The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes

Taghadosi, Mahdi; Adib, Mehrnoosh; Jamshidi, Ahmadreza; Mahmoudi, Mahdi; Farhadi, Elham

doi:10.1007/s12026-021-09202-7

Cited by 30 publications

(23 citation statements)

References 103 publications

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“…Transition missense mutations are the most common type of p53 mutation (approximately 80%), and they are caused by nitric oxide deamination [ 54 ]. Because mutant p53 has a longer half-life, its expression in the synovium is increased in RA [ 55 ] and FLSs may be protected from apoptosis by dominant-negative p53 mutations, which may contribute to FLS invasiveness [ 56 ] ( Figure 2 ).…”

Section: Ros and Synovium Stromal Cellsmentioning

confidence: 99%

The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment

et al. 2022

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Rheumatoid arthritis (RA) is an inflammatory disease that begins with a loss of tolerance to modified self-antigens and immune system abnormalities, eventually leading to synovitis and bone and cartilage degradation. Reactive oxygen species (ROS) are commonly used as destructive or modifying agents of cellular components or they act as signaling molecules in the immune system. During the development of RA, a hypoxic and inflammatory situation in the synovium maintains ROS generation, which can be sustained by increased DNA damage and malfunctioning mitochondria in a feedback loop. Oxidative stress caused by abundant ROS production has also been shown to be associated with synovitis in RA. The goal of this review is to examine the functions of ROS and related molecular mechanisms in diverse cells in the synovial microenvironment of RA. The strategies relying on regulating ROS to treat RA are also reviewed.

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Section: Ros and Synovium Stromal Cellsmentioning

confidence: 99%

The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment

et al. 2022

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“…RA-FLS display tumor-like features, including enhanced cell growth and migration ability in vivo , which contribute to the pathogenesis of cartilage and bone destruction [ 26 ]. Recent studies showed that RA-FLS can spread from destructive arthritis to other distant joints via the vasculature in mice with severe combined immunodeficiency, suggesting the characteristic clinical phenomenon of destructive arthritis spreading between joints might occur through the transmigration of activated FLS [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog Promotes Proliferation and Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Rho/ROCK Signaling

Chen

Zhu

et al. 2022

Journal of Immunology Research

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Objective. To explore the underlying mechanism of the sonic hedgehog (Shh) signaling pathway in promoting cell proliferation and migration in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Method. FLS were collected from 8 patients with RA and 3 patients with osteoarthritis (OA). The expression of smoothened (Smo, the Shh pathway activator) was quantified by real-time PCR and western blot. FLS were incubated with cyclopamine (a Smo antagonist), purmorphamine (a Smo agonist), Y27632 (a Rho/ROCK signaling inhibitor), or a combination of purmorphamine and Y27632, respectively. Cell proliferation was examined using cell counting kit-8 and cell cycle assays while cell migration was measured with Transwell and wound healing assays. Results. The expression of Smo was higher in FLS from RA patients than from OA patients ( p < 0.05 ). RA-FLS treated with purmorphamine showed significantly activated proliferation (119.69 vs. 100.0) and migration (252.38 vs. 178.57) compared to untreated cells (both p < 0.001 ). RA-FLS incubated with cyclopamine or a combination of purmorphamine and Y27632 exhibited significant suppression of proliferation (81.55 vs. 100.0 and 85.84 vs. 100.0) and migration (100 vs. 178.57 and 109.52 vs. 185) ability (all p < 0.001 ). Conclusion. Our results demonstrated that Shh promoted cell growth and migration of FLS in RA patients through the Rho/ROCK signaling pathway.

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“…In addition, p53 loss can exert two more effects; it can enhance chronic inflammation by hyperactivation of NF-κB and can also promote angiogenesis which in turn can promote hyperplasia. 52 RNA editing–mediated effects on the p53 pathway could therefore potentially increase the severity of RA in multiple ways.…”

Section: Discussionmentioning

confidence: 99%

RNA Editing–Associated Post-Transcriptional Gene Regulation in Rheumatoid Arthritis

Ghanekar

Sadasivam

2022

Bioinform Biol Insights

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Background: Rheumatoid arthritis (RA) is an autoimmune disease characterised by systemic inflammation of joints. The observed complexity of RA pathogenesis and studies that have been carried out so far indicate that RA pathogenesis is regulated at multiple levels. Given the role of RNA editing in autoimmune disease, we hypothesised that RNA editing could contribute to RA pathogenesis by regulating gene expression through post-transcriptional mechanisms. Methods: We identified RNA editing events in synovial tissues from early and established RA compared with normal subjects from an available transcriptome data set using REDItools. To investigate the potential effect of these RNA editing events on gene expression, we carried out an analysis of differential exon usage in the vicinity of the differentially edited sites using DEXSeq. We then used STRING to identify putative interactions between differentially edited genes identified from REDItools analysis. We also investigated the possible effects of these RNA editing events on miRNA-target mRNA interactions as predicted by miRanda. Results: Our analysis revealed that there is extensive RNA editing in RA, with 304 and 273 differentially edited events in early RA and established RA, respectively. Of these, 25 sites were within 11 genes in early RA, and 34 sites were within 7 genes in established RA. DEXSeq analysis revealed that RNA editing correlated with differential exon usage in 4 differentially edited genes that have previously also been associated with RA in some measure: ATM, ZEB1, ANXA4, and TIMP3. DEXSeq analysis also revealed enrichment of some non-functional isoforms of these genes, perhaps at the expense of their full-length counterparts. Network analysis using STRING showed that several edited genes were part of the p53 protein-protein interaction network. We also identified several putative miRNA binding sites in the differentially edited genes that were lost upon editing. Conclusions: Our results suggested that the expression of genes involved in DNA repair and cell cycle, including ATM and ZEB1 which are well-known functional regulators of the DNA damage response pathway, could be regulated by RNA editing in RA synovia. This may contribute to an impaired DNA damage response in synovial tissues.

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The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes

Cited by 30 publications

References 103 publications

The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment

The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment

Sonic Hedgehog Promotes Proliferation and Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Rho/ROCK Signaling

RNA Editing–Associated Post-Transcriptional Gene Regulation in Rheumatoid Arthritis

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