Abstract:
INTRODUCTION:Rheumatoid arthritis (RA) is a chronic inflammatory and destructive disease of the joint. The synovial lining consists of two main types of cells: synovial fibroblasts and macrophages. The macrophage-derived cytokine TNFα stimulates RA synovial fibroblasts to proliferate and produce growth factors, chemokines, proteinases and adhesion molecules, making them key players in the RA disease process. If proteins are not correctly folded, cellular stress occurs that can be relieved in part by increased degradation of the aberrant proteins by the proteasome or autophagy. We hypothesized that the activity of the protein degradation pathways would be increased in response to TNFα stimulation in RA synovial fibroblasts compared with control fibroblasts. METHODS:Endoplasmic reticulum (ER) stress markers were examined in synovial fibroblasts by immunoblotting and PCR. Use of the autophagy and proteasome protein degradation pathways in response to TNFα stimulation was determined using a combination of experiments involving chemical inhibition of the autophagy or proteasome pathways followed by immunoblotting for the autophagy marker LC3, measurement of proteasome activity and long-lived protein degradation, and determination of cellular viability. RESULTS:RA synovial fibroblasts are under acute ER stress, and the stress is increased in the presence of TNFα. Autophagy is the main pathway used to relieve the ER stress in unstimulated fibroblasts, and both autophagy and the proteasome are more active in RA synovial fibroblasts compared with control fibroblasts. In response to TNFα, the autophagy pathway but not the proteasome is consistently stimulated, yet there is an increased dependence on the proteasome for cell viability. If autophagy is blocked in the presence of TNFα, an increase in proteasome activity occurs in RA synovial fibroblasts but not in control cells. CONCLUSIONS:TNFα stimulation of synovial fibroblasts results in increased expression of ER stress markers. Survival of synovial fibroblasts is dependent on continuous removal of proteins by both the lysosome/autophagy and ubiquitin/proteasome protein degradation pathways. Both pathways are more active in RA synovial fibroblasts compared with control fibroblasts. These results may provide a better understanding of the mechanism of TNFα on prolonging the survival of synovial fibroblasts in RA tissue.
journal_name
Arthritis Res Therjournal_title
Arthritis research & therapyauthors
Connor AM,Mahomed N,Gandhi R,Keystone EC,Berger SAdoi
10.1186/ar3778subject
Has Abstractpub_date
2012-03-14 00:00:00pages
R62issue
2eissn
1478-6354issn
1478-6362pii
ar3778journal_volume
14pub_type
杂志文章abstract:BACKGROUND:Clinical remission can be maintained after the discontinuation of biological disease-modifying antirheumatic drugs (bDMARDs) in some patients with rheumatoid arthritis (RA) (bDMARD-free remission (BFR)). It is unknown which bDMARD is advantageous for achieving BFR or under which conditions BFR can be conside...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究
doi:10.1186/s13075-018-1673-1
更新日期:2018-08-03 00:00:00
abstract:BACKGROUND:Fluorescence optical imaging (FOI) enables visualization of inflammation in the hands in rheumatic joint diseases with currently a lack of long-term follow-up studies. OBJECTIVE:To investigate FOI for treatment monitoring in a homogenous cohort of patients with early (disease duration < 2 years) and active ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-019-1989-5
更新日期:2019-09-18 00:00:00
abstract:INTRODUCTION:Serious infection, cardiovascular disease, and mortality are increased in rheumatoid arthritis (RA). Whether RA affects the risk for these complications after total joint arthroplasty (TJA) is unknown, we hypothesize that it does. We compared the occurrence of 30-day postoperative complications and mortali...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4385
更新日期:2013-01-01 00:00:00
abstract:INTRODUCTION:Mutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4171
更新日期:2013-02-19 00:00:00
abstract::T-helper (Th) lymphocytes contribute to arthritis pathogenesis by helping B cells to produce antibodies, by producing cytokines that activate effector cells involved in the destruction of cartilage and bone, and by contributing to osteoclast differentiation. There are murine models of arthritis, most notably collagen-...
journal_title:Arthritis research & therapy
pub_type: 评论,社论
doi:10.1186/ar3008
更新日期:2010-01-01 00:00:00
abstract::Synovial fluid from patients with various arthritides contains procoagulant, cell-derived microparticles. Here we studied whether synovial microparticles modulate the release of chemokines and cytokines by fibroblast-like synoviocytes (FLS). Microparticles, isolated from the synovial fluid of rheumatoid arthritis (RA)...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar1706
更新日期:2005-01-01 00:00:00
abstract:INTRODUCTION:Disease-modifying antirheumatic drugs (DMARDs) have become the treatment standard for patients with rheumatoid arthritis (RA). Although several general-population studies document that a large population of patients diagnosed with RA do not use DMARDs, little is known about this group. We explored the char...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4459
更新日期:2014-01-29 00:00:00
abstract:INTRODUCTION:The aim was to evaluate S100A4 protein as a biomarker of disease activity and potential cancer development in patients with myositis. METHODS:Serum levels of S100A4 were determined in 43 dermatomyositis (DM), 39 polymyositis (PM) and 22 cancer associated myositis (CAM) patients as well as in 77 healthy co...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-014-0468-2
更新日期:2014-10-31 00:00:00
abstract:INTRODUCTION:Degeneration of the intervertebral disc (IVD) is characterized by marked degradation and restructuring of the annulus fibrosus (AF). Although several matrix metalloproteinases (MMPs) have been found to be more prevalent in degenerate discs, their coordination and function within the context of the disease ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4224
更新日期:2013-04-27 00:00:00
abstract:INTRODUCTION:Rational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly at...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3911
更新日期:2012-07-12 00:00:00
abstract:INTRODUCTION:Mesenchymal stem cells (MSCs) represent promising applications in rheumatoid arthritis (RA). However, the inflammatory niche in the RA synovium could adversely affect MSC function. This study was designed to investigate biologic and immunologic properties of synovium-derived MSCs (SMSCs) in RA, with partic...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4355
更新日期:2013-10-29 00:00:00
abstract:INTRODUCTION:Adjustment of infliximab dosage for individuals may be useful in improving therapeutic response in rheumatoid arthritis (RA). Herein, we aimed to determine whether measurement of infliximab serum concentration modifies the therapeutic decision and improves the control of disease activity. METHODS:RA patie...
journal_title:Arthritis research & therapy
pub_type: 临床试验,杂志文章
doi:10.1186/ar2867
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abstract:BACKGROUND:The aim of this study was to develop a patient-reported questionnaire that is suitable to detect periodontitis (PD) in patients with rheumatoid arthritis (RA). METHODS:A self-reported questionnaire containing 12 items potentially relevant to PD and dentists' semiquantitative assessment of PD (no/mild/modera...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究
doi:10.1186/s13075-019-1982-z
更新日期:2019-08-29 00:00:00
abstract:INTRODUCTION:In the present systematic review and meta-analysis, we assessed the effectiveness of different forms of balneotherapy (BT) and hydrotherapy (HT) in the management of fibromyalgia syndrome (FMS). METHODS:A systematic literature search was conducted through April 2013 (Medline via Pubmed, Cochrane Central R...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,meta分析,评审
doi:10.1186/ar4603
更新日期:2014-07-07 00:00:00
abstract:BACKGROUND:Sarcopenic obesity, associated with greater risk of cardiovascular disease (CVD) and mortality in rheumatoid arthritis (RA), may be related to dysregulated muscle remodeling. To determine whether exercise training could improve remodeling, we measured changes in inter-relationships of plasma galectin-3, skel...
journal_title:Arthritis research & therapy
pub_type: 临床试验,杂志文章
doi:10.1186/s13075-018-1786-6
更新日期:2018-12-27 00:00:00
abstract::The discovery of the receptor activator of nuclear factor-kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) system and its role in the regulation of bone resorption exemplifies how both serendipity and a logic-based approach can identify factors that regulate cell function. Before this discovery in the mid to late 1990...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar2165
更新日期:2007-01-01 00:00:00
abstract:INTRODUCTION:Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are chronic immune-mediated disorders complicated by vascular organ damage. The aim of this study was to examine the serum levels of the markers of neoangiogenesis: endostatin and vascular endothelial growth factor (VEGF), in our unselecte...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-015-0756-5
更新日期:2015-08-28 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
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar1193
更新日期:2004-01-01 00:00:00
abstract::A series of discoveries over the past several years has provided a new paradigm for understanding autoimmunity in systemic lupus erythematosus. The discoveries of pattern recognition receptors and of how these receptors can be recruited into autoimmune responses underpin this paradigm. The implications of these observ...
journal_title:Arthritis research & therapy
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doi:10.1186/ar2321
更新日期:2007-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3382
更新日期:2011-06-22 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar2535
更新日期:2009-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,已发布勘误
doi:10.1186/s13075-018-1753-2
更新日期:2018-11-05 00:00:00
abstract:INTRODUCTION:Autoantibodies against mutated and citrullinated vimentin (MCV) represent a novel diagnostic marker for rheumatoid arthritis (RA). Recently, an increased sensitivity for anti-MCV compared to autoantibodies against cyclic citrullinated peptides (anti-CCP2) was shown in cohorts of patients with early RA and ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3057
更新日期:2010-01-01 00:00:00
abstract:INTRODUCTION:Anti-malarial drug artesunate can suppress inflammation and prevent cartilage and bone destruction in collagen-induced arthritis model in rats-suggesting it may be a potent drug for rheumatoid arthritis (RA) therapy. We aimed to investigate its effect on the invasive property of fibroblast-like synoviocyte...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-019-1935-6
更新日期:2019-06-24 00:00:00
abstract:BACKGROUND:With advancement in the treatment options of rheumatoid arthritis (RA), optimising the outcomes of difficult-to-treat patients has become increasingly important in clinical practice. In particular, insensitivity to first-line biologic disease-modifying anti-rheumatic drugs (bDMARD) is becoming a significant ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-2122-5
更新日期:2020-03-04 00:00:00
abstract:BACKGROUND:The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. METHODS:To generate expression of the CII-peptide sp...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-016-1037-7
更新日期:2016-06-14 00:00:00
abstract:BACKGROUND:Inhibitor of DNA binding 1 (Id1) is a nuclear protein containing a basic helix-loop-helix (bHLH) domain that regulates cell growth by selective binding and prevention of gene transcription. Sources of Id1 production in rheumatoid arthritis synovial tissue (RA ST) and its range of functional effects in RA rem...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-016-0984-3
更新日期:2016-04-12 00:00:00
abstract:BACKGROUND:Determining the association between body composition and low back pain (LBP) will improve our understanding of the mechanisms by which obesity affects LBP, and inform novel approaches to managing LBP. The aim of this study was to examine the relationship between body composition and LBP intensity and disabi...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-017-1242-z
更新日期:2017-02-10 00:00:00
abstract:INTRODUCTION:Excess C/EBP homologous protein (CHOP) expression is one feature of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress. Here, we focused on CHOP expression and function in chondrocytes. METHODS:We studied human knee osteoarthritis (OA) cartilage, bovine chondrocytes cultured in algin...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4415
更新日期:2013-01-01 00:00:00