Tetraspanin CD82 affects migration, attachment and invasion of rheumatoid arthritis synovial fibroblasts

Neumann, Elena; Schwarz, Maria; Hasseli, Rebecca; Hülser, Marie-Lisa; Claßen, Simon; Sauerbier, Michael; Rehart, Stefan; Müeller-Ladner, Ulf

doi:10.1136/annrheumdis-2018-212954

Cited by 19 publications

(14 citation statements)

References 40 publications

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“…The migratory potential of activated RASFs can affect at least partly joint destruction and the spread of destructive arthritis between joints. 19,20 The behaviors of RASFs were then evaluated using a water-soluble tetrazolium salt-1 (WST-1) assay, Transwell assay, scratch test, and flow cytometry. The results provided evidence that silencing of HOTTIP led to markedly reduced cell proliferation (Figure 1E), invasion (Figure 1F) and migration abilities (Figure 1G), and induced cell apoptosis (Figure 1H).…”

Section: Silencing Of Hottip Inhibits Proliferation and Promotes Apoptosis Of Rasfs In Ramentioning

confidence: 99%

RETRACTED: Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1

Tang

et al. 2020

Molecular Therapy - Nucleic Acids

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Accumulating evidence suggests long non-coding RNAs (lncRNAs) play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Here, we aimed to define the role of HOXA transcript at the distal tip (HOTTIP) in RA pathogenesis in relation to SFRP1 methylation and Wnt signaling pathway. HOTTIP was found highly expressed, and SFRP1 was hypermethylated in RA synovial fibroblasts (RASFs). Next, gain-or lossof-function experiments were conducted in RASFs to explore the effects of HOTTIP on the biological behaviors of RASFs. Silencing of HOTTIP or overexpression of SFRP1 inhibited RASF proliferation, invasion, and migration, while enhancing apoptosis. The relationship among HOTTIP, SFRP1, and Dnmt3b was determined using methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), RNA pull-down, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays. The regulatory mechanisms of HOTTIP/Dnmt3b/SFRP1 were explored by altering their expression in RASFs. It was noted that HOTTIP could induce SFRP1 promoter methylation through recruitment of Dnmt3b and activate the Wnt signaling pathway. Finally, a rat RA model was established in order to evaluate the in vivo effects of HOTTIP and SFRP1, which suggested that HOTTIP silencing or SFRP1 elevation inhibited the progression of RA in vivo. Our key findings demonstrate the anti-inflammatory ability of HOTTIP silencing in RA through SFRP1 promoter demethylation. These findings support HOTTIP as a candidate anti-arthritis target.

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Section: Silencing Of Hottip Inhibits Proliferation and Promotes Apoptosis Of Rasfs In Ramentioning

confidence: 99%

RETRACTED: Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1

Tang

et al. 2020

Molecular Therapy - Nucleic Acids

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“…2 d). In a recently published paper from our group and conducted by using a very similar protocol, CD82 inhibition led to an approximately 50% increase of RASF migration after 16 h 16 . In the present study, we could observe a similar alteration in RASF migration in the younger patients.…”

Section: Resultsmentioning

confidence: 93%

Dopamine induces in vitro migration of synovial fibroblast from patients with rheumatoid arthritis

Nie

Salinas-Tejedor

Dychus

et al. 2020

Sci Rep

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Preventing synovial fibroblast (SF) migration into the adjacent cartilage is a desirable therapeutic target in rheumatoid arthritis (RA). As previous studies demonstrated that RASF and SF from osteoarthritis (OA) patients express dopamine receptors (DR), aim of the present study was to investigate the impact of dopamine on mobility of fibroblasts from patients with chronic arthritides. Synovial tissue and fibroblasts were obtained from RA and OA patients. Immunohistochemistry was performed for all DR-subtypes in the invasion zone. Migration-and motility-assays were performed under DR-stimulation. Cytokines were evaluated using ELISA. Expression of DRs was evaluated by flow cytometry, and DR activation was measured by xCELLigence real-time analysis. All DRs were expressed in RA invasion zone. Migration and motility of RASF and OASF were increased after DR stimulation in patients ≤ 75 years old. Synovial fibroblasts from older RA patients (> 75 years old) expressed lower levels of D1-, D2-and D4-DR than patients ≤ 75 years old. DR activation was not altered in older patients. Our results suggest a possible involvement of dopamine on migration of fibroblasts from arthritis patients. Therefore, the synovial dopaminergic pathway might represent a potential therapeutic target to interfere with progressive joint damage in RA patients. Abbreviations OA Osteoarthritis RA Rheumatoid arthritis SF Synovial fibroblasts DR Dopaminergic receptor RTCA Real time cell analysis FACS Fluorescent activated cell sorting (flow cytometry) Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and progressive joint destruction, which leads to joint deformation and disability. Increasing evidences demonstrate that RA synovial fibroblasts (RASF) are among the key players in joint destruction. For instance, it was shown in a mouse model that activated RASF are able to transmigrate in other joints and are therefore responsible for spreading the disease to the majority of the joints 1. The invasive phenotype of the activated fibroblasts is not dependent from inflammatory processes, as RASF are able to invade and destroy human cartilage and bone in the absence of immune cells 2. This "aggressive" phenotype is particularly relevant in RA fibroblasts. Indeed, also SF from osteoarthritis (OA) patients are activated due to the presence of a damaged cartilage, but RASF are more

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“…Additionally, SFs-dependent pathogenesis is associated with changes in their adhesion and migration capacities, which ultimately creates the pannus, an overgrowth of the synovium observed only in arthritic joints that invades and damages bone and cartilage. As also observed in tumorogenesis, pathological SF migration is a result of dysregulated expression of matrix degrading enzymes, like MMPs, and aberrant upregulation of adhesion molecules, such as cadherin-11, CD82 and integrins or focal adhesion kinase (FAK) (7)(8)(9). The characterisation of functional heterogeneity provided by single-cell RNA-Sequencing (RNA-Seq) has allowed a rapid advance in the understanding of the pathophysiology of SFs in RA (10)(11)(12), but the mechanisms that underpin SFs migration and invasiveness are still unclear.…”

Section: Introductionmentioning

confidence: 95%

GEF Cytohesin-2/ARNO: a novel bridge between cell migration and immunoregulation in synovial fibroblasts

Wang

Çil

Harnett

et al. 2021

Preprint

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The guanine nucleotide exchange factor cytohesin-2 (ARNO) is a major activator of the small GTPase ARF6, and has been shown to play an important role(s) in cell adhesion, migration and cytoskeleton reorganization in various cell types and models of disease. Interestingly, dysregulated cell migration, in tandem with hyper-inflammatory responses, is one of the hallmarks associated with activated synovial fibroblasts (SFs) during chronic inflammatory joint diseases, like rheumatoid arthritis. The role of ARNO in this process was unknown but we hypothesized that the pro-inflammatory milieu of inflamed joints induces local activation of ARNO-mediated pathways in SFs, promoting an invasive cell phenotype that ultimately leads to bone and cartilage damage. Thus, we used small interference RNA to investigate the impact of ARNO on the pathological migration and inflammatory responses of murine SFs, revealing a fully functional ARNO-ARF6 pathway in SFs, which can be rapidly activated by IL-1β. Such activation promotes cell migration and formation of focal adhesions. Unexpectedly, ARNO was also shown to modulate SF-inflammatory responses, dictating the precise cytokine and chemokine expression profile. Our results uncover a novel role for ARNO in SF-dependent inflammation, that potentially links pathogenic migration with initiation of local joint inflammation, offering new approaches for targeting the fibroblast compartment in chronic arthritis and joint disease.

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Tetraspanin CD82 affects migration, attachment and invasion of rheumatoid arthritis synovial fibroblasts

Abstract: CD82 could contribute to RASF migration to sites of inflammation and tissue damage, where CD82 keeps aggressive RASF on site.

Cited by 19 publications

References 40 publications

RETRACTED: Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1

RETRACTED: Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1

Dopamine induces in vitro migration of synovial fibroblast from patients with rheumatoid arthritis

GEF Cytohesin-2/ARNO: a novel bridge between cell migration and immunoregulation in synovial fibroblasts

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