 511 controls) using tag single‐nucleotide polymorphisms on VEGFR1 and VEGFR2 genes.ResultsEPCs from SSc patients had the phenotype of genuine endothelial cells and displayed in vitro angiogenic properties similar to those of HUVECs and control EPCs under basal conditions, as determined by flow cytometry, tube formation, and migration assay. However, after 6 hours of hypoxic exposure, EPCs from SSc patients exhibited lower induced expression of VEGFR‐1 at the messenger RNA and protein levels, but similar VEGF and VEGFR‐2 expression, compared with HUVECs or EPCs from healthy controls. There was no evidence of defective expression of hypoxia‐inducible factor 1α. These results were supported by the lower serum levels of soluble VEGFR‐1 found in SSc patients (n = 187) compared with healthy controls (n = 48) (mean ± SD 163.7 ± 98.5 versus 210.4 ± 109.5 pg/ml; P = 0.0042). These abnormalities did not seem to be related to genomic background.ConclusionOur findings shed new light on the possible role of VEGFR‐1 in the main vascular disturbances that occur in SSc and lead to more severe disease.
HMOX1 promoter polymorphism modulates the relationship between disease activity and joint damage in rheumatoid arthritis
Authors: Wagener Frank A. D. T. G. , Toonen Erik J. M. , Wigman Lonneke , Fransen Jaap , Creemers Marjonne C. W. , Radstake Timothy R. D. J. , Coenen Marieke J. H. , Barrera Pilar , van Riel Piet L. C. M. , Russel Frans G. M. 
Published: October 2008

AbstractObjectiveThe guanine‐thymidine (GT)n repeat in the HMOX1 promoter determines the level of induction of the heme‐degrading enzyme heme oxygenase 1 (HO‐1), which protects against inflammatory and oxidative stress. In individuals with short (GT)n repeats (where n < 25; SS genotype), higher levels of HO‐1 activity are induced more rapidly than in those with long (GT)n repeats (where n ≥ 25; LL genotype). Recently, it was demonstrated that HO‐1 activity protects against the onset of rheumatoid arthritis (RA). The aim of this study was to determine whether the (GT)n‐repeat length within the HMOX1 promoter region is associated with RA disease severity and radiographic joint damage.MethodsA cohort of 325 well‐characterized RA patients and 273 controls was investigated by DNA fragment‐length analysis for the association of (GT)n repeats in the HMOX1 promoter region with RA disease susceptibility and severity.ResultsAlthough no significant differences in genotype or allele frequency were found between controls and RA patients, the odds ratios corresponded well to those in the previously described cohort. Among patients, those carrying the SS genotype had a more favorable radiographic outcome over 9 years than those carrying the LL genotype. This was unexpected since no differences in disease activity were found between the genotypes or alleles.ConclusionPatients with the SS genotype have a better long‐term radiographic outcome despite poor prognostic markers at baseline and despite disease activity at followup similar to that of patients with the LL genotype. This suggests that the HMOX1/HO‐1 system is involved in the uncoupling of disease activity and joint damage and may provide a novel target for the treatment of RA.
Acetylcholine regulation of synoviocyte cytokine expression by the α7 nicotinic receptor
Authors: Waldburger Jean‐Marc , Boyle David L. , Pavlov Valentin A. , Tracey Kevin J. , Firestein Gary S. 
Published: October 2008

AbstractObjectiveThe central nervous system can regulate peripheral inflammation, but the efferent neuronal routes and the mediators remain poorly defined. One candidate is the cholinergic pathway, which releases acetylcholine (ACh). This neurotransmitter can bind to the α7 cholinergic receptor (α7R) expressed by nonneuronal cells and reduce inflammation. To test this possibility, we evaluated the expression of α7R and its potential role as a target in rheumatoid arthritis (RA).MethodsThe expression of α7R in human synovium and fibroblast‐like synoviocytes (FLS) was determined using immunohistochemical, Western blot, and quantitative polymerase chain reaction (PCR) analyses. The effects of ACh in vitro were determined in interleukin‐1 (IL‐1)–stimulated FLS using immunoassays for protein, quantitative PCR for messenger RNA (mRNA), luciferase reporter constructs for IL‐6 and NF‐κB promoter activity, and electrophoretic mobility shift assays. Expression of α7R was knocked down with small interfering RNA (siRNA) or was inhibited with the selective α7R antagonist methyllycaconitine (MLA).ResultsProtein and mRNA for α7R were demonstrated in RA and osteoarthritis synovium and cultured synoviocytes. Expression in synovium was mainly in the intimal lining. ACh significantly reduced the production of IL‐6, CXCL8, CCL2, CCL3, CCL5, and granulocyte colony‐stimulating factor by IL‐1–stimulated FLS. This effect was blocked by the α7R antagonist MLA or by using α7R siRNA to knock down receptor expression. The selective α7R agonist PNU‐282,987 decreased the production of IL‐6 by IL‐1–stimulated FLS. ACh did not reduce IL‐6 transcription, but it decreased IL‐6 mRNA half‐life and reduced IL‐6 mRNA steady‐state levels.ConclusionThe α7 receptor is expressed in the synovium and by synoviocytes. Receptor ligation inhibits cytokine expression in FLS through a posttranscriptional mechanism. Therefore, α7R is a potential therapeutic target for inflammatory diseases.
Vertebral strength changes in rheumatoid arthritis patients treated with alendronate, as assessed by finite element analysis of clinical computed tomography scans: A prospective randomized clinical trial
Authors: Mawatari Taro , Miura Hiromasa , Hamai Satoshi , Shuto Toshihide , Nakashima Yasuharu , Okazaki Ken , Kinukawa Naoko , Sakai Shuji , Hoffmann Paul F. , Iwamoto Yukihide , Keaveny Tony M. 
Published: October 2008

AbstractObjectiveFinite element analysis of clinical computed tomography (CT) scans provides a noninvasive means of assessing vertebral strength that is superior to dual x‐ray absorptiometry (DXA)–measured areal bone mineral density. The present study was undertaken to compare strength changes, measured using this newer method, in rheumatoid arthritis (RA) patients who were treated with alendronate (ALN) versus those who were not.MethodsThirty female RA patients without radiologic signs of L3 compression fractures or a history of osteoporosis medication were enrolled in a prospective randomized clinical trial. Patients were randomly assigned to the ALN group (5 mg orally, once daily) or the control group not receiving antiresorptive treatment. All patients were evaluated by DXA and quantitative CT at baseline and reevaluated after a mean of 12.2 months. Nonlinear finite element analysis was performed on the CT scans (n = 29 available for analysis) to compute an estimate of vertebral compressive strength and to assess strength changes associated with changes in the trabecular compartment and the outer 2 mm of bone (peripheral compartment).ResultsOn average, vertebral strength was significantly decreased from baseline in the control group (n = 15) (median change −10.6%; P = 0.008) but was maintained in the ALN group (n = 14) (median change +0.4%; P = 0.55), with a significant difference between the 2 groups (P < 0.01). Strength decreased more rapidly within the trabecular bone, and ALN treatment was much more effective in the peripheral than the trabecular compartment.ConclusionOur results indicate that patients with RA can lose a substantial amount of vertebral strength over a relatively short period of time, and this loss can be prevented by ALN, primarily via its positive effect on the outer 2 mm of vertebral bone.
Analysis of apoptosis in peripheral blood and synovial tissue very early after initiation of infliximab treatment in rheumatoid arthritis patients
Authors: Wijbrandts Carla A. , Remans Philip H. , Klarenbeek Paul L. , Wouters Diana , van den Bergh Weerman Marius A. , Smeets Tom J. , Vervoordeldonk Margriet J. , Baeten Dominique , Tak Paul P. 
Published: October 2008

AbstractObjectiveInfliximab treatment results in a decrease in synovial cellularity as early as 48 hours after initiation of therapy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether infliximab induces apoptosis within the first 24 hours after infusion.MethodsThe percentage of apoptotic cells was determined by flow cytometry in blood drawn from 21 patients directly before, 1 hour after, and 24 hours after infliximab infusion. Synovial tissue samples obtained before, 1 hour after (n = 5), or 24 hours after (n = 5) initiation of therapy were subjected to immunohistochemistry to detect active caspase 3 and to TUNEL assay and electron microscopy to detect apoptosis. In addition, plasma levels of nucleosomes (generated during apoptosis) and C4b/c (an indicator of complement activation) were measured.ResultsThere were no signs of apoptosis induction in peripheral blood monocytes or lymphocytes after infliximab treatment. Circulating lymphocyte counts were increased within 1 hour after infusion (P < 0.05). There was no definite evidence of apoptosis induction in the synovium, except in 1 patient 24 hours after the infliximab infusion. Consistent with these results, there was no increase in nucleosome levels nor were there signs of complement activation.ConclusionOur findings indicate that the rapid decrease in synovial cellularity observed after initiation of anti–tumor necrosis factor antibody therapy cannot be explained by apoptosis induction at the site of inflammation. It is tempting to speculate that the striking effects on synovial inflammation may be explained by other mechanisms, such as decreased migration toward the synovial compartment and reduced retention in the inflamed synovium.
Treatment of rheumatoid arthritis with a syk kinase inhibitor: A twelve‐week, randomized, placebo‐controlled trial
Authors: Weinblatt Michael E. , Kavanaugh Arthur , Burgos‐Vargas Ruben , Dikranian Ara H. , Medrano‐Ramirez Gabriel , Morales‐Torres Jorge L. , Murphy Frederick T. , Musser Theresa Kane , Straniero Nicholas , Vicente‐Gonzales Angela V. , Grossbard Elliott 
Published: October 2008

AbstractObjectiveSpleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcγ‐activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA).MethodsWe enrolled 189 patients with active RA despite methotrexate therapy in a 3‐month, multicenter, ascending‐dose, double‐blind, placebo‐controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.ResultsTwice‐daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice‐daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin‐6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related.ConclusionThese results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.
Erosive arthritis in a patient with pycnodysostosis: An experiment of nature
Authors: Ainola Mari , Valleala Heikki , Nykänen Pekka , Risteli Juha , Hanemaaijer Roeland , Konttinen Yrjö T. 
Published: October 2008

AbstractObjectiveThe excellent poster painter Henri de Toulouse‐Lautrec is the most famous patient with cathepsin K–deficient pycnodysostosis. Cathepsin K is believed to play a major role in osteoclast‐driven bone resorption. In this study we explored the role of cathepsin K in bone resorption in a patient with a cathepsin K mutation causing pycnodysostosis in whom psoriatic arthritis also developed. We hypothesized that the patient would develop only inflammatory synovitis but would not develop bone erosions or other osteolytic changes.MethodsMonocytes from the patient with pycnodysostosis and normal control monocytes were isolated and stimulated to fuse and form multinuclear osteoclast‐like cells, which were identified by evaluating messenger RNA expression of osteoclast markers. The ability to resorb bone was assessed by determining the extent of pit formation and levels of collagen degradation products generated by cathepsin K (C‐terminal crosslinking telopeptide of type I collagen [CTX]) and matrix metalloproteinases (pyridinoline crosslinked C‐terminal telopeptide of type I collagen). These experiments were also done in normal control cells after incubation with the cathepsin K inhibitor E64 during bone resorption.ResultsIn contrast to our a priori hypothesis, the patient developed a mutilating disease with extensive bony erosions associated with lysis of some of the distal phalanges of her hands and feet. After stimulation of monocytes from this patient, the cells formed multinuclear tartrate‐resistant acid phosphatase–positive and calcitonin receptor–positive multikaryons, which, however, totally lacked cathepsin K. These multinuclear cells were able to resorb bone but, in contrast to normal control osteoclasts, did not produce CTX. The resorption pattern was abnormal in that, unlike normal control osteoclasts, both osteoclasts from the patient and E64‐inhibited osteoclasts did not leave extensive osteoclast trails, but were relatively sessile.ConclusionIn this “experiment of nature” we observed that cathepsin K is not necessary for bone degradation. These findings may be pertinent to our understanding of the functions of cathepsin K inhibitors, which are currently being developed as drugs to treat metabolic bone diseases.
Human muscle cells express the costimulatory molecule B7‐H3, which modulates muscle–immune interactions
Authors: Waschbisch Anne , Wintterle Sabine , Lochmüller Hanns , Walter Maggie C. , Wischhusen Jörg , Kieseier Bernd C. , Wiendl Heinz 
Published: October 2008

AbstractObjectiveInteractions between the family of B7 ligands and their receptors are increasingly recognized as crucial for stimulation and/or inhibition of immune responses. The present study was undertaken to examine the expression and functional relevance of B7 homolog 3 (B7‐H3), a novel B7 homolog attributed significant immunoregulatory functions, in human muscle cells in vivo and in vitro.MethodsThirty‐five muscle biopsy specimens obtained from patients with polymyositis, dermatomyositis, inclusion body myositis, or noninflammatory myopathies and normal controls were analyzed by immunohistochemistry for B7‐H3 expression. The expression of B7‐H3 protein on primary human myoblasts and TE671 muscle rhabdomyosarcoma cells was studied by flow cytometry and Western blot analysis. B7‐H3 small interfering RNA (siRNA) was used to study the impact of knockdown of B7‐H3 on CD8+ cell–mediated lysis in skeletal muscle cells.ResultsB7‐H3 was not detectable on normal muscle fibers. In contrast, its expression was markedly increased on muscle fibers from patients with inflammatory myopathies. Cell‐surface staining was most prominent in the contact areas between muscle fibers and inflammatory cells. B7‐H3 protein was detected on myoblasts cultured from control and myositis patient muscle tissue as well as in TE671 muscle rhabdomyosarcoma cells. Knockdown of B7‐H3 by siRNA in TE671 cells enhanced CD8+ T cell–specific lysis, indicating a functional role of B7‐H3 in the protection of skeletal muscle from immune‐mediated lysis.ConclusionOur results demonstrate that human muscle cells express B7‐H3, a functional coinhibitory molecule of the B7 family. B7‐H3 may play an important role in muscle–immune interactions, providing further evidence of the active role of muscle cells in local immunoregulatory processes.