Apoptosis In Rheumatoid Arthritis Research Articles

Apoptotic cell clearance components in inflammatory arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints that affects ~1% of the human population. Joint swelling and bone erosion, hallmarks of RA, contribute to disability and, sometimes, loss of life. Mechanistically, disease is driven by immune dysregulation characterized by circulating autoantibodies, inflammatory mediators, tissue degradative enzymes, and metabolic dysfunction of resident stromal and recruited immune cells. Cell death by apoptosis has been therapeutically explored in animal models of RA due to the comparisons drawn between synovial hyperplasia and paucity of apoptosis in RA with the malignant transformation of cancer cells. Several efforts to induce cell death have shown benefits in reducing the development and/or severity of the disease. Apoptotic cells are cleared by phagocytes in a process known as efferocytosis, which differs from microbial phagocytosis in its "immuno-silent," or anti-inflammatory, nature. Failures in efferocytosis have been linked to autoimmune disease, whereas administration of apoptotic cells in RA models effectively inhibits inflammatory indices, likely though efferocytosis-mediated resolution-promoting mechanisms. However, the nature of signaling pathways elicited and the molecular identity of clearance mediators in RA are understudied. Furthermore, canonical efferocytosis machinery elements also play important non-canonical functions in homeostasis and pathology. Here, we discuss the roles of efferocytosis machinery components in models of RA and discuss their potential involvement in disease pathophysiology.

Xinfeng Capsules promotes apoptosis of synovial fibroblasts and attenuates inflammation in rheumatoid arthritis by regulating lncRNA MAPKAPK5-AS1

To explore the regulatory effects of Xinfeng Capsules(XFC) on the apoptosis of synovial fibroblasts(FLS) and inflammation in rheumatoid arthritis(RA) via lncRNA MAPKAPK5-AS1(MK5-AS1). Thirty healthy people and 30 patients with RA due to spleen deficiency and dampness exuberance were collected for extracting the peripheral blood mononuclear cells(PBMCs) before and after XFC treatment, which were used to observe the correlation between MK5-AS1 and clinical indicators as well as MK5-AS1 expression before and after XFC treatment. Following the establishment of RA-FLS cell line and the preparation of XFC-containing serum, MK5-AS1-overexpression plasmid was constructed and transfected into RA-FLS for investigating the efficacy of XFC-containing serum in regulating inflammation and apoptosis of RA-FLS via MK5-AS1. The expression of MK5-AS1 in PBMCs of patients with RA due to spleen deficiency and dampness exuberance was decreased(P<0.001). The ROC curve analysis revealed the AUC of 83.9%. Correlation analysis showed that MK5-AS1 was negatively correlated with ESR, CRP, RF, CCP, and spleen deficiency and dampness exuberance syndrome score. The expression of MK5-AS1 increased significantly after XFC treatment(P<0.001). As demonstrated by association analysis, XFC decreased MK5-AS1, ESR, CRP, RF, and spleen deficiency and dampness exuberance syndrome score, with the degree of support all greater than 83%, confidence greater than 80%, and lift greater than 1. The results of RT-qPCR showed that the MK5-AS1 RNA expression significantly decreased after TNF-α stimulation(P<0.01), which, however, increased significantly after the intervention with XFC-containing serum(P<0.05). Such expression rose again after the transfection of pcDNA3.1-MK5-AS1(P<0.01). ELISA results showed that TNF-α stimulation elevated the expression of pro-inflammatory factor IL-17 but lowered the expression of anti-inflammatory factor IL-4(P<0.01). After intervention with XFC-containing serum, the expression of IL-17 decreased while that of IL-4 increased(P<0.01). The transfection of pcDNA3.1-MK5-AS1 contributed to the reduction in IL-17 expression but the elevation in IL-4 expression(P<0.01). The immunofluorescence(IF) findings demonstrated that the expression of pro-apoptotic protein Bax was down-regulated, whereas that of the anti-apoptotic protein Bcl-2 was up-regulated after TNF-α stimulation(P<0.01). After the intervention with XFC-containing serum, the Bax expression was increased, while Bcl-2 expression was decreased(P<0.01), which were remarkably collaborated by the transfection of pcDNA3.1-MK5-AS1(P<0.05). The expression of MK5-AS1 is significantly decreased in both RA-PBMCs and RA-FLS, implying that XFC inhibits inflammatory reaction and promotes the apoptosis in RA by regulating the expression of MK5-AS1.

ZFAS1 knockdown inhibits fibroblast-like synoviocyte proliferation, migration, invasion and inflammation, and promotes apoptosis via miR-3926/FSTL1 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by joint disorders. Long non-coding RNA zinc finger antisense 1 (ZFAS1) is aberrantly expressed in numerous human diseases, including RA. The present study aimed to investigate the functions and underlying mechanisms of ZFAS1 in RA. Reverse transcription-quantitative PCR was performed to determine the expression levels of ZFAS1, microRNA (miR)-3926 and follistatin-like protein 1 (FSTL1). MTT assay, flow cytometric analysis and Transwell assay were performed to examine the proliferation, apoptosis, migration and invasion of fibroblast-like synoviocytes (FLSs), respectively. Western blotting was employed to measure the protein expression levels of cleaved caspase-3, interleukin (IL)-6, IL-1β, tumor necrosis factor-α and FSTL1. Dual-luciferase reporter assay was performed to verify the interaction between miR-3926 and ZFAS1 or FSTL1. The results demonstrated that ZFAS1 and FSTL1 were upregulated, and miR-3926 was downregulated in RA synovial tissues and RA-FLSs. ZFAS1 knockdown suppressed cell proliferation, migration, invasion and inflammatory cytokine production, and induced apoptosis in RA-FLSs. ZFAS1 acted as a sponge for miR-3926, and ZFAS1 overexpression abolished the impact of miR-3926 on the development of RA-FLSs. FSTL1 was a direct target of miR-3926, and the effect of FSTL1 knockdown on the progression of RA-FLSs was rescued by miR-3926 inhibition. Furthermore, ZFAS1 regulated FSTL1 expression levels via sponging miR-3926 in RA-FLSs. In conclusion, ZFAS1 knockdown inhibited RA-FLS proliferation, migration, invasion and inflammatory cytokine production, and induced apoptosis in RA via the miR-3926/FSTL1 axis.

MicroRNA-497 Reduction and Increase of Its Family Member MicroRNA-424 Lead to Dysregulation of Multiple Inflammation Related Genes in Synovial Fibroblasts With Rheumatoid Arthritis.

ObjectivesMounting evidence has demonstrated that microRNAs (miRNAs) participate in rheumatoid arthritis (RA). The role of highly conserved miR-15/107 family in RA has not been clarified yet, and hence investigated in this study.MethodsReverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression of miRNAs and genes. Cell counting kit 8 (CCK-8) and FACS were used to detect proliferation and apoptosis. Protein expression was detected by using Western blotting. mRNA deep sequencing and cytokine antibody array were used to analyze differentially expressed genes, signaling pathways and cytokines.ResultsThe expression of miR-15a, miR-103, miR-497, and miR-646 was found decreased, while miR-424 increased in RA patients. MiR-424 and miR-497 were further investigated and the results showed that they could regulate the expression of multiple genes in rheumatoid arthritis synovial fibroblast (RASF) and affect signaling pathways. At the protein level, miR-497 mimic altered all the selected inflammation-related genes while miR-424 inhibitor only affected part of genes. MiR-497 mimic, rather than miR-424 inhibitor, had significant effects on proliferation and apoptosis of RASF. DICER1 was found to positively regulate the expression of miR-424 and miR-497, while DICER1 was also negatively regulated by miR-424. The increase of miR-424 could reduce miR-497 expression, thus forming a loop, which facilitated explaining the dysregulated miR-424 and miR-497 in RA.ConclusionThe miR-424 and miR-497 of miR-15/107 family affect cell proliferation and apoptosis in RA, and the proposed miR-424-DICER1-miR-497 feedback loop provides a novel insight into regulating miRNA expression and a candidate target for controlling RA.

MiR-20a regulates fibroblast-like synoviocyte proliferation and apoptosis in rheumatoid arthritis.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "MiR-20a regulates fibroblast-like synoviocyte proliferation and apoptosis in rheumatoid arthritis, by X.-J. Wei, X.-W. Li, J.-L. Lu, Z.-X. Long, J.-Q. Liang, S.-B. Wei, C.-X. Lu, W.-Z. Lu, published in Eur Rev Med Pharmacol Sci 2017; 21 (17): 3886-3893-PMID: 28975975" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/13351.

Long non-coding RNA PVT1 knockdown suppresses fibroblast-like synoviocyte inflammation and induces apoptosis in rheumatoid arthritis through demethylation of sirt6

BackgroundAs a type of chronic autoimmune joint disease, rheumatoid arthritis (RA) is a disorder, characterized by a variety of physical symptoms as well as RA fibroblast-like synoviocyte (RA-FLS) proliferation. More recently, long non-coding RNAs (lncRNAs) have been implicated in the progression of various diseases including the progression of RA. Hence, the aim of the current study was to investigate the role by which the lncRNA, plasmacytoma variant translocation 1 (PVT1), influences RA-FLSs and its ability to modulate the methylation of sirtuin 6 (sirt6).MethodsRA rat models were initially established to determine the expression of PVT1 and sirt6 in synovial tissues and RA-FLSs. Elevation or depletion of PVT1 or sirt6 was achieved by means of transformation with plasmids in order to investigate their effects on RA-FLS proliferation, inflammation and apoptosis. The localization of PVT1 and its binding ability to the sirt6 promoter region were also explored in an attempt to elucidate the correlation between PVT1 and sirt6 methylation.ResultsHigh expression of PVT1 and low expression of sirt6 were detected in the synovial tissues and RA-FLSs of the rat models. RA-FLSs treated with sh-PVT1 or oe-sirt6 exhibited suppressed cell proliferation, inflammation and induced apoptosis. PVT1 was predominately localized in the nucleus while evidence was obtained indicating that it could bind to the sirt6 promoter to induce sirt6 methylation, thus inhibiting sirt6 transcription. PVT1 knockdown was observed to restore sirt6 expression through decreasing sirt6 methylation, thereby alleviating RA.ConclusionThe key findings of the study provide evidence suggesting that, PVT1 knockdown is able to restrain RA progression by inhibiting sirt6 methylation to restore its expression.

Eriodictyol inhibits survival and inflammatory responses and promotes apoptosis in rheumatoid arthritis fibroblast-like synoviocytes through AKT/FOXO1 signaling.

2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one (eriodictyol), a flavonoid compound, was proved to possess anti-inflammatory, antioxidative, and antiarthritis activities. However, the effects of eriodictyol on the rheumatoid proliferation, apoptosis, and inflammatory response of arthritis fibroblast-like synoviocytes (RA-FLS) remain unclear. Thus, the objective of this study was to examine the effects of eriodictyol on RA-FLS survival, apoptosis, and inflammatory response, and further explore the potential underlying mechanisms. Our results showed that eriodictyol inhibited the survival of RA-FLSs and promoted its apoptosis. Eriodictyol significantly reduced RA-FLS secretion of tumor necrosis factor α, interleukin 6 (IL-6), IL-8, and IL-1β. Furthermore, eriodictyol prevented the activation of the protein kinase B (AKT) pathway and increased the expression of forkhead box O1 (FOXO1) in RA-FLS. FOXO1 silence reversed the effects of eriodictyol on RA-FLS survival, apoptosis, and inflammation. In conclusion, these findings indicated that eriodictyol inhibits the cell survival and inflammatory response in RA-FLS, and the AKT/FOXO1 signaling pathway is involved in the effect of eriodictyol on the RA-FLS. Thus, eriodictyol might be a potential therapeutic agent for the treatment of rheumatoid arthritis.

Down-regulation of miR-10a-5p promotes proliferation and restricts apoptosis via targeting T-box transcription factor 5 in inflamed synoviocytes.

Synoviocytes from rheumatoid arthritis (RA) patients share certain features with tumor cells, such as over proliferation and invasion. Anomalous microRNA (miRNA) expression may participate in the pathogenesis of RA in different ways. The objective of the present study was to observe the role of miR-10a-5p targeting T-box transcription factor 5 (TBX5) gene on synoviocyte proliferation and apoptosis in RA. Human synovial sarcoma cell line, SW982 cells stimulating with interleukin-1β (IL-1β) were transfected with miR-10a-5p mimic and siRNA of TBX5. The real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis were used to evaluate the expression level of miR-10a-5p and TBX5 in SW982 cells respectively. Further, the proliferation and apoptosis of SW982 cells after treatment were determined by cell counting kit (CCK-8) and flow cytometry analysis respectively. We found that the miR-10a-5p showed down-regulated while TBX5 showed up-regulated expression in synoviocytes after stimulation with IL-1β. The miR-10a-5p mimic treatment showed a decline in cell proliferation while the increased rate of cell apoptosis as compared with control. Moreover, knockdown of TBX5 favored the apoptosis and reduced the cell proliferation as compared with control group. We conclude that down-regulation of miR-10a-5p promotes proliferation and restricts apoptosis via targeting TBX5 in inflamed synoviocytes.

EDHSS206, an Exquisitely Selective Inhibitor of TAK1, Targets Pro Survival TNFFFDependent Signaling, Inducing Apoptosis in Rheumatoid Arthritis and Breast Cancer Models

Tumor necrosis factor alpha (TNFα) administration has shown limited therapeutic utility in cancer and inflammatory disorders due to dose‐limiting side effects. We propose an alternative approach to targeting TNFα‐mediated diseases by selectively inducing the TNFα apoptotic response in TNFα‐rich microenvironments. TAK1 acts as a key mediator between survival and cell death in TNFα signaling. We report a novel potent and exquisitely selective TAK1 inhibitor (EDHS‐206, IC50 9.5nM) that induces apoptosis in a TNFα‐dependent manner in models of metastatic breast cancer and rheumatoid arthritis. Co‐crystallization studies demonstrated that EDHS‐206 inhibits the kinase in a DFG‐in conformation. Kinetic analysis of EDHS‐206‐TAK1 interactions revealed a substrate‐like intermolecular autophosphorylation mechanism for TAK1 activation, during which EDHS‐206 delays the proceedings of the rate‐limiting step. EDHS‐206 represents an attractive starting point for the development of a novel generation of inhibitors that greatly sensitize cells to TNFα‐induced cell death, potentially broadening the therapeutic efficacy of TNFα.

Chondrocyte Apoptosis in Rheumatoid Arthritis: Is Preventive Therapy Possible?

Rheumatoid arthritis (RA) is a systemic, chronic autoimmune disease of unknown etiology. At the tissue and organ level, respectively, RA is associated with sustained synovial joint inflammation which may also go on to affect other peripheral organs [1]. At the cellular level, RA is characterized by defective innate and adaptive immune responses [2]. Thus, experimental studies designed to dissect out the progression of RA changes have noted the extensive presence of activated T-lymphocytes with associated B-cell hyperactivity, as well as heightened migration, adhesion and retention of activated macrophages, dendritic cells and neutrophils emanating from the peripheral circulation and reaching synovial tissue [3]. These cellular events ultimately give rise to activate the normally quiescent synovial tissue fibroblasts which most often results from the action of proinflammatory cytokines and other soluble mediators of inflammation that are abundantly present in the RA synovial joint [4]. The clustering of these aberrant cellular events culminate in subchondral bone erosions. In this regard, bone erosions have also been associated with mechanically-deficient ligaments and tendons as well as a marked increase in the degradation of articular cartilage extracellular matrix proteins. The destruction of articular cartilage generally occurs under these conditions following the up-regulation matrix metalloproteinase (MMP) gene expression [5]. However, paradoxically this increase in MMP gene expression is also accompanied by a marked increase in the frequency of non-viable articular chondrocytes which can result from controlled cell death, also known as programmed cell death or apoptosis [6-8].

Apoptotic Effect of Geniposide on Fibroblast-Like Synoviocytes in Rats with Adjuvant-Induced Arthritis via Inhibiting ERK Signal Pathway In Vitro

Stimulating fibroblast-like synoviocyte (FLS) apoptosis in rheumatoid arthritis (RA) is a promising strategy for clinical treatment. Previous studies have confirmed that geniposide shows a certain anti-arthritic effect in vivo. However, whether geniposide can induce RA FLS apoptosis and the underlying mechanisms has not been elucidated. Herein, adjuvant-induced arthritis (AIA) in rat was induced and FLS was isolated from synovial tissues by tissue explant cultivation method. MTT assay, Hoechst staining, and flow cytometric apoptosis assay were applied to evaluate apoptotic effect of geniposide on AIA FLS. Bcl-2, Bax, and caspase 3 messenger RNA (mRNA) levels, and extracellular-signal-regulated kinases (ERKs) and phosphorylated ERK protein levels were examined by real-time PCR and western blot, respectively. We found that geniposide dose-dependently inhibited AIA FLS proliferation in vitro. AIA FLS treated with geniposide displayed typical apoptotic morphological characteristics including nuclear shrinkage and chromatin condensation. Flow cytometric apoptosis assay indicated that geniposide significantly increased the apoptosis rate of AIA FLS. Additionally, geniposide treatment on AIA FLS decreased Bcl-2 mRNA level and increased Bax and caspase 3 mRNA levels, accompanied by reduced protein levels of phosphorylated-ERK1/2, without affecting total ERK1/2. In conclusion, geniposide effectively induces AIA FLS apoptosis through regulating the apoptosis-related gene expressions and inhibiting ERK signal pathway.

Inhibition of B-cell apoptosis is mediated through increased expression of Bcl-2 in patients with rheumatoid arthritis.

Abnormal B-cell apoptosis is believed to have a role in rheumatoid arthritis (RA) pathogenesis, but the exact mechanisms of B-cell apoptosis in RA have not been elucidated. We therefore investigated the percentage of circulatingB cells and its relationship with apoptosis in a cohort of patients with RA. B cells were quantified by flow cytometry in RA patients and matched controls, and the relationships between these proportions and RA disease parameters were calculated. Rates of apoptosis were determined by annexin V/propidium iodine analysis, and Bcl-2 and caspase-3 protein levels were determined by western blot. RA patients had significantly higher percentage of B cells in the peripheral blood than healthy controls but a significantly lower rate of B-cell apoptosis. The percentage of B cells correlated with Disease Activity Score of 28 joints and serum immunoglobulin G concentration in RA patients. Expression of anti-apoptosis protein Bcl-2 was higher in RA patients than in healthy controls, whereas expression of apoptosis marker caspase-3 in B cells was lower. The higher percentage of B cells in the peripheral blood of RA patients may be due, at least partially, to disruption of the normal pathway of apoptosis in these cells. The inhibition of B-cell apoptosis in these patients may be attributable to the enhanced expression of Bcl-2 in these cells.

Menaquinone-7 as a novel pharmacological therapy in the treatment of rheumatoid arthritis: A clinical study

Menaquinones (MKs) have been reported to induce apoptosis in rheumatoid arthritis (RA) synovial cells. Recently, menaquinone-4 (MK-4) was proven as a new potential agent for the treatment of RA. However, menaquinone-7 (MK-7) has greater bioavailability and efficacy than MK-4 after oral administration. Yet, the therapeutic benefits of MK-7 in the management of patients with RA have never been addressed. This study was designed to clarify the therapeutic role of MK-7 added to normal therapeutic regimen of RA in patients with different stages of the disease with a clinical follow up through a randomized clinical trial. In a cross sectional study, 84 RA patients (24 male, 60 female) (average age=47.2 years) were enrolled in this study. The patients were divided into MK-7 treated group (n=42) and MK-7 naïve group (n=42). MK-7 capsules were administered in a dose of 100µg/day for three months in the first group without changing in other medications. The clinical and biochemical markers on RA patients treated with MK-7 and naïve group were assessed. In MK-7 treated group, serum concentrations of MK-7 were monitored before and after three months of MK-7 administration. In the cross sectional study, a significant decrease in MK-7 treated group for the levels of undercarboxylated osteocalcin (ucOC), erythrocyte sedimentation rate (ESR), disease activity score assessing 28 joints with ESR (DAS28-ESR), C-reactive protein (CRP) and matrix metalloproteinase (MMP-3) was found. In MK-7 treated group, a marked decrease in RA clinical and biochemical markers for moderate and good response compared to non-responders was observed in ucOC, ESR and DAS28-ESR. A marked increase in the levels of MK-7 for the moderate and good responders compared to non-responders was observed. The results suggest that MK-7 improves disease activity in RA patients. Therefore, MK-7 represents a new promising agent for RA in combination therapy with other disease modifying antirheumatic drugs.

TNF-α confers resistance to Fas-mediated apoptosis in rheumatoid arthritis through the induction of soluble Fas

AimsRheumatoid arthritis (RA) is a chronic inflammatory arthritis that is characterized by hyperplastic synovial tissue containing activated synovial fibroblasts. Contradictory findings in the apoptosis of fibroblast-like synoviocytes (FLS) have been described elsewhere, showing that RA FLS have an enhanced susceptibility to Fas (also known as CD95)-mediated apoptosis in vitro in contrast to the observed lack of apoptosis in the RA synovium in vivo. However, the potential mechanisms responsible for this discrepancy remain under investigation. The soluble form of Fas (sFas) was found to inhibit Fas-induced apoptosis by binding to Fas ligand (FasL), thereby preventing the interaction between FasL and membrane-bound Fas. Main methodsWe determined the levels of soluble FasL (sFasL) and sFas in patients with RA and the effects of proinflammatory mediators, including TNF-α, on the induction of apoptotic mediators in RA FLS. Key findingsThe levels of sFasL and sFas were significantly elevated in the synovial fluids of RA patients compared with control subjects. In addition, we found that the sFas is substantially induced in RA FLS by TNF-α, which were abundantly present in the synovial fluid of RA. SignificanceThese findings suggest that TNF-α confers resistance to Fas-mediated apoptosis through sFas induction, which could explain the apparent resistance of RA synovial cells to apoptosis in vivo.

Vitamin K2 administration is associated with decreased disease activity in patients with rheumatoid arthritis

Objectives Vitamin K2 (VitK2) is reported to induce not only bone mineralization of human osteoblasts and apoptosis of osteoclasts, but also apoptosis of rheumatoid arthritis (RA) synovial cells, while its clinical effect on disease activity of RA remains unknown.Methods 158 female RA patients (mean age 62.5 years) who had not been treated with warfarin, biologics, or teriparatide were enrolled in this study. VitK2 (45 mg/day) was administered in 70 patients with a serum undercarboxylated osteocalcin level of >4.5 ng/ml or with decreased bone mineral density in spite of the treatment with other anti-osteoporosis medications, regardless of RA disease activity. A longitudinal study was conducted in 52 patients who were additionally treated with VitK2 without changing their other medications for three months.Results In the cross-sectional study, as compared to the VitK2-naïve group (n = 88), the VitK2-treated group (n = 70) showed lower serum CRP (1.7 ± 0.2 vs. 0.5 ± 0.1 mg/dl; P < 0.001), MMP-3 (220.4 ± 21.9 vs. 118.0 ± 14.4 ng/ml; P < 0.001), and DAS28-CRP (2.9 ± 0.1 vs. 2.4 ± 0.1; P < 0.05). In the longitudinal study, patients who were additionally treated with VitK2 showed significant decreases in serum CRP (1.1 ± 0.2 to 0.6 ± 0.2 mg/dl; P < 0.001), MMP-3 (160.1 ± 25.6 to 125.0 ± 17.8 ng/ml; P < 0.05), and DAS28-CRP (3.1 ± 0.2 to 2.4 ± 0.1; P < 0.001).Conclusions VitK2 may have the potential to improve disease activity besides osteoporosis in RA.

Relation of the Fas and FasL gene polymorphisms with susceptibility to and severity of rheumatoid arthritis

To investigate associations of the Fas and FasL genes polymorphisms with rheumatoid arthritis (RA). One hundred patients with RA and age-, sex- and ethnically matched 101 controls were included. Four polymorphisms of Fas (-670 A>G rs1800682, -1377 G>A rs2234767) and FasL (IVS2nt-124 A>G rs5030772, -844 T>C rs763110) genes were typed from genomic DNA. Genotype distributions and allelic frequencies were compared between patients and control subjects. After the history and clinical examination of patients with RA, in terms of pain, fatigue and general health status were evaluated by visual analogue scale. Thereafter, erythrocyte sedimentation rate, C-reactive protein, blood count and rheumatoid factor levels were measured. The Disease Activity Score-28, Health Assessment Questionnaire and modified Sharp score were used to evaluate the disease activity, functional disability and radiological damage, and their relationships with the Fas and FasL gene polymorphisms were investigated. In patients with RA, CT and TT genotypes of FasL-844, polymorphism were twofold and 4.8-fold higher, and AA genotype of FasL IVS2nt-124 polymorphism was 3.4-fold higher than the control group (respectively, p = 0.05, p = 0.002, p = 0.039). T allele of FasL-844 polymorphism was more frequent in patients than controls (respectively, 52.5 vs. 41.4 %, p = 0.027). Any association was not detected between Fas (-670 A>G, -1377 G>A) and FasL (-844 T>C, IVS2nt-124 A>G) gene polymorphisms with the disease activity scores, functional disability and radiological damage. However, the Fas-670 A>G polymorphism was associated with drug therapy (p = 0.049). The distribution of GG genotype was higher compared to GA or AA genotypes in patients using triple disease-modifying antirheumatic drug therapy (71.4, 14.3 and 14.3 %, respectively). These findings suggest that the -844 T>C and IVS2nt-124 A>G polymorphisms in the FasL gene related with apoptosis may increase genetic susceptibility to RA in a Turkish population. In addition, the Fas-670 A>G gene polymorphism may be associated with disease progression. There is a need for further studies to clarify the genetic role of apoptosis in RA.

THU0099 Adenovirus-Mediated IGFBP-3 Gene Transfer Induces Apoptosis and Suppresses Inflammation and Bone Destruction in Rheumatoid Arthritis

BackgroundInsulin-like growth factor binding protein-3 (IGFBP-3) is known to interfere NF-κB signaling pathway and effectively promotes apoptosis in tumor cells by a variety of mechanisms.ObjectivesDue to the pivotal roles of...

OP0307 Inhibitory Effects of IL-17 on Chondrogenic Differentiation of Human Mesenchymal Stem Cells Through the Phosphorylation of Sox9

BackgroundMesenchymal stem cells (MSCs) are multipotent cells that are able to differentiate into chondrocytes. Existence of MSCs in the articular cartilage suggests the contribution of MSCs to cartilage homeostasis with...

Accumulation of CD4+CD28-PD-1lowOX40+ T cells and its clinical significance in rheumatoid and collagen-induced arthritis

Event Abstract Back to Event Accumulation of CD4+CD28-PD-1lowOX40+ T cells and its clinical significance in rheumatoid and collagen-induced arthritis Juean Jiang1, Cuiping Liu1, Yongjing Chen2, Jianhua Jiang1, Ranran Zhu2, Ting Wang2, Min Wu3 and Xueguang Zhang1* 1 The First Affiliated Hospital of Soochow University, China 2 Soochow University, China 3 The Third Affiliated Hospital of Soochow University, China CD4+CD28- T cells play a key role in the immunopathogenesis of rheumatoid arthritis (RA). Co-inhibitory molecule of PD-1 has a crucial role in suppression of T cell responses. However, presence of PD-1 and absence of CD28 do not induce CD4+ T cells into apoptosis in RA. In this study, we characterized a novel CD4+CD28-PD-1lowOX40+ T cells subset and investigated its clinical significance in rheumatoid and collagen-induced arthritis (CIA). Peripheral blood samples were collected from RA, osteoarthritis and healthy subjects. CIA was induced in DBA/1 mice. After separation of mononuclear cells from peripheral blood of the patients or spleen of CIA mice, CD4+CD28-PD-1lowOX40+ T cells were examined by flow cytometry. In RA patients and CIA mice, there were increased expressions of PD-1 and OX40 on CD4+ T cells, with PD-L1 and OX40L expressions augmented on monocytes and B cells. Analyses showed that CD4+CD28-PD-1lowOX40+ T cells were accumulated and closely correlated with clinicopathological features of RA patients and CIA mice. Moreover, immunosuppressive therapy significantly reduced the percentage of CD4+CD28-PD-1lowOX40+ T cells. Additionally, CD4+CD28-PD-1low T cells displayed a phenotype of CD45RAlowCD45ROhighCD25low. In summary, low PD-1 and enhanced OX40 expression implied longevity and persistent activation of these T cells both in RA patients and CIA mice. A phenotype of memory T cells and fine correlations with clinicopathological features suggested that these T cells may be involved in the immunopathogenesis of RA and CIA. Interventions with pathological functions of this T cells subset may provide a new therapeutic interesting in RA. Acknowledgements This study was supported by the National Natural Science Foundation of China (Grants: 30930085, 81001337 and 31170834), the Research and Innovation Project for College Graduates of Jiangsu Province (Grant: CXLX11_0077), and Science and Technology Support Program of Suzhou City (Grant: SS201246). Keywords: Rheumatoid arthritis, Autoreactive T cells, CD28, PD-1, OX40 Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Jiang J, Liu C, Chen Y, Jiang J, Zhu R, Wang T, Wu M and Zhang X (2013). Accumulation of CD4+CD28-PD-1lowOX40+ T cells and its clinical significance in rheumatoid and collagen-induced arthritis. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00742 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Xueguang Zhang, The First Affiliated Hospital of Soochow University, Suzhou, China, xueguangzh@126.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Juean Jiang Cuiping Liu Yongjing Chen Jianhua Jiang Ranran Zhu Ting Wang Min Wu Xueguang Zhang Google Juean Jiang Cuiping Liu Yongjing Chen Jianhua Jiang Ranran Zhu Ting Wang Min Wu Xueguang Zhang Google Scholar Juean Jiang Cuiping Liu Yongjing Chen Jianhua Jiang Ranran Zhu Ting Wang Min Wu Xueguang Zhang PubMed Juean Jiang Cuiping Liu Yongjing Chen Jianhua Jiang Ranran Zhu Ting Wang Min Wu Xueguang Zhang Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Vitamin K2 administration is associated with decreased disease activity in patients with rheumatoid arthritis

Vitamin K2 (VitK2) is reported to induce not only bone mineralization of human osteoblasts and apoptosis of osteoclasts, but also apoptosis of rheumatoid arthritis (RA) synovial cells, while its clinical effect on disease activity of RA remains unknown. 158 female RA patients (mean age 62.5years) who had not been treated with warfarin, biologics, or teriparatide were enrolled in this study. VitK2 (45mg/day) was administered in 70 patients with a serum undercarboxylated osteocalcin level of >4.5ng/ml or with decreased bone mineral density in spite of the treatment with other anti-osteoporosis medications, regardless of RA disease activity. A longitudinal study was conducted in 52 patients who were additionally treated with VitK2 without changing their other medications for threemonths. In the cross-sectional study, as compared to the VitK2-naïve group (n=88), the VitK2-treated group (n=70) showed lower serum CRP (1.7±0.2 vs. 0.5±0.1mg/dl; P<0.001), MMP-3 (220.4±21.9 vs. 118.0±14.4ng/ml; P<0.001), and DAS28-CRP (2.9±0.1 vs. 2.4±0.1; P<0.05). In the longitudinal study, patients who were additionally treated with VitK2 showed significant decreases in serum CRP (1.1±0.2 to 0.6±0.2mg/dl; P<0.001), MMP-3 (160.1±25.6 to 125.0±17.8ng/ml; P<0.05), and DAS28-CRP (3.1±0.2 to 2.4±0.1; P<0.001). VitK2 may have the potential to improve disease activity besides osteoporosis in RA.