bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADAMTS‐9 is synergistically induced by interleukin‐1β and tumor necrosis factor α in OUMS‐27 chondrosarcoma cells and in human chondrocytes
Authors: Demircan Kadir , Hirohata Satoshi , Nishida Keiichiro , Hatipoglu Omer F. , Oohashi Toshitaka , Yonezawa Tomoko , Apte Suneel S. , Ninomiya Yoshifumi 
Published: May 2005

AbstractObjectiveTo compare induction of the aggrecanases (ADAMTS‐1, ADAMTS‐4, ADAMTS‐5, ADAMTS‐8, ADAMTS‐9, and ADAMTS‐15) by interleukin‐1β (IL‐1β) and tumor necrosis factor α (TNFα) in chondrocyte‐like OUMS‐27 cells and human chondrocytes, and to determine the mechanism of induction of the most responsive aggrecanase gene.MethodsOUMS‐27 cells were stimulated for different periods of time and with various concentrations of IL‐1β and/or TNFα. Human chondrocytes obtained from osteoarthritic joints and human skin fibroblasts were also stimulated with IL‐1β and/or TNFα. Total RNA was extracted, reverse transcribed, and analyzed by quantitative real‐time polymerase chain reaction and Northern blotting. ADAMTS‐9 protein was examined by Western blotting, and the role of the MAPK signaling pathway for ADAMTS9 induction in IL‐1β–stimulated OUMS‐27 cells was investigated.ResultsIL‐1β increased messenger RNA (mRNA) levels of ADAMTS4, ADAMTS5, and ADAMTS9 but not ADAMTS1 and ADAMTS8. The fold increase for ADAMTS9 mRNA was greater than that for mRNA of the other aggrecanase genes. The increase of ADAMTS9 mRNA by IL‐1β stimulation was greater in chondrocytes than in fibroblasts. The combination of IL‐1β and TNFα had a synergistic effect, resulting in a considerable elevation in the level of ADAMTS9 mRNA. ADAMTS‐9 protein was also induced in IL‐1β–stimulated OUMS‐27 cells. The MAPK inhibitors SB203580 and PD98059 decreased ADAMTS9 up‐regulation in OUMS‐27 cells.ConclusionADAMTS9 is an IL‐1β– and TNFα‐inducible gene that appears to be more responsive to these proinflammatory cytokines than are other aggrecanase genes. Furthermore, these cytokines had a synergistic effect on ADAMTS9. Together with the known ability of ADAMTS‐9 to proteolytically degrade aggrecan and its potential to cleave other cartilage molecules, the data suggest that ADAMTS‐9 may have a pathologic role in arthritis.
Type I collagen α1 Sp1 transcription factor binding site polymorphism is associated with reduced risk of hip osteoarthritis defined by severe joint space narrowing in elderly women
Authors: Lian K. , Zmuda J. M. , Nevitt M. C. , Lui L. , Hochberg M. C. , Greene D. , Li J. , Wang J. , Lane N. E. 
Published: May 2005

AbstractObjectiveA common G/T substitution at an Sp1 binding site in intron 1 of the COL1A1 gene has been reported to be associated with reduced bone mineral density and increased risk of osteoporotic fracture. The purpose of this study was to examine whether there is an association between COL1A1 Sp1 polymorphism and radiographic osteoarthritis (OA) of the hip in elderly women in the Study of Osteoporotic Fractures.MethodsRadiographic hip OA status of subjects was defined by the presence of 1 of the following criteria in either hip: a joint space narrowing (JSN) score of ≥3, a Croft summary grade of ≥3, or both definite (score ≥2) osteophytes and JSN in the same hip. Cases of radiographic OA of the hip were further subdivided into those with JSN score ≥3 and those with a femoral osteophyte score ≥2 and JSN score ≤2. The COL1A1 Sp1 polymorphism was genotyped using allele‐specific kinetic polymerase chain reaction in 4,746 women. Multivariate logistic regression was performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs).ResultsRadiographic OA of the hip was present in 571 women (12%). Of these patients, 325 (57%) had severe JSN (score ≥3), and 131 (23%) had moderate or moderate‐to‐severe femoral osteophytosis (score ≥2). There was no association of the T/T genotype with either radiographic hip OA or radiographic hip OA characterized by osteophytosis. For radiographic OA of the hip characterized by moderate‐to‐severe JSN, the odds of disease were significantly reduced among subjects with the T/T compared with the G/G genotype (OR 0.30, 95% CI 0.11–0.81, P = 0.02) and did not change after adjustment for potential confounders (OR 0.36, 95% CI 0.13–0.99, P = 0.048).ConclusionThe T/T genotype of the COL1A1 Sp1 polymorphism was associated with a reduced risk of radiographic OA of the hip characterized by JSN. This association should be confirmed in other populations to determine if mechanistic studies are warranted.
Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor α in collagen‐induced arthritis
Authors: Djouad Farida , Fritz Vanessa , Apparailly Florence , Louis‐Plence Pascale , Bony Claire , Sany Jacques , Jorgensen Christian , Noël Danièle 
Published: May 2005

AbstractObjectiveAdult mesenchymal stem cells (MSCs) represent promising tools for therapeutic applications such as tissue engineering and cellular therapy. Recent data suggest that, due to their immunosuppressive nature, MSCs may be of interest to enhance allogeneic hematopoietic engraftment and prevent graft‐versus‐host disease. Using a murine model of rheumatoid arthritis (RA), this study investigated whether the immunosuppressive properties of MSCs could be of therapeutic value to inhibit reactive T cells in autoimmune diseases such as RA.MethodsIn mice with collagen‐induced arthritis (CIA), we injected various doses of C3 MSCs at the time of immunization or booster injection, and subsequently evaluated the clinical and immunologic parameters. The immunosuppressive properties of MSCs were determined in vitro in mixed lymphocyte reactions with or without the addition of tumor necrosis factor α (TNFα).ResultsIn the CIA model of arthritis, MSCs did not confer any benefit. Both the clinical and the immunologic findings suggested that MSCs were associated with accentuation of the Th1 response. Using luciferase‐expressing MSCs, we were unable to detect labeled cells in the articular environment of the knee, suggesting that worsening of the symptoms was unlikely due to the homing of MSCs in the joints. Experiments in vitro showed that the addition of TNFα was sufficient to reverse the immunosuppressive effect of MSCs on T cell proliferation, and this observation was associated with an increase in interleukin‐6 secretion.ConclusionOur data suggest that environmental parameters, in particular those related to inflammation, may influence the immunosuppressive properties of MSCs.
Association between single‐nucleotide polymorphisms in the SEC8L1 gene, which encodes a subunit of the exocyst complex, and rheumatoid arthritis in a Japanese population
Authors: Hamada Daisuke , Takata Yoichiro , Osabe Dai , Nomura Kyoko , Shinohara Syuichi , Egawa Hiroshi , Nakano Syunji , Shinomiya Fumio , Scafe Charles R. , Reeve Vincent M. , Miyamoto Tatsuro , Moritani Maki , Kunika Kiyoshi , Inoue Hiroshi , Yasui Natsuo , Itakura Mitsuo 
Published: May 2005

AbstractObjectiveTo identify rheumatoid arthritis (RA) susceptibility genes in a Japanese population by conducting a large‐scale case–control association analysis and linkage disequilibrium (LD) mapping on chromosome 7q31–34, a candidate susceptibility locus identified in a preliminary genome‐wide scan in 53 Japanese families, using single‐nucleotide polymorphisms (SNPs).MethodsWe prepared 728 dense, evenly spaced SNPs with a minor allele frequency >0.15 in each gene locus on chromosome 7q31–34. Using these SNPs, a 2‐stage case–control analysis was performed on 760 RA patients (157 men and 603 women) and 806 non‐RA controls (189 men and 617 women). Haplotypes and LD mapping results were assessed based on SNP genotypes in 380 controls.ResultsForty‐eight SNPs showed allele associations (P < 0.05) in the first set of DNA samples (380 RA cases and 380 non‐RA controls; first‐stage analysis). For 4 of the SNPs in the SEC8L1 gene, the association was replicated (P < 0.05) in the second, independent set of DNA samples (an additional 380 RA cases and 380 non‐RA controls; second‐stage analysis). When data from the 2 groups were combined, the most significant allele association was observed with SNP 441, an intronic SNP of the SEC8L1 gene (P = 0.000059). The SEC8L1 SNPs with significant allele associations were all located in a single conserved LD block (block 4). Haplotype analysis revealed the disease‐risk (P = 0.0015) and disease‐protective (P = 0.0000062) haplotypes. Resequencing of coding exons within block 4 did not identify any nonsynonymous SNPs. Real‐time quantitative polymerase chain reaction revealed that SEC8L1 was expressed ubiquitously in human tissues, including fibroblast‐like synoviocytes from RA patients.ConclusionOur locus‐wide association and LD analyses identified intronic SNPs and haplotypes in the SEC8L1 gene that are strongly associated with RA. We propose that SEC8L1, which encodes a component of the exocyst complex, is a candidate susceptibility gene for RA in the Japanese population.
A 48‐week, randomized, double‐blind, double‐observer, placebo‐controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: Results of the METGO study
Authors: Lehman Allen J. , Esdaile John M. , Klinkhoff Alice V. , Grant Eric , Fitzgerald Avril , Canvin Janice ,   The METGO Study Group
Published: May 2005

AbstractObjectiveTo evaluate the efficacy and safety of adding intramuscular (IM) gold to the treatment regimen of patients with rheumatoid arthritis (RA) who have a suboptimal response to methotrexate (MTX).MethodsA randomized, double‐blind, double‐observer, placebo‐controlled multicenter trial of 48 weeks was conducted. Sixty‐five RA patients who had a suboptimal response to ≥12 weeks of MTX therapy were randomly assigned to receive weekly IM gold or placebo in addition to MTX. Gold was administered according to a standard protocol developed for the study. The primary outcome measure was the percentage of patients who met the American College of Rheumatology (ACR) 20% improvement criteria (achieved an ACR20 response) at week 48. Secondary outcomes included the percentages of patients achieving ACR50 and ACR70 responses, the individual criteria that make up the primary outcome, quality of life, direct and indirect health care costs, intraarticular steroid use, and adverse events, among other measures. Statistical analyses were based on an intent‐to‐treat strategy.ResultsSixty‐one percent of patients receiving gold achieved an ACR20 response compared with 30% of patients receiving placebo (χ2 = 6.04, P = 0.014; logistic regression odds ratio 3.64 [95% confidence interval 1.3, 10.4], P = 0.016). Twenty‐six percent of patients receiving gold achieved an ACR50 response compared with 4% of patients receiving placebo (P = 0.017), and 21% of patients receiving gold achieved an ACR70 response compared with 0% of patients receiving placebo (P = 0.011). From both clinical and cost‐effectiveness perspectives, gold was the preferred and dominant strategy. Study treatment was discontinued in 23 patients (14 in the placebo group compared with 9 in the gold group; P = 0.022) due to loss to followup, adverse events, or lack of efficacy.ConclusionIn RA patients with a suboptimal response to MTX, adding weekly IM gold causes significant clinical improvement. Adverse events were minor, and IM gold–related adverse events led to discontinuation in only 11% of the gold group over 48 weeks.
Evidence for a role of the genomic region of the gene encoding for the α1 chain of type IX collagen (COL9A1) in hip osteoarthritis: A population‐based study
Authors: Alizadeh B. Z. , Njajou O. T. , Bijkerk C. , Meulenbelt I. , Wildt S. C. De , Hofman A. , Pols H. A. P. , Slagboom P. E. , Duijn C. M. Van 
Published: May 2005

AbstractObjectiveType IX collagen proteoglycan is an important protein in collagen networks and has been implicated in hip osteoarthritis (OA). We studied 2 COL9A1 markers (509‐8B2 and 509‐12B1) in relation to radiographic OA, within the framework of the Rotterdam Study, a population‐based study of 7,983 subjects ages 55 years and older.MethodsWe used 2 different designs, as follows: 1) a linkage study of 83 probands with multiple joints affected with radiographic OA and their 221 siblings, yielding 445 sibpairs who participated in the study, and 2) an association study in a series of 71 patients with radiographic hip OA and 269 controls without radiographic OA. All subjects were characterized for the 2 COL9A1 markers, 509‐8B2 and 509‐12B1. The mean test was used to assess the proportion of alleles shared in concordantly affected and unaffected sibpairs. The chi‐square test was used to compare the allele distributions in patients and controls.ResultsAffected sibpairs with radiographic hip OA shared alleles identical by descent at markers 8B2 and 12B1 significantly more often than expected (mean ± SD 0.66 ± 0.07 and 0.65 ± 0.08, respectively; P < 0.05). No excess sharing for radiographic OA was observed at other joint sites. When comparing the frequency of marker 8B2 and 12B1 alleles in subjects with radiographic OA and controls, the frequency of 8B2 alleles in subjects with radiographic OA differed significantly(P = 0.01) from that in controls.ConclusionOur data suggest that susceptibility for hip OA is conferred within or close to the COL9A1 gene in linkage disequilibrium with the COL9A1 509‐8B2 marker.
ADAMTS‐1–Knockout mice do not exhibit abnormalities in aggrecan turnover in vitro or in vivo
Authors: Little Chris B. , Mittaz Laureane , Belluoccio Daniele , Rogerson Fraser M. , Campbell Ian K. , Meeker Clare T. , Bateman John F. , Pritchard Melanie A. , Fosang Amanda J. 
Published: May 2005

AbstractObjectiveTo determine the role of the proteinase ADAMTS‐1 in normal and accelerated catabolism of aggrecan in articular and growth plate cartilage of mice.MethodsExpression of ADAMTS‐1 was determined using reverse transcriptase–polymerase chain reaction (RT‐PCR) analysis of RNA isolated from microdissected chondrocytes from different zones of mouse growth plate and articular cartilage. Real‐time RT‐PCR for ADAMTS‐4, ADAMTS‐5, and ADAMTS‐9 was performed on femoral head cartilage of wild‐type (WT) and ADAMTS‐1–knockout (KO) mice. Histologic and immunohistologic evaluation of growth plate and articular cartilage was performed in WT and KO mice from birth to 12 weeks of age. The effect of ADAMTS‐1 ablation on cartilage proteoglycan loss was studied in antigen‐induced arthritis (AIA). Aggrecan catabolism in WT and KO mice was studied in an in vitro model of cartilage degradation, by quantitation of glycosaminoglycan loss and histologic, immunohistologic, and Western immunoblot analyses.ResultsADAMTS‐1 messenger RNA (mRNA) was expressed in normal mouse articular and growth plate cartilage and was up‐regulated in terminal hypertrophic differentiation of growth plate chondrocytes. There was no difference in mRNA levels in the cartilage of WT compared with KO mice for the other potential aggrecanases ADAMTS‐4, ADAMTS‐5, or ADAMTS‐9. ADAMTS‐1–KO mice were significantly smaller than their WT littermates; however, no morphologic differences between the genotypes were evident in growth plate or articular cartilage from birth to skeletal maturity (12–16 weeks). Similarly, no difference in cartilage aggrecan content or presence of aggrecan degradation products was detected between WT and KO mice. There was no difference between WT and KO mice in the degree of synovial inflammation or depletion of cartilage aggrecan in AIA. There was no difference between WT and KO cartilage in either basal or stimulated aggrecan loss in vitro; however, subtle changes in the aggrecanase‐generated aggrecan catabolites were observed in interleukin‐1–treated cartilage.ConclusionAlthough ADAMTS‐1 is expressed in articular and growth plate cartilage and is able to cleave aggrecan at physiologically relevant sites, our results indicate that it does not play a significant nonredundant role in normal cartilage and bone development and growth. Similarly, ablation of ADAMTS‐1 offered no protection from accelerated aggrecanolysis in an inflammatory model of arthritis or in an in vitro model of early cartilage degradation. ADAMTS‐1 does not appear to be a viable target for treatment of cartilage destruction in arthritis.
Selection of knee radiographs for trials of structure‐modifying drugs in patients with knee osteoarthritis: A prospective, longitudinal study of lyon schuss knee radiographs with the definition of adequate alignment of the medial tibial plateau
Authors: Conrozier Thierry , Mathieu Pierre , Piperno Muriel , Favret Huguette , Colson Frédéric , Vignon Martine , Conrozier Sylvie , Vignon Eric 
Published: May 2005

AbstractObjectiveThe quality of medial tibial plateau (MTP) alignment, which is assessed by measuring the distance between the anterior and posterior margins (intermargin distance [IMD]) of the tibial plateau, and the reproducibility of alignment in serial radiographs are suggested to be key elements in determining the accuracy and sensitivity to change in knee radiographs in patients with tibiofemoral osteoarthritis (OA). We evaluated the influence of both MTP alignment and radiograph superimposition on the sensitivity to change in radiographic joint space narrowing (JSN) in knee OA.MethodsThe study group comprised 106 patients with knee pain (73 with OA). Lyon schuss radiographic images of the knee were obtained twice (at baseline [month 0] and 12 months later), using a standardized radiographic procedure. Computerized measurement of the IMD for the assessment of MTP alignment was compared with the grading of MTP alignment by 2 observers using a 5‐point scale (excellent, good, fair, poor, bad). To obtain the rate of JSN, computerized measurement of the joint space width was performed at month 0 and month 12. The sensitivity of the joint space width to change over 1 year was evaluated by the standardized response mean (SRM).ResultsThe mean (±SD) IMD was 1.2 ± 0.9 mm. The correlation between scoring and computer measurement of MTP alignment was highly significant. The cutoff value for satisfactory alignment (excellent or good) was an IMD of ≤1.2 mm. In OA knees, the mean (±SD) annual rate of JSN and the SRM were statistically higher in knees with an IMD of ≤1.2 mm at both month 0 and month 12 (0.34 ± 0.50 mm and 0.68, respectively) than in knees with an IMD of >1.2 mm at month 0 and/or month 12.ConclusionThe quality of MTP alignment at both baseline and the end point highly influences the sensitivity to change in radiographic JSN in knee OA. To obtain relevant data, only radiographs showing an IMD of ≤1.2 mm at both baseline and the end point would have to be analyzed in studies of structure‐modifying OA drugs.
Activation of the interferon‐α pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease
Authors: Kirou Kyriakos A. , Lee Christina , George Sandhya , Louca Kyriakos , Peterson Margaret G. E. , Crow Mary K. 
Published: May 2005

AbstractObjectiveGene‐expression studies have demonstrated increased expression of interferon (IFN)–inducible genes (IFIGs) in peripheral blood mononuclear cells (PBMCs) of many patients with systemic lupus erythematosus (SLE), with a predominant effect of type I IFN. This study examined the hypothesis that increased disease severity and activity, as well as distinct autoantibody specificities, characterize SLE patients with activation of the type I IFN pathway.MethodsFreshly isolated PBMCs from 77 SLE patients, 22 disease controls, and 28 healthy donors were subjected to real‐time polymerase chain reaction for 3 IFIGs that are preferentially induced by IFNα, and the data were used to derive IFNα scores for all individuals. Expression of IFIGs was significantly higher in SLE patients compared with disease controls or healthy donors. SLE patients with high and low IFNα scores were compared for clinical manifestations of disease, disease severity, disease activity, serologic features, and potential confounders, by bivariate and multivariate analyses.ResultsSLE patients with a high IFNα score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did SLE patients with low IFNα scores. Patients with high scores showed increased disease activity, as measured by lower C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti–double‐stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score. The presence of antibodies specific for Ro, U1 RNP, Sm, and dsDNA, but not phospholipids, was significantly associated with a high IFNα score. Logistic regression analysis confirmed that renal disease, higher SDI scores, low complement levels, and presence of anti–RNA binding protein (RBP) autoantibodies were associated with a high IFNα score.ConclusionActivation of the IFNα pathway defines a subgroup of SLE patients whose condition is characterized by increased disease severity, including renal disease, increased disease activity, reflected in complement activation, and autoreactivity to RBP.
T cell costimulation by fractalkine‐expressing synoviocytes in rheumatoid arthritis
Authors: Sawai Hirokazu , Park Yong Wook , Roberson James , Imai Toshio , Goronzy Jörg J. , Weyand Cornelia M. 
Published: May 2005

AbstractObjectivePatients with rheumatoid arthritis (RA) accumulate prematurely aged T cells that have acquired a new profile of regulatory receptors. Many of the de novo–expressed receptors are typically found on natural killer cells, including CX3CR1, the receptor for the chemokine fractalkine (FKN). This study explored whether interactions between CX3CR1 and FKN are relevant for T cell functions in rheumatoid synovitis.MethodsFKN expression was examined by real‐time polymerase chain reaction and immunohistochemistry. CX3CR1 expression on peripheral blood T cells was analyzed by flow cytometry. T cell activation was quantified by determining proliferative responses, interferon‐γ (IFNγ) secretion, and granule release. Fibroblast‐like synoviocyte (FLS)/T cell adhesion was measured by the retention of 5‐carboxyfluorescein diacetate succinimidyl ester–labeled T cells on FLS monolayers.ResultsFKN was expressed on cultured synovial fibroblasts and hyperplastic synoviocytes in the rheumatoid tissue. Among CD4+ T cells, only senescent CD28− T cells were positive for CX3CR1 (P < 0.001). Such CD4+,CD28−,CX3CR1+ T cells strongly adhered to FLS, with soluble FKN blocking the interaction. FKN expressed on FLS costimulated T cell–activating signals and amplified proliferation, IFNγ production, and expulsion of cytoplasmic granules.ConclusionSenescent CD4+ T cells that accumulate in rheumatoid arthritis aberrantly express CX3CR1. FKN, which is membrane‐anchored on synoviocytes, enhances CD4+ T cell adhesion, provides survival signals, and costimulates the production of proinflammatory cytokines as well as the release of granules. By virtue of their altered receptor profile, senescent CD4+ T cells receive strong stimulatory signals from nonprofessional antigen‐presenting cells in the synovial microenvironment.