Promising targets and drugs in rheumatoid arthritis

Li, Xingyan; Yang, Yong; Sun, Guozhe; Dai, Wanwu; Xing, Jie; Du, Yi; Huang, Runjie; Zhang, Jiaming

doi:10.1302/2046-3758.98.bjr-2019-0301.r1

Cited by 19 publications

(4 citation statements)

References 56 publications

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“…Our novel finding suggests a central role of KLHDC7B-DT in LN disease activity. The third lncRNA, FAM30A, has previously been detected to interact with hub genes in a WGCNA analysis of a rheumatoid arthritis study (59), with our study revealing a similar central role of FAM30A in LN for the first time. Lastly, MIR600HG has been shown in a recent study to be differentially expressed between SLE patients and HC (60).…”

Section: Discussionsupporting

confidence: 76%

A network-based approach reveals long non-coding RNAs associated with disease activity in lupus nephritis: key pathways for flare and potential biomarkers to be used as liquid biopsies

Sentis,

Loukogiannaki,

Malissovas

et al. 2023

Front. Immunol.

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ObjectiveA blood-based biomarker is needed to assess lupus nephritis (LN) disease activity, minimizing the need for invasive kidney biopsies. Long non-coding RNAs (lncRNAs) are known to regulate gene expression, appear to be stable in human plasma, and can serve as non-invasive biomarkers.MethodsTranscriptomic data of whole blood samples from 74 LN patients and 20 healthy subjects (HC) were analyzed to identify differentially expressed (DE) lncRNAs associated with quiescent disease and flares. Weighted gene co-expression network analysis (WGCNA) was performed to uncover lncRNAs with a central role (hub lncRNAs) in regulating key biological processes that drive LN disease activity. The association of hub lncRNAs with disease activity was validated using RT-qPCR on an independent cohort of 15 LN patients and 9 HC. cis- and trans-targets of validated lncRNAs were explored in silico to examine potential mechanisms of their action.ResultsThere were 444 DE lncRNAs associated with quiescent disease and 6 DE lncRNAs associated with flares (FDR <0.05). WGCNA highlighted IFN signaling and B-cell activity/adaptive immunity as the most significant processes contributing to nephritis activity. Four disease-activity-associated lncRNAs, namely, NRIR, KLHDC7B-DT, MIR600HG, and FAM30A, were detected as hub genes and validated in an independent cohort. NRIR and KLHDC7B-DT emerged as potential key regulators of IFN-mediated processes. Network analysis suggests that FAM30A and MIR600HG are likely to play a central role in the regulation of B-cells in LN through cis-regulation effects and a competing endogenous RNA mechanism affecting immunoglobulin gene expression and the IFN-λ pathway.ConclusionsThe expression of lncRNAs NRIR, KLHDC7B-DT, FAM30A, and MIR600HG were associated with disease activity and could be further explored as blood-based biomarkers and potential liquid biopsy on LN.

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Section: Discussionsupporting

confidence: 76%

A network-based approach reveals long non-coding RNAs associated with disease activity in lupus nephritis: key pathways for flare and potential biomarkers to be used as liquid biopsies

Sentis,

Loukogiannaki,

Malissovas

et al. 2023

Front. Immunol.

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“…Previous studies have also shown a significant reduction in arthritis severity and migration of Th17 cells to joints following the use of monoclonal antibodies against CCR6 [ 55 ]. HLA-DPA1 was identified as a common drug target for both Sjogren's syndrome and multiple sclerosis in a previous study [ 56 ], while another study more directly by weighted gene co-expression network (WGCNA) and linkage map (CMap) of illustrating HLA-DPA1 as a drug target for RA [ 57 ]. HLA-DRB1 is a recognised susceptibility-associated gene [ 58 ] with the strongest association with autoantibody-positive RA [ 59 , 60 ] and the HLA-DRB1*13 allele was found to confer strong protection against RA [ 61 ], which is consistent with the results of this study.IFNGR2 is a known causally associated gene for RA [ 62 ] and has also been identified as a potential target for the autoimmune disease, psoriasis [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of potential drug targets for rheumatoid arthritis from genetic insights: a Mendelian randomization study

Cao,

Yang,

et al. 2023

J Transl Med

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Introduction Rheumatoid arthritis (RA) is a chronic inflammatory illness that mostly affects the joints of the hands and feet and can reduce life expectancy by an average of 3 to 10 years. Although tremendous progress has been achieved in the treatment of RA, a large minority of patients continue to respond poorly to existing medications, owing in part to a lack of appropriate therapeutic targets. Methods To find therapeutic targets for RA, a Mendelian randomization (MR) was performed. Cis-expression quantitative trait loci (cis-eQTL, exposure) data were obtained from the eQTLGen Consortium (sample size 31,684). Summary statistics for RA (outcome) were obtained from two largest independent cohorts: sample sizes of 97,173 (22,350 cases and 74,823 controls) and 269,377 (8279 cases and 261,098), respectively. Colocalisation analysis was used to test whether RA risk and gene expression were driven by common SNPs. Drug prediction and molecular docking was further used to validate the medicinal value of drug targets. Results Seven drug targets were significant in both cohorts in MR analysis and supported by localization. PheWAS at the gene level showed only ATP2A1 associated with other traits. These genes are strongly associated with immune function in terms of biological significance. Molecular docking showed excellent binding for drugs and proteins with available structural data. Conclusion This study identifies seven potential drug targets for RA. Drugs designed to target these genes have a higher chance of success in clinical trials and is expected to help prioritise RA drug development and save on drug development costs.

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“…Differentially expressed transcripts were defined by the criteria of |log 2 (fold change)| > 1 (|log 2 FC| > 1) and FDR < 0.05 for mRNA and lncRNA, p -value < 0.05 for miRNA and circRNA, respectively. The expression of transcripts was visualized by the R package pheatmap (v1.0.12) ( Li et al, 2020 ). Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by the R package clusterProfiler (v3.11) ( Yu et al, 2012 ).…”

Section: Methodsmentioning

confidence: 99%

Whole Transcriptome Mapping Identifies an Immune- and Metabolism-Related Non-coding RNA Landscape Remodeled by Mechanical Stress in IL-1β-Induced Rat OA-like Chondrocytes

et al. 2022

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Background: Osteoarthritis (OA) is a common degenerative joint disease. The aims of this study are to explore the effects of mechanical stress on whole transcriptome landscape and to identify a non-coding transcriptome signature of mechanical stress.Methods: Next-generation RNA sequencing (RNA-seq) was performed on IL-1β-induced OA-like chondrocytes stimulated by mechanical stress. Integrated bioinformatics analysis was performed and further verified by experimental validations.Results: A total of 5,022 differentially expressed mRNAs (DEMs), 88 differentially expressed miRNAs (DEMIs), 1,259 differentially expressed lncRNAs (DELs), and 393 differentially expressed circRNAs (DECs) were identified as the transcriptome response to mechanical stress. The functional annotation of the DEMs revealed the effects of mechanical stress on chondrocyte biology, ranging from cell fate, metabolism, and motility to endocrine, immune response, and signaling transduction. Among the DELs, ∼92.6% were identified as the novel lncRNAs. According to the co-expressing DEMs potentially regulated by the responsive DELs, we found that these DELs were involved in the modification of immune and metabolism. Moreover, immune- and metabolism-relevant DELs exhibited a notable involvement in the competing endogenous RNA (ceRNA) regulation networks. Silencing lncRNA TCONS_00029778 attenuated cellular senescence induced by mechanical stress. Moreover, the expression of Cd80 was elevated by mechanical stress, which was rescued by silencing TCONS_00029778.Conclusion: The transcriptome landscape of IL-1β-induced OA-like chondrocytes was remarkably remodeled by mechanical stress. This study identified an immune- and metabolism-related ncRNA transcriptome signature responsive to mechanical stress and provides an insight of ncRNAs into chondrocyte biology and OA.

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Promising targets and drugs in rheumatoid arthritis

Cited by 19 publications

References 56 publications

A network-based approach reveals long non-coding RNAs associated with disease activity in lupus nephritis: key pathways for flare and potential biomarkers to be used as liquid biopsies

A network-based approach reveals long non-coding RNAs associated with disease activity in lupus nephritis: key pathways for flare and potential biomarkers to be used as liquid biopsies

Identification of potential drug targets for rheumatoid arthritis from genetic insights: a Mendelian randomization study

Whole Transcriptome Mapping Identifies an Immune- and Metabolism-Related Non-coding RNA Landscape Remodeled by Mechanical Stress in IL-1β-Induced Rat OA-like Chondrocytes

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