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Impaired ATM Activation in B Cells Promotes Osteoclastogenic Cytokine Production and Bone Erosion in Patients with Rheumatoid Arthritis

ABSTRACT: Impaired ATM Activation in B Cells Promotes Osteoclastogenic Cytokine Production and Bone Erosion in Patients with Rheumatoid Arthritis

PROVIDER: PRJNA549247 | ENA |

REPOSITORIES: ENA

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Impaired ATM Activation in B Cells Promotes Osteoclastogenic Cytokine Production and Bone Erosion in Patients with Rheumatoid Arthritis

Project description:Rheumatoid arthritis (RA) patients may display atypical CD21-/lo B cells in their blood but the significance of this observation remains unclear. We report here that the group of RA patients with elevated frequencies of CD21-/lo B cells shows decreased ataxia-telangiectasia mutated (ATM) expression and activation in B cells compared with other RA patients and healthy donor controls. In agreement with ATM involvement in the regulation of V(D)J recombination, RA patients with defective ATM function displayed a skewed B cell receptor (BCR) Igk repertoire, which resembled that of ataxia-telangiectasia (AT) patients. This repertoire was characterized by increased Jk1 and decreased upstream Vk gene segment usage, suggesting improper secondary recombination processes and selection. In addition, altered ATM function in B cells was associated with decreased osteoprotegerin (OPG) and increased RANKL production. These changes favor bone loss and correlated with a higher prevalence of erosive disease in RA patients with impaired ATM function. Using a humanized mouse model, we also show that ATM inhibition in vivo induces an altered Igk repertoire and RANKL production by immature B cells in the bone marrow, leading to decreased bone density. We conclude that dysregulated ATM function in B cells promotes bone erosion and the emergence of circulating CD21-/lo B cells, thereby contributing to RA pathophysiology.

2019-11-23 | GSE132832 | GEO

IL-1β–driven osteoclastogenic Tregs accelerate bone erosion in arthritis

Project description:IL-1β–driven osteoclastogenic Tregs accelerate bone erosion in arthritis

| PRJNA759793 | ENA

Transcriptomic characterization of classical monocytes highlights the involvement of immuno-inflammation in bone erosion in Rheumatoid Arthritis

Project description:Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with localized bone involvement characterized by the presence of bone erosions. Evidence-based data suggest that under inflammatory conditions, classical monocytes are the main source of osteoclasts and might be involved in bone erosion pathophysiology. Here, we analyze the transcriptomic profile of classical monocytes in erosive and non-erosive rheumatoid arthritis patients in order to better understand their contribution to bone erosion. Thirty-nine premenopausal RA patients and 20 healthy age-matched women were recruited for this study. Classical monocytes were isolated from peripheral blood through negative selection. Sequencing library was constructed using the Quant-seq® 30 mRNA-Seq Library Prep Kit (Lexogen®) and sequenced using an Illumina Seq 2500 platform (Illumina®). Differential expression analysis was performed between patients and control groups. Therefore, gene sets analysis was performed to identify the enriched biological pathways. Results suggested that alterations in pathways related to the inflammatory process and impairment of bone formation have an important role in the pathophysiology of bone erosions in patients with rheumatoid arthritis.

2023-09-19 | E-MTAB-13361 | biostudies-arrayexpress

Transcription profiling of mouse osteoclastogenic splenocytes

Project description:Effect of c-fos expression in osteoclastogenic splenocytes.

2008-06-15 | E-GEOD-676 | biostudies-arrayexpress

Transcriptome Analysis of Synovial CD14+ cells in Rheumatoid Arthritis Patients

Project description:To understand the pathogenic mechanisms of bone erosion in rheumatoid arthritis (RA), we investigated osteoclast-specific epigenetic programs, RANKL-responsive super-enhancers (SEs) and SE-associated enhancer RNAs (SE-eRNAs) in human osteoclasts. In this dataset, we sought for functional SE-eRNAs in RA patients' synovial monocytes.

2022-11-01 | GSE203357 | GEO

Effect of c-fos expression in osteoclastogenic splenocytes

Project description:Effect of c-fos expression in osteoclastogenic splenocytes. Keywords: other

2004-09-19 | GSE676 | GEO

Monocytic MDSCs skew Th17 cells toward a pro-osteoclastogenic phenotype and potentiate bone erosion in rheumatoid arthritis.

Project description:ObjectivesWhile myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown.MethodsWe investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs.ResultsHuman MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice.ConclusionOur findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.

| S-EPMC8121448 | biostudies-literature

Comparison of saliva from healthy and patients with dental erosion

Project description:To compare the salivary proteins from healthy and dental erosion patients to determine if there is an absence of proteins forming the enamel pellicle that may reduce their protection from acid erosion

2023-05-10 | PXD035565 | Pride

Transcriptomic characterization of classical monocytes highlights the involvement of immuno-inflammation in bone erosion in Rheumatoid Arthritis

Project description:Transcriptomic characterization of classical monocytes highlights the involvement of immuno-inflammation in bone erosion in Rheumatoid Arthritis

| PRJEB66223 | ENA

IL-1β-driven osteoclastogenic Tregs accelerate bone erosion in arthritis.

Project description:IL-1β is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1β contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1β blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1β accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1β-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.

| S-EPMC8439607 | biostudies-literature

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