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

Wang, Xing; Fan, Danping; Cao, Xiaoxue; Ye, Qinbin; Wang, Qiong; Zhang, Mengxiao; Xiao, Cheng

doi:10.3390/antiox11061153

Cited by 58 publications

(35 citation statements)

References 216 publications

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“…Epidemiologic, biologic, environmental, and genetic human studies, as well as animal models, have implicated oxidative stress in the pathogenesis of RA [125]. Consistent with that conclusion, impairments of antioxidative defense system [126], increased ROS formation, and oxidative damage to biomolecules have all been identified in serum and synovial fluids of RA patients [127,128] and in animal models [129]. Furthermore, biomarkers of oxidative stress have been found to correlate with higher disease activity [130], whereas interventions with products rich in antioxidants have produced disease amelioration [131][132][133].…”

Section: Reactive Intermediates Oxidative Stress and The Interplay Wi...mentioning

confidence: 58%

Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases

Scavuzzi

Holoshitz

2022

Antioxidants

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Background: The endoplasmic reticulum (ER) is a multi-functional organelle responsible for cellular homeostasis, protein synthesis, folding and secretion. It has been increasingly recognized that the loss of ER homeostasis plays a central role in the development of autoimmune inflammatory disorders, such as rheumatic diseases. Purpose/Main contents: Here, we review current knowledge of the contribution of ER stress to the pathogenesis of rheumatic diseases, with a focus on rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We also review the interplay between protein folding and formation of reactive oxygen species (ROS), where ER stress induces oxidative stress (OS), which further aggravates the accumulation of misfolded proteins and oxidation, in a vicious cycle. Intervention studies targeting ER stress and oxidative stress in the context of rheumatic diseases are also reviewed. Conclusions: Loss of ER homeostasis is a significant factor in the pathogeneses of RA and SLE. Targeting ER stress, unfolded protein response (UPR) pathways and oxidative stress in these diseases both in vitro and in animal models have shown promising results and deserve further investigation.

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Section: Reactive Intermediates Oxidative Stress and The Interplay Wi...mentioning

confidence: 58%

Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases

Scavuzzi

Holoshitz

2022

Antioxidants

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“…From a pathogenic perspective, the multifactoriality and polygenicity of OA recognize, in the exacerbation of oxidative stress and in the overproduction of ROS, an essential common denominator [ 80 ]. The increased production of ROS can damage joint structural biomolecules, and ROS, as an intracellular signaling component, is associated with the induction of numerous pro-inflammatory genes and inflammation-related events in OS, including the infiltration of inflammatory cells, angiogenesis, and osteophyte formation [ 81 , 82 ]. As a result, many efforts have been made to find therapeutics that intercept/reduce the formation of ROS.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Anti-Inflammatory and Anti-Osteoarthritic Potential of Flonat Fast®, a Combination of Harpagophytum Procumbens DC. ex Meisn., Boswellia Serrata Roxb., Curcuma longa L., Bromelain and Escin (Aesculus hippocastanum), Evaluated in In Vitro Models of Inflammation Relevant to Osteoarthritis

et al. 2022

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Osteoarthritis (OA) is a joint disease characterized by inflammation of the synovium, angiogenesis, cartilage degradation, and osteophyte formation. Harpagophytum Procumbens DC. ex Meisn., Boswellia Serrata Roxb., Curcuma longa L., Bromelain and Escin (Aesculus hippocastanum) are plants which extracts, together to Bromelain and Escin (Aesculus hippocastanum) are traditionally used in OA. However, their mechanistic role remains unclear. We aimed to investigate whether these bioactives alone or in combination (as in Flonat Fast®) can suppress TNF-α-induced inflammation, angiogenesis, and osteophyte formation using two cell models involved in OA: endothelial cells and monocytes. Each plant extract was evaluated for its polyphenol content, antioxidant activity, and toxicity. In endothelial cells and monocytes, expression of genes involved in OA was assessed, functional assays for inflammation and angiogenesis were performed, and impairment of reactive oxygen species production (ROS) was evaluated. Exposure of cells to the bioactives alone and in combination before cytokine stimulation resulted in differential counterregulation of several gene and protein expressions, including those for cyclooxygenases-2, metalloproteinase-9, transforming growth factor β1, and bone morphogenic protein-2. We demonstrated that these bioactives modulated monocyte adhesion to endothelial cells as well as cell migration and endothelial angiogenesis. Consistent with radical scavenging activity in the cell-free system, the bioactives curbed TNF-α-stimulated intracellular ROS production. We confirmed the potential anti-inflammatory and antiangiogenic effects of the combination of Harpagophytum procumbens, Boswellia, Curcuma, Bromelain, and Escin and provided new mechanistic evidence for their use in OA. However, further clinical studies are needed to evaluate the true clinical utility of these bioactives as supportive, preventive, and therapeutic agents.

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“…RA is characterized by extensive infiltration of immune cells in the synovium, synovial hyperplasia, joint inflammation and excessive pro-inflammatory cytokine production. Oxidative stress caused by increased production of reactive oxygen species (ROS) and inflammatory cytokines contributes to the pathogenesis of RA (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in microRNA binding site of SET8 regulate the risk of rheumatoid arthritis

et al. 2023

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Rheumatoid arthritis (RA) is a complex, heterogeneous, progressive and long-term autoimmune disease characterized by symmetrical joint inflammation and bone erosion. The etiology of RA is unclear, but its pathogenesis is associated with oxidative stress and inflammatory cytokines. Single nucleotide polymorphisms (SNPs) in the microRNA (miRNA)-binding sites modify the development of rheumatic disease by regulating the expression of target genes. The present study investigated whether SNPs in the miRNA binding site in the 3' untranslated region (3'-UTR) of SET domain containing lysine methyltransferase) 8 (SET8) and Keratin 81 (KRT81), namely rs16917496 and rs3660, respectively, were associated with the occurrence of RA. The polymerase chain reaction-ligase detection reaction assay showed that the distribution frequencies of the CC genotype (P=0.025) of SNP rs16917496 in SET8 were significantly higher in patients with RA than in healthy controls, which indicated that the CC genotype was associated with an increased risk of RA. SET8 expression in the blood samples of CC genotype carriers was lower than that of TT genotype carriers. Moreover, the CC genotype carriers exhibited higher reactive oxygen species (ROS) levels (1011.500±536.426 vs. 548.616±190.508, P=0.032) and lower interleukin-10 (IL-10) levels (P<0.001). The present study demonstrated that SNP rs16917496 in the 3'-UTR of SET8 was a predictor of RA risk and may regulate RA development by mediating expression of SET8, thereby regulating the levels of ROS and IL-10.

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

Cited by 58 publications

References 216 publications

Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases

Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases

Polymorphisms in microRNA binding site of SET8 regulate the risk of rheumatoid arthritis

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