bluuebunny/crossref_metadata_2025_split huggingface dataset:
Very early treatment with infliximab in addition to methotrexate in early, poor‐prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: Results from a twelve‐month randomized, double‐blind, placebo‐controlled trial
Authors: Quinn Mark A. , Conaghan Philip G. , O'Connor Philip J. , Karim Zunaid , Greenstein Adam , Brown Andrew , Brown Clare , Fraser Alexander , Jarret Stephen , Emery Paul 
Published: January 2005

AbstractObjectiveAnti–tumor necrosis factor α agents are among the most effective therapies for rheumatoid arthritis (RA). However, their optimal use is yet to be determined. This 12‐month double‐blind study attempted remission induction using standard therapy with or without infliximab in patients with early, poor‐prognosis RA. The primary end point was synovitis (measured by magnetic resonance imaging [MRI]). Clinical observations continued to 24 months.MethodsAll patients had fewer than 12 months of symptoms. Assessments included full metrologic evaluation, laboratory tests, radiographs, functional evaluation using the Health Assessment Questionnaire (HAQ), and quality of life measurement using the RA Quality of Life (RAQoL) questionnaire. MRI was performed at 0, 4, 14, and 54 weeks; MR images were scored blindly. Patients received methotrexate (MTX) and were randomized to receive either infliximab or placebo for 12 months.ResultsTwenty patients were recruited (mean age 52 years, mean symptom duration 6 months, mean C‐reactive protein level 42 mg/liter, and 65% rheumatoid factor positive). At 1 year, all MRI scores were significantly better, with no new erosions in the infliximab plus MTX group; a greater percentage of infliximab plus MTX–treated patients fulfilled the American College of Rheumatology (ACR) 50% and 70% improvement criteria (78% versus 40% in the placebo plus MTX group and 67% versus 30%, respectively) and had a greater functional benefit (P < 0.05 for all comparisons). Importantly, at 1 year after stopping induction therapy, response was sustained in 70% of the patients in the infliximab plus MTX group, with a median Disease Activity Score in 28 joints (DAS28) of 2.05 (remission range). At 2 years, there were no significant between‐group differences in the DAS28, ACR response, or radiographic scores, but differences in the HAQ and RAQoL scores were maintained (P < 0.05).ConclusionRemission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year. At 2 years, functional and quality of life benefits were sustained, despite withdrawal of infliximab therapy. These data may have significant implications for the optimal use of expensive biologic therapies.
Use of bone morphogenetic protein 2 and diffusion chambers to engineer cartilage tissue for the repair of defects in articular cartilage
Authors: Nawata Masashi , Wakitani Shigeyuki , Nakaya Hiroyuki , Tanigami Akira , Seki Toyokazu , Nakamura Yukio , Saito Naoto , Sano Kenji , Hidaka Eiko , Takaoka Kunio 
Published: January 2005

AbstractObjectiveTo examine the ability of cartilage‐like tissue, generated ectopically in a diffusion chamber using recombinant human bone morphogenetic protein 2 (rHuBMP‐2), to repair cartilage defects in rats.MethodsMuscle‐derived mesenchymal cells were prepared by dissecting thigh muscles of 19‐day postcoital rat embryos. Cells were propagated in vitro in monolayer culture for 10 days and packed within diffusion chambers (106/chamber) together with type I collagen (CI) and 0, 1, or 10 μg rHuBMP‐2, and implanted into abdominal subfascial pockets of adult rats. Tissue pellets were harvested from the diffusion chambers at 2 days to 6 weeks after implantation, and examined by histology, by reverse transcription–polymerase chain reaction (PCR) for aggrecan, CII, CIX, CX, and CXI, MyoD1, and core binding factor a1/runt‐related gene 2, and by real‐time PCR for CII. Tissue pellets generated in the chamber 5 weeks after implantation were transplanted into a full‐thickness cartilage defect made in the patellar groove of the same strain of adult rat.ResultsIn the presence of 10 μg rHuBMP‐2, muscle‐derived mesenchymal cells expressed CII messenger RNA at 4 days after transplantation, and a mature cartilage mass was formed 5 weeks after transplantation in the diffusion chamber. Cartilage was not formed in the presence of 1 μg rHuBMP‐2 or in the absence of rHuBMP‐2. Defects receiving cartilage engineered with 10 μg rHuBMP‐2 were repaired and restored to normal morphologic condition within 6 months after transplantation.ConclusionThis method of tissue engineering for repair of articular defects may preclude the need to harvest cartilage tissue prior to mosaic arthroplasty or autologous chondrocyte implantation. Further studies in large animals will be necessary to validate this technique for application in clinical practice.
Inhibition of interleukin‐1β–induced cyclooxygenase 2 expression in human synovial fibroblasts by 15‐deoxy‐Δ12,14‐prostaglandin J2 through a histone deacetylase–independent mechanism
Authors: Farrajota Katherine , Cheng Saranette , Martel‐Pelletier Johanne , Afif Hassan , Pelletier Jean‐Pierre , Li Xinfang , Ranger Pierre , Fahmi Hassan 
Published: January 2005

AbstractObjectiveThe cyclooxygenase (COX) metabolite, 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2), has been reported to inhibit the expression of a number of genes involved in the pathogenesis of arthritis. However, its effects on COX‐2 remain controversial. We undertook this study to investigate the effects of 15d‐PGJ2 on interleukin‐1β (IL‐1β)–induced COX‐2 expression in human synovial fibroblasts (HSFs).MethodsHSFs were cultured with IL‐1β in the absence or presence of 15d‐PGJ2, and the levels of COX‐2 protein and messenger RNA (mRNA) expression were evaluated using Western blotting and real‐time reverse transcriptase–polymerase chain reaction, respectively. COX‐2 promoter activity was analyzed in transient transfection experiments. Chromatin immunoprecipitation assays were performed to evaluate the level of histone acetylation and the recruitment of histone deacetylases (HDACs) 1, 2, and 3 and histone acetylase (HAT) p300 to the COX‐2 promoter.ResultsIL‐1β–induced COX‐2 protein and mRNA expression, as well as COX‐2 promoter activation, were inhibited by 15d‐PGJ2. Troglitazone, a selective peroxisome proliferator–activated receptor γ (PPARγ) ligand, enhanced COX‐2 expression, while GW9662, a specific PPARγ antagonist, relieved the suppressive effect of 15d‐PGJ2. IL‐1β–induced histone H3 acetylation was selectively blocked by 15d‐PGJ2. The reduction of histone H3 acetylation did not correlate with the recruitment of HDACs to the COX‐2 promoter. Also, treatment with the specific HDAC inhibitor, trichostatin A, did not relieve the suppressive effect of 15d‐PGJ2, indicating that HDACs are not involved in the inhibitory effect of 15d‐PGJ2. Furthermore, 15d‐PGJ2 blocked IL‐1β–induced recruitment of p300 to the COX‐2 promoter, which may be the mechanism for decreased histone H3 acetylation and COX‐2 expression. In accordance with this, overexpression of p300, but not of a mutant p300 lacking HAT activity, relieved the inhibitory effect of 15d‐PGJ2 on COX‐2 promoter activation.ConclusionThese data suggest that 15d‐PGJ2 can inhibit IL‐1β–induced COX‐2 expression by an HDAC‐independent mechanism, probably by interfering with HAT p300.
Serum hyaluronan levels and radiographic knee and hip osteoarthritis in African Americans and Caucasians in the Johnston County Osteoarthritis Project
Authors: Elliott Alan L. , Kraus Virginia B. , Luta Gheorghe , Stabler Thomas , Renner Jordan B. , Woodard Janice , Dragomir Anca D. , Helmick Charles G. , Hochberg Marc C. , Jordan Joanne M. 
Published: January 2005

AbstractObjectiveSerum hyaluronan (HA) has been proposed as a potential biomarker of osteoarthritis (OA). We examined associations between serum HA and radiographic OA in an ethnically diverse, population‐based sample.MethodsParticipants were selected from the Johnston County Osteoarthritis Project, using stratified simple random sampling to achieve balance according to radiographic knee OA status, ethnic group, sex, and age group. Serum HA was measured by enzyme‐linked immunosorbent assay. Radiographic OA variables included knee OA, knee OA laterality, knee OA severity, concomitant knee and hip OA, and total number of OA‐affected knee and hip joints. Analysis of covariance was used to assess differences in mean serum levels of natural log–transformed HA (ln serum HA) between groups, adjusting for ethnicity, sex, age, body mass index (BMI), and self‐reported comorbidities.ResultsLevels of ln serum HA were positively associated with all definitions of radiographic OA (P < 0.0001). Levels of ln serum HA were higher in Caucasians (P = 0.0094) and in men (P = 0.0038) and were moderately correlated with age (r = 0.35, P < 0.0001). The associations with radiographic OA, ethnicity, sex, and age remained statistically significant after adjustment (P < 0.0045). There were no interactions between ethnicity and the other covariates.ConclusionThese cross‐sectional data support a role for serum HA as a biomarker of radiographic OA. The variations in levels of serum HA attributable to ethnicity, sex, and age were not explained by radiographic OA, BMI, or comorbidities. The lack of strong confounding between serum HA and comorbidities further supports a role for serum HA as a potential biomarker.
Interleukin‐6 receptor shedding is enhanced by interleukin‐1β and tumor necrosis factor α and is partially mediated by tumor necrosis factor α–converting enzyme in osteoblast‐like cells
Authors: Franchimont Nathalie , Lambert Cécile , Huynen Pascale , Ribbens Clio , Relic Biserka , Chariot Alain , Bours Vincent , Piette Jacques , Merville Marie‐Paule , Malaise Michel 
Published: January 2005

AbstractObjectiveInterleukin‐6 (IL‐6) and soluble IL‐6 receptor (sIL‐6R) activation of gp130 represents an alternative pathway for osteoclast development in inflammatory conditions. The goal of the present study was to investigate changes in sIL‐6R levels in response to the inflammatory cytokines IL‐1β and tumor necrosis factor α (TNFα) and to determine the role of TNFα‐converting enzyme (TACE) in this process.MethodsLevels of sIL‐6R in the culture media of MG63 and SAOS‐2 osteoblast‐like cell lines after exposure to various agents were determined by immunoassay. TACE protein levels were measured by Western immunoblotting. Cells were transfected with small interfering RNA (siRNA) or with an expression plasmid for IL‐6R and TACE to determine the potential involvement of TACE in IL‐6R shedding.ResultsIL‐1β and TNFα increased the levels of sIL‐6R in the culture media of MG63 osteoblast‐like cells. This effect was not influenced by cycloheximide or 5,6‐dichlorobenzimidazole riboside but was markedly inhibited by the calcium chelator EGTA and by the TACE and matrix metalloproteinase inhibitor hydroxamate (Ru36156). IL‐1β and TNFα had no influence on the alternatively spliced form of IL‐6R RNA. Levels of sIL‐6R were reduced when MG63 cells were transiently transfected with TACE siRNA. Transfection of SAOS‐2 cells with expression plasmids for IL‐6R and TACE produced a dose‐dependent increase in sIL‐6R levels.ConclusionIL‐1β‐ and TNFα‐mediated induction of IL‐6R shedding in osteoblast‐like cells is at least partly dependent on TACE activation.
Role of interleukin‐8 in PiT‐1 expression and CXCR1‐mediated inorganic phosphate uptake in chondrocytes
Authors: Cecil Denise L. , Rose David M. , Terkeltaub Robert , Liu‐Bryan Ru 
Published: January 2005

AbstractObjectiveThe proinflammatory chemokine interleukin‐8 (IL‐8) induces chondrocyte hypertrophy. Moreover, chondrocyte hypertrophy develops in situ in osteoarthritic (OA) articular cartilage and promotes dysregulated matrix repair and calcification. Growth plate chondrocyte hypertrophy is associated with expression of the type III sodium‐dependent inorganic phosphate (Pi) cotransporter phosphate transporter/retrovirus receptor 1 (PiT‐1). This study was undertaken to test the hypothesis that IL‐8 promotes chondrocyte hypertrophy by modulating chondrocyte PiT‐1 expression and sodium‐dependent Pi uptake, and to assess differential roles in this activity.MethodsThe selective IL‐8 receptor CXCR1 and the promiscuous chemokine receptor CXCR2 were used. Human knee OA cartilage, cultured normal bovine knee chondrocytes, and immortalized human articular chondrocytic CH‐8 cells were transfected with CXCR1/CXCR2 chimeric receptors in which the 40–amino acid C‐terminal cytosolic tail domains were swapped and site mutants of a CXCR1‐specific region were generated.ResultsUp‐regulated PiT‐1 expression was detected in OA cartilage. IL‐8, but not IL‐1 or the CXCR2 ligand growth‐related oncogene α, induced PiT‐1 expression and increased sodium‐dependent Pi uptake by >40% in chondrocytes. The sodium/phosphate cotransport inhibitor phosphonoformic acid blocked IL‐8–induced chondrocyte hypertrophic differentiation. Signaling mediated by kinase Pyk‐2 was essential for IL‐8 induction of PitT‐1 expression and Pi uptake. Signaling through the TSYT346–349 region of the CXCR1 cytosolic tail, a region divergent from the CXCR2 cytosolic tail, was essential for IL‐8 to induce Pi uptake.ConclusionOur results link low‐grade IL‐8–mediated cartilaginous inflammation in OA to altered chondrocyte differentiation and disease progression through PiT‐1 expression and sodium‐dependent Pi uptake mediated by CXCR1 signaling.
Mature dendritic cells readily break tolerance in normal mice but do not lead to disease expression
Authors: Georgiev Maria , Agle Lucila M. A. , Chu Jia Li , Elkon Keith B. , Ashany Dalit 
Published: January 2005

AbstractObjectiveTo examine the ability of mature dendritic cells (DCs) or macrophages intentionally exposed to lipopolysaccharide or apoptotic or necrotic cells to break tolerance in normal mice.MethodsWe adoptively transferred into C57BL/6 mice a variety of syngeneic myeloid antigen‐presenting cell populations exposed to different activation stimuli as well as to meals of necrotic and apoptotic cells. We studied expression of autoimmunity in the immunized mice by serologic evaluation of autoantibody production, subclass analysis of Ig production, clinical evidence of kidney disease, glomerular immune complex deposition, and renal pathology.ResultsInjection of mice with DCs incubated with apoptotic or necrotic cells, as well as, surprisingly, with DCs cultured in media alone, induced high levels of IgG autoantibodies, including anti–double‐stranded DNA (anti‐dsDNA) antibodies. In striking contrast, transfer of equivalent‐treated macrophages failed to generate IgG autoantibodies. IgG was deposited in the kidneys of mice vaccinated with DCs, but despite high levels of anti‐dsDNA antibodies, these mice did not develop overt nephritis. Serologic evaluation of the antibody response revealed that the mice primarily developed elevated levels of IgG1 antibodies, including high levels of IgG1 anti‐dsDNA.ConclusionThe data suggest that mature myeloid DCs are able to break tolerance and induce lupus autoantibodies in normal hosts, but that other susceptibility factors must be in place to induce long‐lasting autoimmunity and clinical expression of disease.
Synovial fluid levels and serum pharmacokinetics in a large animal model following treatment with oral glucosamine at clinically relevant doses
Authors: Laverty Sheila , Sandy John D. , Celeste Christophe , Vachon Pascal , Marier Jean‐Francois , Plaas Anna H. K. 
Published: January 2005

AbstractObjectiveTo examine the concentration of glucosamine in the synovial fluid and its pharmacokinetics in serum in a large animal model following dosing with glucosamine HCl at clinically relevant levels.MethodsEight adult female horses were studied. After an overnight fast, glucosamine HCl (20 mg/kg of body weight) was administered by either nasogastric (NG) intubation or intravenous (IV) injection. Blood samples were collected before dosing and at 5, 15, 30, 60, 120, 180, 240, 360, 480, and 720 minutes after dosing. Synovial fluid samples were collected from the radiocarpal joints 48 hours before dosing and at 1 and 12 hours after dosing. Glucosamine was assayed by fluorophore‐assisted carbohydrate electrophoresis.ResultsThe maximum concentration of glucosamine in serum reached ∼300 μM(∼50 μg/ml) following IV dosing and ∼6 μM(∼1 μg/ml) following NG dosing. Synovial fluid concentrations reached 9–15 μMwith IV dosing and 0.3–0.7 μMwith NG dosing, and remained elevated (range 0.1–0.7 μM) in most animals even at 12 hours after dosing. Following NG dosing, the median serum maximal concentration of 6.1 μM(range 4.38–7.58) was attained between 30 minutes and 4 hours postdose. The mean apparent volume of distribution was 15.4 liters/kg, the mean bioavailability was 5.9%, and the mean elimination half‐life was 2.82 hours.ConclusionClinically relevant dosing of glucosamine HCl in this large monogastric animal model results in serum and synovial fluid concentrations that are at least 500‐fold lower than those reported to modify chondrocyte anabolic and catabolic activities in tissue and cell culture experiments. We conclude that the apparent therapeutic benefit of dietary glucosamine on pain and joint space width in humans and animals may be secondary to its effects on nonarticular tissues, such as the intestinal lining, liver, or kidney, since these may be exposed to much high levels of glucosamine following ingestion.
Role of interleukin‐1 and tumor necrosis factor α in matrix degradation of human osteoarthritic cartilage
Authors: Kobayashi Masahiko , Squires Ginette R. , Mousa Aisha , Tanzer Michael , Zukor David J. , Antoniou John , Feige Ulrich , Poole A. Robin 
Published: January 2005

AbstractObjectiveTo determine whether interleukin‐1 (IL‐1) or tumor necrosis factor α (TNFα), or both, plays a role in the excessive degradation that is observed in cultured osteoarthritic (OA) articular cartilage.MethodsAntagonists of IL‐1 and TNFα, namely, IL‐1 receptor antagonist and the PEGylated soluble TNFα receptor I, respectively, were added at different concentrations to explant cultures of nonarthritic (5 obtained at autopsy) and OA (15 obtained at arthroplasty) articular cartilage. The cleavage of type II collagen (CII) by collagenase was measured by an immunoassay in cartilage and culture media. Proteoglycan (mainly aggrecan) content and degradation were measured by a colorimetric assay for glycosaminoglycan (GAG) content in cartilage and culture media. Reverse transcriptase–polymerase chain reaction was used to analyze gene expression of matrix metalloproteases (MMPs) 1, 3, and 13, CII, aggrecan, IL‐1, and TNFα.ResultsAntagonists of IL‐1 and TNFα inhibited the increase in CII cleavage by collagenase as well as the increase in GAG release observed in OA cartilage compared with normal cartilage. Inhibition was significant in tissue from some patients but not from others, although significant inhibition was observed when all the results were analyzed together. An increase in the GAG content in cartilage was seen in 4 of 15 cases. However, this increase was not significant when all the data were combined. Preliminary results indicated no effect of these antagonists on nonarthritic cartilage from 3 different donors. Independent analyses of gene expression in cultured cartilage from 9 other OA patients revealed that IL‐1 or TNFα blockade, either alone and/or in combination, frequently down‐regulated MMP‐1, MMP‐3, and MMP‐13 expression. Expression of IL‐1 and TNFα was inhibited by either antagonist or by the combination in essentially half the cases. The combined blockade up‐regulated aggrecan and CII gene expression in approximately half the cases.ConclusionThese results suggest that the autocrine/paracrine activities of TNFα and IL‐1 in articular cartilage may play important roles in cartilage matrix degradation in OA patients but not in all patients. Inhibition of either or both of these cytokines may offer a useful therapeutic approach to the management of OA by reducing gene expression of MMPs involved in cartilage matrix degradation and favoring its repair.
A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease
Authors: Martin Tammy M. , Zhang Ge , Luo Jingchun , Jin Li , Doyle Trudy M. , Rajska Barbara M. , Coffman Jessica E. , Smith Justine R. , Becker Matthias D. , Mackensen Friederike , Khan Muhammad A. , Levinson Ralph D. , Schumacher H. Ralph , Wade N. Kevin , Rosenbaum James T. , Reveille John D. 
Published: January 2005

AbstractObjectiveUveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects ∼40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation—AAU—of a multisystem, inflammatory, genetically complex disease, AS.MethodsIndividuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD‐10, and at the HLA–B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two‐point and multipoint nonparametric linkage analyses were performed, and 1‐parameter allele‐sharing model logarithm of odds (LOD) scores were determined.ResultsAs previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA–B). Strong linkage was seen at a region on chromosome 9p21–9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23–1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS.ConclusionThis is the first study in which a genetic region for AAU has been identified by genome‐wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21–9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue‐specific pathology of complex inflammatory diseases.