bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of interleukin‐1β on osteogenic protein 1–induced signaling in adult human articular chondrocytes
Authors: Elshaier Amel M. , Hakimiyan Arnavaz A. , Rappoport Lev , Rueger David C. , Chubinskaya Susan 
Published: December 2008

AbstractObjectiveTwo major receptor‐activated Smad (R‐Smad) signaling pathways, bone morphogenetic protein (BMP) and MAPK, were examined in a model of interleukin‐1β (IL‐1β)–induced cartilage degeneration to investigate the effect of IL‐1β on osteogenic protein 1 (OP‐1) signaling in adult human articular chondrocytes.MethodsChondrocytes from the ankles of 26 normal human donors were cultured in high‐density monolayers in serum‐free medium. The effect of IL‐1β on BMP receptors was studied by reverse transcription–polymerase chain reaction and flow cytometry. Phosphorylation of R‐Smads was tested in cells treated with IL‐1β (10 ng/ml), OP‐1 (100 ng/ml), or the combination of IL‐1β and OP‐1. Cell lysates were analyzed by Western blotting with polyclonal antibodies against 2 R‐Smad phosphorylation sites (BMP‐ and MAPK‐mediated) or with total, nonphosphorylated R‐Smad as a control. To identify which MAPKs play a role in IL‐1β activation of the linker region, chondrocytes were preincubated with specific MAPK inhibitors (PD98059 for MAP/ERK, SP600125 for JNK, and SB203580 for p38).ResultsIL‐1β reduced the number of activin receptor–like kinase 2 (ALK‐2) and ALK‐3 receptors, inhibited expression of Smad1 and Smad6, delayed and prematurely terminated the onset of OP‐1–mediated R‐Smad phosphorylation, and affected nuclear translocation of R‐Smad/Smad4 complexes. The alternative phosphorylation of R‐Smad in the linker region via the MAPK pathway (primarily p38 and JNK) was observed to be a possible mechanism through which IL‐1β offsets OP‐1 signaling and the response to OP‐1. Conversely, OP‐1 was found to directly inhibit phosphorylation of p38.ConclusionThese findings describe new mechanisms of the crosstalk between OP‐1 and IL‐1β in chondrocytes. The study also identifies potential targets for therapeutic interventions in the treatment of cartilage‐degenerative processes.
Association of the TRAF1/C5 locus with increased mortality, particularly from malignancy or sepsis, in patients with rheumatoid arthritis
Authors: Panoulas Vasileios F. , Smith Jacqueline P. , Nightingale Peter , Kitas George D. 
Published: December 2008

AbstractObjectiveRecent genome‐wide association studies have identified TRAF1/C5 as a rheumatoid arthritis (RA) susceptibility locus. Tumor necrosis factor receptor–associated factor 1 (TRAF1) has been implicated in the regulation of antiapoptotic pathways, whereas C5 has a well‐established role in defense against infection. The purpose of this study was to examine the association of the TRAF1/C5 locus with death in patients with RA.MethodsGenomic DNA samples were collected from a prospective cohort of 400 RA patients. TRAF1/C5 rs3761847 was identified using real‐time polymerase chain reaction and melting curve analyses. The association of TRAF1/C5 rs3761847 alleles with the risk of death was assessed using Cox proportional hazards regression analyses.ResultsTRAF1/C5 rs3761847 GG homozygote status was associated with an increased risk of death (hazard ratio 3.96 [95% confidence interval 1.24–12.6], P = 0.020) as compared with AA homozygote status. The excess mortality was attributed to deaths due to malignancies and sepsis but not cardiovascular disease (CVD). This polymorphism was one of the strongest predictors of death in RA (for TRAF1/C5 GG versus AA, hazard ratio 3.85 [95% confidence interval 1.18–12.59], P = 0.026) alongside the erythrocyte sedimentation rate, triglyceride level, prednisolone use, and age.ConclusionThe risk of death in RA is increased in TRAF1/C5 rs3761847 GG homozygotes and appears to be independent of RA activity and severity as well as comorbidities relevant to CVD. If this finding is replicated in future studies, TRAF1/C5 genotyping could identify patients at increased risk of death, particularly death due to malignancy or sepsis.
Activation of synoviolin promoter in rheumatoid synovial cells by a novel transcription complex of interleukin enhancer binding factor 3 and GA binding protein α
Authors: Izumi Toshihiko , Fujii Ryoji , Izumi Tomonori , Nakazawa Minako , Yagishita Naoko , Tsuchimochi Kaneyuki , Yamano Yoshihisa , Sato Tomoo , Fujita Hidetoshi , Aratani Satoko , Araya Natsumi , Azakami Kazuko , Hasegawa Daisuke , Kasaoka Shunji , Tsuruta Ryosuke , Yokouti Masahiro , Ijiri Kosei , Beppu Moroe , Maruyama Ikuro , Nishioka Kusuki , Maekawa Tsuyoshi , Komiya Setsuro , Nakajima Toshihiro 
Published: December 2008

AbstractObjectiveSynoviolin is an E3 ubiquitin ligase, and its overexpression is implicated in the pathogenesis of rheumatoid arthritis (RA). We reported previously that Ets binding site 1 (EBS‐1) within the synoviolin promoter is crucial for the expression of synoviolin, and GA binding protein (GABP) binds to this site. This study was undertaken to elucidate the precise mechanisms of transcriptional regulation via EBS‐1.MethodsWe performed purification and identification of complex components that bind to EBS‐1 and inspected their contributions to the transcriptional regulation of synoviolin in rheumatoid synovial cells. We biochemically purified proteins that had EBS‐1 binding activity and identified the proteins using liquid chromatography tandem mass spectrometry analysis. The identified proteins were verified to recruit and form the complex on EBS‐1 using electrophoretic mobility shift assay and coimmunoprecipitation assay. Furthermore, their transcription activities were tested by reporter assays and RNA interference experiments.ResultsWe identified interleukin enhancer binding factor 3 (ILF‐3) as a novel factor in the complex. ILF‐3 was demonstrated to activate the synoviolin promoter via association with GABPα in rheumatoid synovial cells. In addition, further activation was observed with ILF‐2 and GABPβ, previously reported interactants of ILF‐3 and GABPα, respectively. Moreover, ILF‐3–knockdown experiments showed reduced expression of the synoviolin gene.ConclusionOur findings indicate that ILF‐3, which has been known to regulate IL‐2 expression in T cells, up‐regulates synoviolin expression with GABPα in rheumatoid synovial cells. ILF‐3 might be a target for RA treatment through its effect on IL‐2 in T cells and synoviolin in rheumatoid synovial cells.
The chromosome 7q region association with rheumatoid arthritis in females in a british population is not replicated in a North American case–control series
Authors: Korman Benjamin D. , Seldin Michael F. , Taylor Kimberly E. , Le Julie M. , Lee Annette T. , Plenge Robert M. , Amos Christopher I. , Criswell Lindsey A. , Gregersen Peter K. , Kastner Daniel L. , Remmers Elaine F. 
Published: December 2008

AbstractObjectiveThe single‐nucleotide polymorphism (SNP) rs11761231 on chromosome 7q has been reported to be sexually dimorphic marker for rheumatoid arthritis (RA) susceptibility in a British population. We sought to replicate this finding and to better characterize susceptibility alleles in the region in a North American population.MethodsDNA from 2 North American collections of RA patients and controls (1,605 cases and 2,640 controls) was genotyped for rs11761231 and 16 additional chromosome 7q tag SNPs using Sequenom iPlex assays. Association tests were performed for each collection and also separately, contrasting male cases with male controls and female cases with female controls. Principal components analysis (EigenStrat) was used to determine association with RA before and after adjusting for population stratification in the subset of the samples for which there were whole‐genome SNP data (772 cases and 1,213 controls).ResultsWe failed to replicate an association of the 7q region with RA. Initially, rs11761231 showed evidence for association with RA in the North American Rheumatoid Arthritis Consortium (NARAC) collection (P = 0.0073), and rs11765576 showed association with RA in both the NARAC (P = 0.038) and RA replication (P = 0.0013) collections. These markers also exhibited sex differentiation. However, in the whole‐genome subset, neither SNP showed significant association with RA after correction for population stratification.ConclusionWhile 2 SNPs on chromosome 7q appeared to be associated with RA in a North American cohort, the significance of this finding did not withstand correction for population substructure. Our results emphasize the need to carefully account for population structure to avoid false‐positive disease associations.
Quadriceps strength and the risk of cartilage loss and symptom progression in knee osteoarthritis
Authors: Amin Shreyasee , Baker Kristin , Niu Jingbo , Clancy Margaret , Goggins Joyce , Guermazi Ali , Grigoryan Mikayel , Hunter David J. , Felson David T. 
Published: December 2008

AbstractObjectiveTo determine the effect of quadriceps strength in individuals with knee osteoarthritis (OA) on loss of cartilage at the tibiofemoral and patellofemoral joints (assessed by magnetic resonance imaging [MRI]) and on knee pain and function.MethodsWe studied 265 subjects (154 men and 111 women, mean ± SD age 67 ± 9 years) who met the American College of Rheumatology criteria for symptomatic knee OA and who were participating in a prospective, 30‐month natural history study of knee OA. Quadriceps strength was measured at baseline, isokinetically, during concentric knee extension. MRI of the knee at baseline and at 15 and 30 months was used to assess cartilage loss at the tibiofemoral and patellofemoral joints, with medial and lateral compartments assessed separately. At baseline and at followup visits, knee pain was assessed using a visual analog scale, and physical function was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index.ResultsThere was no association between quadriceps strength and cartilage loss at the tibiofemoral joint. Results were similar in malaligned knees. However, greater quadriceps strength was protective against cartilage loss at the lateral compartment of the patellofemoral joint (for highest versus lowest tertile of strength, odds ratio 0.4 [95% confidence interval 0.2, 0.9]). Those with greater quadriceps strength had less knee pain and better physical function over followup (P< 0.001).ConclusionGreater quadriceps strength had no influence on cartilage loss at the tibiofemoral joint, including in malaligned knees. We report for the first time that greater quadriceps strength protected against cartilage loss at the lateral compartment of the patellofemoral joint, a finding that requires confirmation. Subjects with greater quadriceps strength also had less knee pain and better physical function over followup.
Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis
Authors: Akhmetshina Alfiya , Venalis Paulius , Dees Clara , Busch Nicole , Zwerina Jochen , Schett Georg , Distler Oliver , Distler Jörg H. W. 
Published: December 2008

AbstractObjectiveImatinib is a small‐molecule tyrosine kinase inhibitor capable of selective, dual inhibition of the transforming growth factor β and platelet‐derived growth factor (PDGF) pathways. Imatinib has previously been shown to prevent the development of inflammation‐driven experimental fibrosis when treatment was initiated before administration of the profibrotic stimulus. The aim of this study was to confirm the efficacy of imatinib in a murine model of systemic sclerosis (SSc) that is less driven by inflammation and to investigate whether imatinib is also effective for the treatment of established fibrosis.MethodsThe tight skin 1 (TSK‐1) mouse model of SSc was used to evaluate the antifibrotic effects of imatinib in a genetic model of the later stages of SSc. In addition, the efficacy of imatinib for the treatment of preestablished fibrosis was analyzed in a modified model of bleomycin‐induced dermal fibrosis in which the application of bleomycin was prolonged and the onset of treatment was late.ResultsTreatment with imatinib reduced dermal and hypodermal thickening in TSK‐1 mice and prevented the differentiation of resting fibroblasts into myofibroblasts. In the model of preestablished dermal fibrosis, imatinib not only stopped further progression of fibrosis but also induced regression of preexisting dermal fibrosis, with a reduction in dermal thickness below pretreatment levels.ConclusionThese results indicate that combined inhibition of the tyrosine kinase c‐Abl and PDGF receptor might be effective in the later, less inflammatory stages of SSc and for the treatment of established fibrosis. Thus, imatinib might be an interesting candidate for clinical trials in patients with longstanding disease and preexisting tissue fibrosis.
Requirement of transforming growth factor β–activated kinase 1 for transforming growth factor β–induced α‐smooth muscle actin expression and extracellular matrix contraction in fibroblasts
Authors: Shi‐Wen Xu , Parapuram Sunil K. , Pala Daphne , Chen Yunliang , Carter David E. , Eastwood Mark , Denton Christopher P. , Abraham David J. , Leask Andrew 
Published: December 2008

AbstractObjectiveFibrosis is believed to occur through normal tissue remodeling failing to terminate. Tissue repair intimately involves the ability of fibroblasts to contract extracellular matrix (ECM), and enhanced ECM contraction is a hallmark of fibrotic cells in various conditions, including scleroderma. Some fibrogenic transcriptional responses to transforming growth factor β (TGFβ), including α‐smooth muscle actin (α‐SMA) expression and ECM contraction, require focal adhesion kinase/Src (FAK/Src). The present study was undertaken to assess whether TGFβ‐activated kinase 1 (TAK1) acts downstream of FAK/Src to mediate fibrogenic responses in fibroblasts.MethodsWe used microarray, real‐time polymerase chain reaction, Western blot, and collagen gel contraction assays to assess the ability of wild‐type and TAK1‐knockout fibroblasts to respond to TGFβ1.ResultsThe ability of TGF to induce TAK1 was blocked by the FAK/Src inhibitor PP2. JNK phosphorylation in response to TGFβ1 was impaired in the absence of TAK1. TGFβ could not induce matrix contraction or expression of a group of fibrotic genes, including α‐SMA, in the absence of TAK1.ConclusionThese results suggest that TAK1 operates downstream of FAK/Src in mediating fibrogenic responses and that targeting of TAK1 may be a viable antifibrotic strategy in the treatment of certain disorders, including scleroderma.
Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus
Authors: Bertsias George K. , Nakou Magda , Choulaki Christianna , Raptopoulou Amalia , Papadimitraki Eva , Goulielmos George , Kritikos Herakles , Sidiropoulos Prodromos , Tzardi Maria , Kardassis Dimitris , Mamalaki Clio , Boumpas Dimitrios T. 
Published: December 2008

AbstractObjectiveA putative regulatory intronic polymorphism (PD1.3) in the programmed death 1 (PD‐1) gene, a negative regulator of T cells involved in peripheral tolerance, is associated with increased risk for systemic lupus erythematosus (SLE). We undertook this study to determine the expression and function of PD‐1 in SLE patients.MethodsWe genotyped 289 SLE patients and 256 matched healthy controls for PD1.3 by polymerase chain reaction–restriction fragment length polymorphism analysis. Expression of PD‐1 and its ligand, PDL‐1, was determined in peripheral blood lymphocytes and in renal biopsy samples by flow cytometry and immunohistochemistry. A crosslinker of PD‐1 was used to assess its effects on anti‐CD3/anti‐CD28–induced T cell proliferation and cytokine production.ResultsSLE patients had an increased frequency of the PD1.3 polymorphism (30.1%, versus 18.4% in controls; P = 0.006), with the risk A allele conferring decreased transcriptional activity in transfected Jurkat cells. Patients homozygous for PD1.3—but not patients heterozygous for PD1.3—had reduced basal and induced PD‐1 expression on activated CD4+ T cells. In autologous mixed lymphocyte reactions (AMLRs), SLE patients had defective PD‐1 induction on activated CD4+ cells; abnormalities were more pronounced among homozygotes. PD‐1 was detected within the glomeruli and renal tubules of lupus nephritis patients, while PDL‐1 was expressed by the renal tubules of both patients and controls. PD‐1 crosslinking suppressed proliferation and cytokine production in both normal and lupus T cells; addition of serum from patients with active SLE significantly ameliorated this effect on proliferation.ConclusionSLE patients display aberrant expression and function of PD‐1 attributed to both direct and indirect effects. The expression of PD‐1/PDL‐1 in renal tissue and during AMLRs suggests an important role in regulating peripheral T cell tolerance.
Identification of the core element responsive to runt‐related transcription factor 2 in the promoter of human type x collagen gene
Authors: Higashikawa Akiro , Saito Taku , Ikeda Toshiyuki , Kamekura Satoru , Kawamura Naohiro , Kan Akinori , Oshima Yasushi , Ohba Shinsuke , Ogata Naoshi , Takeshita Katsushi , Nakamura Kozo , Chung Ung‐Il , Kawaguchi Hiroshi 
Published: December 2008

AbstractObjectiveType X collagen and runt‐related transcription factor 2 (RUNX‐2) are known to be important for chondrocyte hypertrophy during skeletal growth and repair and development of osteoarthritis (OA) in mice. Aiming at clinical application, this study was undertaken to investigate transcriptional regulation of human type X collagen by RUNX‐2 in human cells.MethodsLocalization of type X collagen and RUNX‐2 was determined by immunohistochemistry, and their functional interaction was examined in cultured mouse chondrogenic ATDC‐5 cells. Promoter activity of the human type X collagen gene (COL10A1) was examined in human HeLa, HuH7, and OUMS27 cells transfected with a luciferase gene containing a 4.5‐kb promoter and fragments. Binding to RUNX‐2 was examined by electrophoretic mobility shift assay and chromatin immunoprecipitation.ResultsRUNX‐2 and type X collagen were co‐localized in mouse limb cartilage and bone fracture callus. Gain and loss of function of RUNX‐2 revealed that RUNX‐2 is essential for type X collagen expression and terminal differentiation of chondrocytes. Human COL10A1 promoter activity was enhanced by RUNX‐2 alone and more potently by RUNX‐2 in combination with the coactivator core‐binding factor β in all 3 human cell lines examined. Deletion, mutagenesis, and tandem repeat analyses identified the core responsive element as the region between −89 and −60 bp (termed the hypertrophy box [HY box]), which showed specific binding to RUNX‐2. Other putative RUNX‐2 binding motifs in the human COL10A1 promoter did not respond to RUNX‐2 in human cells.ConclusionOur findings indicate that the HY box is the core element responsive to RUNX‐2 in human COL10A1 promoter. Studies on molecular networks related to RUNX‐2 and the HY box will lead to treatments of skeletal growth retardation, bone fracture, and OA.
Pneumomediastinum in interstitial lung disease associated with dermatomyositis and polymyositis
Authors: Le Goff Benoit , Chérin Patrick , Cantagrel Alain , Gayraud Martine , Hachulla Eric , Laborde Fyriel , Papo Thomas , Sibilia Jean , Zabraniecki Laurent , Ravaud Philippe , Puéchal Xavier 
Published: December 2008

AbstractObjectiveSpontaneous pneumomediastinum is a rare complication of dermatomyositis (DM) and polymyositis (PM). The aim of this study was to characterize this complication and determine its prognostic factors.MethodsWe retrospectively collected a multicenter series of PM/DM cases complicated by pneumomediastinum. We analyzed all published cases and combined those that were exploitable with ours for an investigation of the factors associated with poor survival.ResultsWe collected 11 PM/DM cases complicated by interstitial lung disease and pneumomediastinum. Five of the 9 DM patients had clinically amyopathic DM without muscle weakness and high serum creatine kinase levels. The outcome was favorable in 7 of these patients and 6 had no sequelae. In total, ∼25% of our patients of the 21 analyzable cases studied died within 1 month. With a median followup of 240 days, the cumulative estimated Kaplan‐Meier survival rate was 64% at 1 year and 55% at 2 years. Poor survival was associated with absence of muscle weakness (P = 0.02), initial low vital capacity (P = 0.006), and initial low carbon monoxide diffusion capacity (P = 0.04).ConclusionIn this first large series of patients with connective tissue disease complicated by pneumomediastinum to be reported, most patients had DM and half amyopathic DM, as in previous reports. Pneumomediastinum may occur before DM diagnosis and may thus reveal DM with minimal or no muscle involvement. Death was associated with an absence of muscle weakness and severe pulmonary involvement before the onset of pneumomediastinum. Corticosteroids and immunosuppressive therapy can result in complete recovery, as in half our cases.
Helix‐coil energetics for helix formers and breakers reflect context and temperature: Mutants of helically robust, guest‐sensitive homopeptide hosts
Authors: Nasr Khaled A. , Schubert Christian R. , Török Marianna , Kennedy Robert J. , Kemp Daniel S. 
Published: December 2008

AbstractThe natural amino acids are primarily helix breakers at the low assignment temperatures characteristic of many studies, but recent genomic analyses of thermophilic proteins suggest that at high temperatures, some breakers may become strong helix formers. Moreover, the breaker/former inventory has not been previously characterized at the physiologically relevant temperature of 37°C. The versatility of 13CO NMR chemical shifts as helicity reporters allows construction of two mutant peptide series, tailored to expand the range of temperature assignments for helical propensities and derived from the core hosts tL‐Ala9XxxAla9‐tL and tL‐AlaNva4XxxNva4Ala9‐tL, Nva = norvaline. For three limiting guests Xxx, the helix former Nva and the breakers Gly and Pro, we report wXxx[T] assignments at seven temperatures from 2 to 80°C, validating our reasoning and paving the way for assignment of a definitive wXxx[T] data‐base. © 2008 Wiley Periodicals, Inc. Biopolymers 91: 311–320, 2009.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
Shaping the Polypropionate Biosynthesis in the Solar‐Powered Mollusc Elysia viridis
Authors: Cutignano Adele , Cimino Guido , Villani Guido , Fontana Angelo 
Published: December 2008

AbstractPolypropionates that incorporate pyrones are a family of polyketides featuring the chemistry of a few marine molluscs capable of phototrophic CO2 fixation as a result of storing viable symbiotic chloroplasts in their bodies. The role and origin of these molecules is poorly investigated, although the unusual biological activities and chemistry of these natural products have recently received renewed interest. Here, we report the results of in vivo studies on production of γ‐pyrone‐containing polypropionates in the Mediterranean mollusc Elysia viridis. Biosynthesis of the metabolites in the sacoglossan is shown to proceed through condensation of eight intact C3 units by polyketide synthase assembly. LC–MS and NMR spectroscopic studies demonstrate that the process involves a pyrone tetraene (10) as key intermediate, whereas the levels of the final polypropionates (6, 7 and 9) are related to each other and show a significant dependence upon light conditions.