Decreased expression of alpha-enolase inhibits the proliferation of hypoxia-induced rheumatoid arthritis fibroblasts-like synoviocytes

Fan, Sha Sha; Zong, Min‐Hua; Zhang, Hui; Lü, Ying; Lu, Tian Bao; Fan, Lie Ying

doi:10.3109/14397595.2015.1014141

Cited by 18 publications

(14 citation statements)

References 26 publications

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“…The majority of the identified CD109-interacting partners are involved in processes such as metabolism, signalling pathways, protein processing and modification, and cell cycle and apoptosis (online supplementary table 2). ENO1 was selected for further investigation as it is also localised on the cell surface and regulates cytokine production and apoptotic resistance in RA FLSs 30–32. Co-immunoprecipitation (figure 4A) and immunofluorescence (figure 4B) analyses confirmed the specific association between CD109 and ENO1 on the surface of RA FLSs; the interaction was enhanced by TNF-α or IL-1β treatment.…”

Section: Resultsmentioning

confidence: 90%

CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis

et al. 2019

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ObjectiveThe aim of this study was to investigate the role of CD109 in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) and to evaluate its potential as a therapeutic target.MethodsCD109 expression was examined in synovial tissues and FLSs from RA patients and collagen-induced arthritis (CIA) model mice. CD109-deficient mice were developed to evaluate the severity of CIA. Small interfering RNAs and a neutralising antibody against CD109 (anti-CD109) were designed for functional or treatment studies in RA FLSs and CIA.ResultsCD109 was found to be abundantly expressed in the synovial tissues from RA patients and CIA mice. CD109 expression in RA FLSs was upregulated by inflammatory stimuli, such as interleukin-1β and tumour necrosis factor-α. Silencing of CD109 or anti-CD109 treatment reduced proinflammatory factor production, cell migration, invasion, chemoattractive potential and osteoclast differentiation, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. Mice lacking CD109 were protected against arthritis in the CIA model. Anti-CD109 treatment prevented the onset and ameliorated the severity of CIA lesions.ConclusionOur study uncovers an antiarthritic role for CD109 and suggests that CD109 inhibition might serve as a promising novel therapeutic strategy for RA.

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Section: Resultsmentioning

confidence: 90%

CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis

et al. 2019

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“…FLSs from RA patients were found to display uncontrolled proliferation, which is causally related to the hypoxic microenvironment [ 27 ]. Our previous study has found that hypoxic exposure promotes the proliferation and reduces the apoptosis of RA-FLSs [ 28 ]. The increased level of Trx1 is closely correlated with the disease activity of RA, suggesting that Trx1 may become a useful clinical biomarker of RA [ 21 – 23 ].…”

Section: Discussionmentioning

confidence: 99%

Thioredoxin 1 is associated with the proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes

Zong

Fan

et al. 2017

Clin Rheumatol

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We aimed to investigate the possible effects of thioredoxin 1 (Trx1) on the proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and elucidate the possible mechanisms involved. We investigated the distribution and expression of Trx1 in synovial tissues from RA and osteoarthritis (OA) patients by immunohistochemistry and real-time polymerase chain reaction (RT-PCR) analyses. RA-FLSs were isolated and cultured under normoxic (21% oxygen) or hypoxic (3% oxygen) concentrations. Transfection of Trx1-siRNAs and a Trx1 overexpression construct was conducted to manipulate the expression of Trx1. Protein expression was detected by Western blot. Doxorubicin (Adriamycin, ADR) was used to induce apoptosis. LY-294002 was used for the inhibition of PI3K-Akt. Cell proliferation and apoptosis were determined by MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt) assay and flow cytometry, respectively. The mRNA and protein expression of Trx1 in RA tissues was higher than that in OA tissues. The expression levels of Trx1 and cell proliferation in RA-FLSs were increased under hypoxia in comparison to those under normoxia. In hypoxia, downregulation of Trx1 significantly suppressed FLS proliferation, and the expression of PI3Kp85, phospho-Akt, and Bcl-2, while notably increased FLS apoptosis and the expression of active Caspase3 and Bax. In normoxia, Trx1 overexpression promoted the FLS proliferation and the expression of PI3Kp85, phospho-Akt, and Bcl-2, but inhibited FLS apoptosis and the expression of active Caspase3 and Bax in FLSs. Such effects were partially repressed by LY-294002 treatment. Trx1 may play an important role in regulating the proliferation and apoptosis of RA-FLSs by modulating PI3K-Akt activation.

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“…Enolase plays multiple roles in growth control, immune activation, inflammation, and allergic responses (4–8). Cell-surface expression of enolase is often detected on activated monocytes/macrophages, microglia, and astrocytes, which promotes degradation of extracellular matrix (ECM), production of pro-inflammatory cytokines/chemokines, and invasion of inflammatory cells in the sites of injury (2, 9–11).…”

Section: Introductionmentioning

confidence: 99%

Targeting Enolase in Reducing Secondary Damage in Acute Spinal Cord Injury in Rats

et al. 2017

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Spinal cord injury (SCI) is a complex debilitating condition leading to permanent life-long neurological deficits. The complexity of SCI suggests that a concerted multi-targeted therapeutic approach is warranted to optimally improve function. Damage to spinal cord is complicated by an increased detrimental response from secondary injury factors mediated by activated glial cells and infiltrating macrophages. While elevation of enolase especially Neuron Specific Enolase (NSE) in glial and neuronal cells is believed to trigger inflammatory cascades in acute SCI, alteration of NSE and its subsequent effects in acute SCI remains unknown. This study measured NSE expression levels and key inflammatory mediators after acute SCI and investigated the role of ENOblock, a novel small molecule inhibitor of enolase, in a male Sprague-Dawley (SD) rat SCI model. Serum NSE levels as well as cytokines/chemokines and metabolic factors were evaluated in injured animals following treatment with vehicle alone or ENOblock using Discovery assay. Spinal cord samples were also analyzed for NSE and MMPs 2 and 9 as well as glial markers by Western blotting. The results indicated a significant decrease in serum inflammatory cytokines/chemokines and NSE, alterations of metabolic factors and expression of MMPs in spinal cord tissues after treatment with ENOblock (100μg/kg, twice). These results support the hypothesis that activation of glial cells and inflammation status can be modulated by regulation of NSE expression and activity. Analysis of SCI tissue samples by immunohistochemistry confirmed that ENOblock decreased gliosis which may have occurred through reduction of elevated NSE in rats. Overall, elevation of NSE is deleterious as it promotes extracellular degradation and production of inflammatory cytokines/chemokines and metabolic factors which activates glia and damages neurons. Thus, reduction of NSE by ENOblock may have potential therapeutic implications in acute SCI.

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Decreased expression of alpha-enolase inhibits the proliferation of hypoxia-induced rheumatoid arthritis fibroblasts-like synoviocytes

Abstract: ENO1 may be crucial in the regulation of the proliferation and survival of synovial fibroblasts.

Cited by 18 publications

References 26 publications

CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis

CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis

Thioredoxin 1 is associated with the proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes

Targeting Enolase in Reducing Secondary Damage in Acute Spinal Cord Injury in Rats

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