bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of interleukin‐1β–induced matrix metalloproteinases 1 and 13 production in human osteoarthritic chondrocytes by prostaglandin D2
Authors: Zayed Nadia , Afif Hassan , Chabane Nadir , Mfuna‐Endam Leandra , Benderdour Mohamed , Martel‐Pelletier Johanne , Pelletier Jean‐Pierre , Motiani Rajender K. , Trebak Mohamed , Duval Nicolas , Fahmi Hassan 
Published: October 2008

AbstractObjectiveTo investigate the effects of prostaglandin D2 (PGD2) on interleukin‐1β (IL‐1β)–induced matrix metalloproteinase 1 (MMP‐1) and MMP‐13 expression in human chondrocytes and the signaling pathways involved in these effects.MethodsChondrocytes were stimulated with IL‐1 in the presence or absence of PGD2, and expression of MMP‐1 and MMP‐13 proteins was evaluated by enzyme‐linked immunosorbent assay. Messenger RNA (mRNA) expression and promoter activity were analyzed by real‐time reverse transcription–polymerase chain reaction and transient transfections, respectively. The role of the PGD2 receptors D prostanoid receptor 1 (DP1) and chemoattractant receptor–like molecule expressed on Th2 cells (CRTH2) was evaluated using specific agonists and antibody‐blocking experiments. The contribution of the cAMP/protein kinase A (PKA) pathway was determined using cAMP‐elevating agents and PKA inhibitors.ResultsPGD2 decreased in a dose‐dependent manner IL‐1–induced MMP‐1 and MMP‐13 protein and mRNA expression as well as their promoter activation. DP1 and CRTH2 were expressed and functional in chondrocytes. The effect of PGD2 was mimicked by BW245C, a selective agonist of DP1, but not by 13,14‐dihydro‐15‐keto‐PGD2, a selective agonist of CRTH2. Furthermore, treatment with an anti‐DP1 antibody reversed the effect of PGD2, indicating that the inhibitory effect of PGD2 is mediated by DP1. The cAMP‐elevating agents 8‐Br‐cAMP and forskolin suppressed IL‐1–induced MMP‐1 and MMP‐13 expression, and the PKA inhibitors KT5720 and H89 reversed the inhibitory effect of PGD2, suggesting that the effect of PGD2 is mediated by the cAMP/PKA pathway.ConclusionPGD2 inhibits IL‐1–induced production of MMP‐1 and MMP‐13 by chondrocytes through the DP1/cAMP/PKA signaling pathway. These data also suggest that modulation of PGD2 levels in the joint may have therapeutic potential in the prevention of cartilage degradation.
Coculture of osteoclast precursors with rheumatoid synovial fibroblasts induces osteoclastogenesis via transforming growth factor β–mediated down‐regulation of osteoprotegerin
Authors: Hase Hidenori , Kanno Yumiko , Kojima Hidefumi , Sakurai Daisuke , Kobata Tetsuji 
Published: October 2008

AbstractObjectiveThe mechanisms of osteoclast maturation and the role of rheumatoid arthritis (RA) synovial fibroblasts in the control of osteoclastogenesis remain unclear. The purpose of this study was to determine the humoral factors that influence osteoclast differentiation resulting from mutual interactions between osteoclast progenitor cells and synovial fibroblasts.MethodsThe cloned mouse macrophage cell line RAW 264.7 or isolated human CD14+ monocytes were cocultured with RA or osteoarthritis (OA) synovial fibroblasts in the presence of RANKL. Osteoclasts were visualized by staining for tartrate‐resistant acid phosphatase (TRAP), and their functions were evaluated by bone resorption assay. Transforming growth factor β (TGFβ) and osteoprotegerin (OPG) levels were measured by enzyme‐linked immunosorbent assay. Expression of pSmad2 and Smad7 was analyzed by Western blotting.ResultsRANKL‐mediated osteoclast formation was observed in cocultures of RAW cells with RA synovial cells, but not with OA synovial cells. This formation was inhibited by TGFβ receptor kinase inhibitor or neutralizing TGFβ antibody. Human CD14+ monocytes showed the same results with RAW 264.7, and bone resorption activity was consistent with osteoclast formation. RA synovial fibroblasts produced TGFβ in response to cell–cell contact with RAW cells in a RANKL‐dependent manner. TGFβ reduced OPG production by RA synovial fibroblasts, but dose‐dependently increased OPG secretion in OA synovial fibroblasts. TGFβ decreased the expression of pSmad2 and increased the expression of Smad7 in RA synovial fibroblasts, but not OA synovial fibroblasts.ConclusionSuppression of OPG production by down‐regulation of TGFβ/Smad2 signaling may contribute to RANKL‐mediated osteoclastogenesis from RA synovial fibroblasts.
Borrelia burgdorferi NapA–driven Th17 cell inflammation in lyme arthritis
Authors: Codolo Gaia , Amedei Amedeo , Steere Allen C. , Papinutto Elena , Cappon Andrea , Polenghi Alessandra , Benagiano Marisa , Paccani Silvia Rossi , Sambri Vittorio , Del Prete Gianfranco , Baldari Cosima Tatiana , Zanotti Giuseppe , Montecucco Cesare , D'Elios Mario Milco , de Bernard Marina 
Published: October 2008

AbstractObjectiveHuman Lyme arthritis caused by Borrelia burgdorferi is characterized by an inflammatory infiltrate that consists mainly of neutrophils and T cells. This study was undertaken to evaluate the role of the innate and acquired immune responses elicited by the neutrophil‐activating protein A (NapA) of B burgdorferi in patients with Lyme arthritis.MethodsSerum anti‐NapA antibodies were measured in 27 patients with Lyme arthritis and 30 healthy control subjects. The cytokine profile of synovial fluid T cells specific for NapA was investigated in 5 patients with Lyme arthritis. The cytokine profile induced by NapA in neutrophils and monocytes was also investigated.ResultsSerum anti‐NapA antibodies were found in 48% of the patients with Lyme arthritis but were undetectable in the healthy controls. T cells from the synovial fluid of patients with Lyme arthritis produced interleukin‐17 (IL‐17) in response to NapA. Moreover, NapA was able to induce the expression of IL‐23 in neutrophils and monocytes, as well as the expression of IL‐6, IL‐1β, and transforming growth factor β (TGFβ) in monocytes, via Toll‐like receptor 2.ConclusionThese findings indicate that NapA of B burgdorferi is able to drive the expression of IL‐6, IL‐1β, IL‐23, and TGFβ by cells of the innate immune system and to elicit a synovial fluid Th17 cell response that might play a crucial role in the pathogenesis of Lyme arthritis.
Antiinflammatory effect of Rho kinase blockade via inhibition of NF‐κB activation in rheumatoid arthritis
Authors: He Ya , Xu Hanshi , Liang Liuqin , Zhan Zhongping , Yang Xiuyan , Yu Xueqing , Ye Yujin , Sun Lin 
Published: October 2008

AbstractObjectiveThere is increasing evidence that the RhoA signaling pathway may play a critical role in the inflammatory response. This study was undertaken to examine the effects of RhoA and its downstream effector Rho kinase (ROK) in synovial inflammation in rheumatoid arthritis (RA).MethodsRhoA activity was assessed by pull‐down assay. Fasudil and Y27632, both specific inhibitors of ROK, were used to examine the role of ROK in inflammatory responses in vivo and in vitro. Nuclear translocation of NF‐κB was measured by confocal fluorescence microscopy, and DNA binding activity was assessed with a sensitive multiwell colorimetric assay. Enzyme‐linked immunosorbent assay was used to detect cytokine production.ResultsIncreased activation of RhoA was found in inflamed synovial membrane cells isolated from patients with RA and from rats with collagen‐induced arthritis (CIA). Intraperitoneal administration of fasudil in rats with CIA significantly reduced synovial inflammation and ROK activity. In vitro, treatment with fasudil or Y27632 decreased production of tumor necrosis factor α (TNFα), interleukin‐1β (IL‐1β), and IL‐6 by synovial membrane cells, peripheral blood mononuclear cells, and fibroblast‐like synoviocytes from patients with active RA. Inhibition of ROK by specific inhibitors or ROK small interfering RNA suppressed lipopolysaccharide‐ or TNFα‐induced NF‐κB nuclear translocation, DNA binding activity, luciferase reporter gene expression, and IκBα degradation.ConclusionThe results of this study provide new evidence that blockade of ROK inhibits activation of NF‐κB and production of proinflammatory cytokines, suggesting a critical role of ROK in the synovial inflammation of RA. Specific inhibition of ROK may be a novel therapeutic approach in RA.
A CD40–CD154 interaction in tissue fibrosis
Authors: Kawai Masataka , Masuda Ayako , Kuwana Masataka 
Published: October 2008

AbstractObjectiveTo examine the role of an interaction between fibroblasts and mononuclear infiltrates through CD40–CD154 engagement in the development of tissue fibrosis.MethodsCultured dermal fibroblasts derived from healthy skin were induced to express CD40 by adenoviral gene transfer, stimulated with soluble CD154, and evaluated for proliferation, gene expression, and protein expression in vitro. The skin of mice with bleomycin‐induced skin sclerosis, a model for systemic sclerosis (SSc), was assessed for CD40 and CD154 expression, in vivo fibroblast proliferation, and the expression of specific genes. The effects of an anti‐CD154 monoclonal antibody on bleomycin‐induced skin sclerosis were also examined.ResultsUpon stimulation with soluble CD154, cultured fibroblasts induced to express CD40 by adenoviral gene transfer proliferated and showed up‐regulation of the genes for intercellular adhesion molecule 1, interleukin‐6 (IL‐6), IL‐8, monocyte chemoattractant protein 1 (MCP‐1), and RANTES, as well as up‐regulation of their proteins. In the skin from bleomycin‐treated mice, dermal fibroblasts expressed CD40, and mast cells and CD4+ T cells expressed CD154. Electron microscopic analysis revealed fibroblasts attached to mast cells and T cells with primitive contacts. The proliferation of fibroblasts and the up‐regulated MCP‐1 gene expression preceded thickening of the dermis. Finally, the anti‐CD154 antibody inhibited the bleomycin‐induced skin sclerosis by suppressing fibroblast proliferation and down‐regulating MCP‐1 expression.ConclusionThe interaction between fibroblasts and mast cells or T cells through CD40–CD154 signaling is critical for fibroblast activation early in the course of fibrosis. Blockade of the CD40–CD154 signal may be a novel therapeutic strategy for human fibrotic diseases, such as SSc.
Reduced limb length and worsened osteoarthritis in adult mice after genetic inhibition of p38 MAP kinase activity in cartilage
Authors: Namdari Surena , Wei Lei , Moore Douglas , Chen Qian 
Published: October 2008

AbstractObjectiveMAP kinase p38 is part of an intracellular signaling pathway activated by environmental stress and inflammatory factors. Since in vitro studies show that inhibiting p38 activity leads to a reduction in the release of degenerative metalloproteinase from chondrocytes, we speculated that inactivation of p38 in vivo may be chondroprotective. To test this hypothesis, we examined the morphology of adult mice that express a dominant‐negative (DN) p38 MAPK transgene in a cartilage‐specific manner.MethodsThe in vivo effects of the genetic inhibition of p38 MAPK activity in cartilage were investigated in 1‐year‐old heterozygous DN p38–transgenic mice (n = 10) using morphologic measurements, microfocal computed tomography scanning, biomechanical testing, and histologic analysis. Results were compared with those in wild‐type (WT) littermates (n = 9).ResultsAdult DN p38 MAPK+/−–transgenic mice exhibited 50% p38 MAPK activity in articular chondrocytes as compared with WT mice. They were significantly shorter in overall body length as well as in the femur and tibia lengths. There were no differences in bone material or mechanical properties between the transgenic and WT mice. Surprisingly, the transgenic mice had higher grades of osteoarthritis of the knee joint.ConclusionGenetic inhibition of p38 MAPK activity in cartilage results in shortened limb length and defects in the articular cartilage of the knee joints of adult mice. Our findings demonstrate that chronic life‐long reduction of p38 MAPK activity may be harmful to joint health and suggest that the timing of p38 inhibition for chondroprotection in vivo is an important variable that warrants further investigation.
Fibroblast growth factor 2 inhibits induction of aggrecanase activity in human articular cartilage
Authors: Sawaji Yasunobu , Hynes Judith , Vincent Tonia , Saklatvala Jeremy 
Published: October 2008

AbstractObjectiveArticular chondrocytes are surrounded by an extracellular pool of fibroblast growth factor 2 (FGF‐2). We undertook this study to investigate the possible role of FGF‐2 in aggrecan catabolism by aggrecanase in human articular cartilage.MethodsAggrecan catabolism was induced by interleukin‐1α (IL‐1α) in normal human articular cartilage and assessed by measuring the release of glycosaminoglycan (GAG) and aggrecanase‐dependent fragments by Western blotting with antibodies against neoepitopes. ADAMTS‐4 and ADAMTS‐5 messenger RNA (mRNA) expression was measured by quantitative real‐time reverse transcriptase–polymerase chain reaction. Production of matrix metalloproteinases (MMPs) 1, 3, and 13 and tissue inhibitors of metalloproteinases (TIMPs) 1 and 3 was measured by Western blotting. IL‐6 and IL‐8 were measured by enzyme‐linked immunosorbent assay. Proteoglycan synthesis was monitored by 35S‐sulfate incorporation.ResultsIL‐1α caused cleavage of aggrecan in cultured human articular cartilage explants, with release of GAG and aggrecan fragments containing ARGS and AGEG neoepitopes. This was inhibited by FGF‐2 (1–100 ng/ml). Tumor necrosis factor α and retinoic acid also stimulated release of neoepitope, and this was also suppressed by FGF‐2. IL‐1α induced ADAMTS‐4 and ADAMTS‐5 mRNA in primary human chondrocytes, and this was inhibited by FGF‐2. IL‐1α–induced aggrecan breakdown was inhibited by TIMP‐1 or by the N‐terminal portion of TIMP‐3, although FGF‐2 did not affect production of the inhibitors TIMP‐1 and TIMP‐3 when IL‐1α was present. FGF‐2 did not prevent IL‐1α suppression of proteoglycan synthesis and did not negate its ability to stimulate the production of IL‐6, IL‐8, and MMPs 1, 3, and 13.ConclusionOur findings suggest that FGF‐2 may play a chondroprotective role in human articular cartilage by controlling the expression and activity of the aggrecanases ADAMTS‐4 and ADAMTS‐5.
Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis
Authors: Dalrymple Judith M. , Stamp Lisa K. , O'Donnell John L. , Chapman Peter T. , Zhang Mei , Barclay Murray L. 
Published: October 2008

AbstractObjectiveThere is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu) concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of MTXGlu1–5 is required for optimal timing of blood sampling. The aim of this study was to determine the time to steady state and the half‐life of accumulation of red blood cell (RBC) MTXGlu1–5 in patients with RA commencing oral MTX, and the time for RBC MTXGlu1–5 to become undetectable and the half‐life of elimination of RBC MTXGlu1–5 in patients ceasing treatment with oral MTX.MethodsTen patients beginning treatment and 10 patients stopping treatment with low‐dose oral MTX were recruited. Blood samples were initially collected weekly, with gradual extension to monthly collection over the study period. RBC MTXGlu1–5 concentrations were assayed by high‐performance liquid chromatography. Results were analyzed using a first‐order exponential method.ResultsThe median times to reach steady state in RBCs (defined as 90% of the maximum concentration) were 6.2, 10.6, 41.2, 149, and 139.8 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half‐life of accumulation for RBC MTXGlu1–5 ranged from 1.9 weeks to 45.2 weeks. The median times for MTXGlus to become undetectable in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half‐life of elimination for RBC MTXGlu1–5 ranged from 1.2 weeks to 4.3 weeks.ConclusionThere is wide interpatient variability of RBC MTXGlu1–5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu1–5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.
Myotonic dystrophy type 2 found in two of sixty‐three persons diagnosed as having fibromyalgia
Authors: Auvinen Satu , Suominen Tiina , Hannonen Pekka , Bachinski Linda L. , Krahe Ralf , Udd Bjarne 
Published: October 2008

AbstractBecause of its high prevalence, fibromyalgia (FM) is a major general health issue. Myotonic dystrophy type 2 (DM2) is a recently described autosomal‐dominant multisystem disorder. Besides variable proximal muscle weakness, myotonia, and precocious cataracts, muscle pain and stiffness are prominent presenting features of DM2. After noting that several of our mutation‐positive DM2 patients had a previous diagnosis of FM, suggesting that DM2 may be misdiagnosed as FM, we invited 90 randomly selected patients diagnosed as having FM to undergo genetic testing for DM2. Of the 63 patients who agreed to participate, 2 (3.2%) tested positive for the DM2 mutation. Their cases are described herein. DM2 was not found in any of 200 asymptomatic controls. We therefore suggest that the presence of DM2 should be investigated in a large sample of subjects diagnosed as having FM, and clinicians should be aware of overlap in the clinical presentation of these 2 distinct disorders.
Prevalence and course of forefoot impairments and walking disability in the first eight years of rheumatoid arthritis
Authors: Leeden Marike Van Der , Steultjens Martijn P. M. , Ursum Jennie , Dahmen Rutger , Roorda Leo D. , Schaardenburg Dirkjan Van , Dekker Joost 
Published: October 2008

AbstractObjectiveTo evaluate the prevalence and 8‐year course of forefoot impairments and walking disability in patients with rheumatoid arthritis (RA).MethodsA total of 848 patients with recent‐onset RA from 1995 through the present were included. The patients were assessed annually. Pain and swelling of the metatarsophalangeal (MTP) joints, erosions and joint space narrowing of the MTP joints and first interphalangeal joints, and the Health Assessment Questionnaire walking subscale were analyzed using descriptive and correlational techniques.ResultsPain and swelling of ≥1 MTP joint was present in 70% of patients at baseline, decreasing to ∼40–50% after 2 years. The forefoot erosion score was ≥1 in 19% of the patients at baseline, and the prevalence of forefoot erosion increased to ∼60% after 8 years, during which the mean forefoot erosion score increased from 1.3 to 7.9. At least mild walking disability was present in 57% of patients at baseline, stabilizing at ∼40% after 1 year.ConclusionThe prevalence rates for pain and swelling of the MTP joints and walking disability are initially high and then stabilize, but the prevalence and severity of forefoot joint damage increase during an 8‐year course of RA. The findings of this study quantitatively emphasize the importance of forefoot involvement in patients with RA.
Gout and the risk of parkinson's disease: A cohort study
Authors: De Vera Mary , Rahman M. Mushfiqur , Rankin James , Kopec Jacek , Gao Xiang , Choi Hyon 
Published: October 2008

AbstractObjectiveSeveral studies have suggested that higher serum uric acid levels lead to a lower risk of Parkinson's disease (PD) because uric acid exerts antioxidant effects on neurons. Our objective was to examine the relationship between gout and the risk of PD in persons age ≥65 years.MethodsWe conducted a population‐based cohort study using the British Columbia Linked Health Database and PharmaCare data (i.e., prescription drug data for those age ≥65 years). We compared incidence rates of PD between 11,258 gout patients and 56,199 controls matched on age, sex, date of gout diagnosis, and length of medical record. Cox proportional hazards models were used to estimate the relative risk (RR) of PD, adjusting for age, sex, prior comorbid conditions, and use of diuretics and nonsteroidal antiinflammatory drugs.ResultsOver an 8‐year median followup, we identified 1,182 new cases of PD. Compared with individuals without gout, the multivariate RR of PD among those with gout was 0.70 (95% confidence interval [95% CI] 0.59–0.83). In subgroup analyses, the inverse association was similarly present in both sexes and was evident among those who did not use diuretics (RR 0.66, 95% CI 0.54–0.81), but not among diuretic users (RR 0.80, 95% CI 0.58–1.10, P for interaction 0.35).ConclusionOur population‐based data provide evidence for a protective effect of gout on the risk of PD and support the purported protective role of uric acid.
Vitamin E in the primary prevention of rheumatoid arthritis: The women's health study
Authors: Karlson Elizabeth W. , Shadick Nancy A. , Cook Nancy R. , Buring Julie E. , Lee I.‐min 
Published: October 2008

AbstractObjectiveVitamin E supplements may reduce the risk of developing rheumatoid arthritis (RA) through antioxidant effects. Although previous observational studies have investigated this question, no randomized trial data are available.MethodsThe Women's Health Study is a randomized, double‐blind, placebo‐controlled trial designed to evaluate the benefits and risks of low‐dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer among 39,876 female health professionals age ≥45 years throughout the US, conducted between 1992 and 2004. After excluding women with self‐reported RA at baseline, 39,144 women were included in the present study. The primary end point, definite RA, was confirmed using a connective tissue disease screening questionnaire, followed by medical record review for American College of Rheumatology criteria.ResultsDuring an average followup of 10 years, 106 cases of definite RA occurred, 50 in the vitamin E group and 56 in the placebo group. Sixty‐four (60%) RA cases were rheumatoid factor positive and 42 (40%) were rheumatoid factor negative. There was no significant association between vitamin E and risk of definite RA (relative risk [RR] 0.89, 95% confidence interval [95% CI] 0.61–1.31). There were also no significant risk reductions for either seropositive RA (RR 0.64, 95% CI 0.39–1.06) or seronegative RA (RR 1.47, 95% CI 0.79–2.72).ConclusionSix hundred IU of vitamin E supplements taken every other day is not associated with a significant reduction in the risk of developing RA among women in a randomized, double‐blind, placebo‐controlled trial.