Abstract:
:Hypoxia, which leads to dysfunctional cell metabolism, and complement activation both play central roles in the pathogenesis of rheumatoid arthritis (RA). Recent studies have reported that mice deficient for the complement-inhibitory protein CD59 show enhanced susceptibility to antigen-induced arthritis and reported that statins have anti-inflammatory effects in RA. We hypothesized that the anti-inflammatory effect of statins in RA relates in part to their ability to increase CD59 expression in hypoxic conditions and therefore to reduce complement activation. Flow-cytometric analysis showed that CD59 expression on endothelial cells (EC) was unaffected by atorvastatin in normoxia (21% O2), whereas in hypoxic conditions (1% O2) an up to threefold dose-dependent increase in CD59 expression was seen. This effect of hypoxia was confirmed by treatment of EC with chemical mimetics of hypoxia. The upregulation of CD59 protein expression in hypoxia was associated with an increase in steady-state mRNA. L-Mevalonate and geranylgeraniol reversed the response, confirming a role for inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and geranylgeranylation. Likewise, inhibition by NG-monomethyl-L-arginine and NG-nitro-L-arginine methyl ester confirmed that CD59 upregulation in hypoxia was nitric oxide dependent. The expression of another complement-inhibitory protein, decay-accelerating factor (DAF), is known to be increased by atorvastatin in normoxia; this response was also significantly enhanced under hypoxic conditions. The upregulation of CD59 and DAF by atorvastatin in hypoxia prevented the deposition of C3, C9 and cell lysis that follows exposure of reoxygenated EC to serum. This cytoprotective effect was abrogated by inhibitory anti-CD59 and anti-DAF mAbs. The modulation of EC CD59 and DAF by statins under hypoxic conditions therefore inhibits both early and late complement activation and may contribute to the anti-inflammatory effects of statins in RA.
journal_name
Arthritis Res Therjournal_title
Arthritis research & therapyauthors
Kinderlerer AR,Steinberg R,Johns M,Harten SK,Lidington EA,Haskard DO,Maxwell PH,Mason JCdoi
10.1186/ar2019subject
Has Abstractpub_date
2006-01-01 00:00:00pages
R130issue
4eissn
1478-6354issn
1478-6362pii
ar2019journal_volume
8pub_type
杂志文章abstract:INTRODUCTION:Monosodium urate monohydrate (MSU) crystals synergize with various toll-like receptor (TLR) ligands to induce cytokine production via activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome. This has been demonstrated in vitro using human cell lines or monocytes of ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3898
更新日期:2012-07-04 00:00:00
abstract:INTRODUCTION:Brain-derived neurotrophic factor (BDNF) was first identified in the intervertebral disc (IVD) when its molecular upregulation was observed in sections of nucleus pulposus cultured under conditions of increased osmolarity. BDNF is now known to be involved in a number of biologic functions, including regula...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar2456
更新日期:2008-01-01 00:00:00
abstract::The objective of this study was to evaluate the safety and possible efficacy of IFN-beta-1a for the treatment of patients with rheumatoid arthritis (RA). Twenty-two patients with active RA were enrolled in a phase II randomized, double-blind, placebo-controlled trial of 30 microg IFN-beta-1a by weekly self-injection f...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar1026
更新日期:2004-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-016-1013-2
更新日期:2016-05-21 00:00:00
abstract:INTRODUCTION:Systemic lupus erythematosus (SLE) patients have lower bone mineral density and increased fracture risk when compared with healthy individuals, due to distinct factors and mechanisms. Bone remodeling is a tightly orchestrated process dependent on several factors, including the balance between receptor acti...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究
doi:10.1186/ar3500
更新日期:2011-01-01 00:00:00
abstract:INTRODUCTION:The Vβ12-transgenic mouse was previously generated to investigate the role of antigen-specific T cells in collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. This mouse expresses a transgenic collagen type II (CII)-specific T-cell receptor (TCR) β-chain and consequently displays an ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3108
更新日期:2010-01-01 00:00:00
abstract::The aim of this study was to evaluate the efficacy and safety of mycophenolate sodium (MPS) in patients with primary Sjögren syndrome (pSS) refractory to other immunosuppressive agents. Eleven patients with pSS were treated with MPS up to 1,440 mg daily for an observation period of 6 months in this single-center, open...
journal_title:Arthritis research & therapy
pub_type: 临床试验,杂志文章
doi:10.1186/ar2322
更新日期:2007-01-01 00:00:00
abstract:BACKGROUND:The aim was to assess patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with filgotinib during two phase 2b, 24-week, randomized, placebo-controlled studies. METHODS:Patients with moderate-to-severe active RA and an inadequate response to methotrexate (MTX) were randomized ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1186/s13075-018-1541-z
更新日期:2018-03-23 00:00:00
abstract::A variety of cytokines and growth factors use the Janus kinase (Jak)-STAT signaling pathway to transmit extracellular signals to the nucleus. STATs (signal transducers and activators of transcription) are latent cytoplasmic transcription factors. There are seven mammalian STATs and they have critical, nonredundant rol...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar1197
更新日期:2004-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-016-1117-8
更新日期:2016-10-04 00:00:00
abstract:INTRODUCTION:Semaphorin 3A (sema3A) and neuropilin-1 (NP-1) play a regulatory role in immune responses and have a demonstrated effect on the course of collagen induced arthritis. This study was undertaken to evaluate the role of sema3A and NP-1 in the pathogenesis of systemic lupus erythematosus (SLE) and the specific ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3881
更新日期:2012-06-14 00:00:00
abstract:INTRODUCTION:Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies and immune complex deposition in various organs. Aberrations in the T lymphocyte compartment and dysregulated cytokine production are key features of SLE pathogenesis and disease progression. Recently...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3194
更新日期:2010-01-01 00:00:00
abstract::In clinic studies, altered hypothalamic-pituitary-adrenal (HPA) axis function has been associated with fibromyalgia, a syndrome characterised by chronic widespread body pain. These results may be explained by the associated high rates of psychological distress and somatisation. We address the hypothesis that the latte...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar1772
更新日期:2005-01-01 00:00:00
abstract:INTRODUCTION:Soluble immune aggregates bearing intact Fc fragments are effective treatment for a variety of autoimmune disorders in mice. The better to understand the mechanisms by which Fc-bearing immune complexes suppress autoimmunity, and to develop a platform for clinical translation, we created a series of fully r...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4024
更新日期:2012-08-20 00:00:00
abstract::Platelet-rich plasma (PRP) is an autologous concentrated cocktail of growth factors and inflammatory mediators, and has been considered to be potentially effective for cartilage repair. In addition, the fibrinogen in PRP may be activated to form a fibrin matrix to fill cartilage lesions, fulfilling the initial require...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar4493
更新日期:2014-02-25 00:00:00
abstract::Bone morphogenetic proteins (BMPs) are expressed during osteogenesis and their action is regulated by corresponding BMP inhibitors. Chordin (a well recognized BMP inhibitor) and BMP-2 are expressed during osteogenic differentiation of human mesenchymal stem cells. Chordin inhibition induces human mesenchymal stem cell...
journal_title:Arthritis research & therapy
pub_type: 社论
doi:10.1186/ar2467
更新日期:2008-01-01 00:00:00
abstract:INTRODUCTION:Previous studies have shown that the number of myoblastically differentiated fibroblasts known as myofibroblasts (MFs) is significantly increased in stiff joint capsules, indicating their crucial role in the pathogenesis of post-traumatic joint stiffness. Although the mode of MFs' function has been well de...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar2902
更新日期:2010-01-01 00:00:00
abstract:INTRODUCTION:Rheumatoid arthritis (RA) frequently involves the loss of tolerance to citrullinated antigens, which may play a role in pathogenicity. Citrullinated fibrinogen is commonly found in inflamed synovial tissue and is a frequent target of autoantibodies in RA patients. To obtain insight into the B-cell response...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3205
更新日期:2010-01-01 00:00:00
abstract::TNF inhibitors are currently considered both effective and cost-effective in patients with active rheumatoid arthritis (RA), particularly in patients who have not responded fully to methotrexate. There is substantial doubt about the cost-effectiveness of TNF inhibitors as initial treatment for active RA. New data from...
journal_title:Arthritis research & therapy
pub_type: 评论,社论
doi:10.1186/ar2970
更新日期:2010-01-01 00:00:00
abstract:INTRODUCTION:Patients with recent-onset rheumatoid arthritis (RA) have impaired brachial artery endothelial function compared with controls matched for age, sex and cardiovascular risk factors. The present study examined endothelium-dependent (flow-mediated dilatation (FMD)) and independent (glyceryl trinitrate (GTN)-m...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar2668
更新日期:2009-01-01 00:00:00
abstract:BACKGROUND:To determine whether lung involvement is related to microvascular perturbations, nailfold videocapillaroscopy (NVC) was performed in patients with systemic sclerosis (SSc). METHODS:A cross-sectional study was consecutively accomplished in 152 SSc patients. NVC, a pulmonary function test and echocardiography...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-018-1775-9
更新日期:2018-12-19 00:00:00
abstract:BACKGROUND:Antibodies and upregulated cytokines and chemokines predate the onset of rheumatoid arthritis (RA) symptoms. We aimed to identify the pathways related to the early processes leading to RA development, as well as potential novel biomarkers, using multiple protein analyses. METHODS:A case-control study was co...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-019-2066-9
更新日期:2019-12-16 00:00:00
abstract:BACKGROUND:The aim was to further characterize immunoglobulin G4-related disease (IgG4-RD) by a large-scale multicenter study of its clinical and laboratory features conducted by multidisciplinary physicians of IgG4-RD in Japan. METHODS:Various specialists retrospectively evaluated IgG4-RD patients diagnosed between 1...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究
doi:10.1186/s13075-017-1467-x
更新日期:2017-12-01 00:00:00
abstract:BACKGROUND:As an initial step in the development of a local therapeutic to treat osteoarthritis (OA), a number of agents were tested for their ability to block activation of inflammation through nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), subchondral bone changes through receptor activator of nu...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-016-0921-5
更新日期:2016-01-21 00:00:00
abstract:BACKGROUND:Anti-Jo-1 autoantibodies which recognize histidyl-tRNA synthetase identify patients with the rare rheumatologic disease, anti-histidyl-tRNA synthetase syndrome (Jo-1 ARS), a phenotypically distinct subset of idiopathic inflammatory myopathies (IIM). Jo-1-binding B cells (JBCs) are implicated in disease patho...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-02412-8
更新日期:2021-01-19 00:00:00
abstract:INTRODUCTION:A higher prevalence of metabolic syndrome (MetS) has been described in rheumatoid arthritis (RA), along with an association with disease activity. Objectives were to describe prevalence of MetS at RA diagnosis in a cohort of Mexican Mestizo early RA patients, and to define a causal association between MetS...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-015-0549-x
更新日期:2015-02-20 00:00:00
abstract:BACKGROUND:Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint stiffness, finally leading to tissue destruction. Connective tissue growth factor (CTGF) is a critical factor in RA progression, which promotes fibroblast-like synoviocyte (FLS) proliferation, pannus formation, ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-2133-2
更新日期:2020-03-27 00:00:00
abstract:INTRODUCTION:Studies investigating genetic risk factors for susceptibility to rheumatoid arthritis (RA) studied anti-citrullinated peptide antibody (CCP)-positive RA more frequently than anti-CCP-negative RA. One of the reasons for this is the perception that anti-CCP-negative RA may include patients that fulfilled cri...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3505
更新日期:2011-01-01 00:00:00
abstract:BACKGROUND:Interstitial lung disease (ILD) is the principal cause of death in polymyositis/dermatomyositis (PM/DM). Here we investigated prognostic factors for death and serious infection in PM/DM-ILD using the multicenter database. METHODS:We retrospectively reviewed baseline demographic, clinical and laboratory find...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-017-1506-7
更新日期:2018-01-11 00:00:00
abstract:INTRODUCTION:Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a p...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1186/ar2740
更新日期:2009-01-01 00:00:00