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Background: Smad7 is protective in a mouse model of rheumatoid arthritis. Here we investigated whether Smad7-expressing CD4 + T cells and the methylation of Smad7 gene in CD4 + T cells contribute to the disease activity of RA in patients., Methods: Peripheral CD4 + T cells were collected from 35 healthy controls and 57 RA patients. Smad7 expression by CD4 + T cells were determined and correlated with the clinical parameters of RA including RA score and serum levels of IL-6, CRP, ESR, DAS28-CRP, DAS28-ESR, Swollen joints and Tender joints. Bisulfite sequencing (BSP-seq) was used to determine the DNA methylation in Smad7 promoter (-1000 to +2000) region in CD4 + T cells. In addition, a DNA methylation inhibitor, 5-Azacytidine (5-AzaC), was added to CD4 + T cells to examine the possible role of Smad7 methylation in CD4 + T cell differentiation and functional activity., Results: Compared to the heath controls, Smad7 expression was significantly decreased in CD4 + T cells from RA patients and inversely correlated with the RA activity score and serum levels of IL-6 and CRP. Importantly, loss of Smad7 in CD4 + T cell was associated with the alteration of Th17/Treg balance by increasing Th17 over the Treg population. BSP-seq detected that DNA hypermethylation occurred in the Smad7 promoter region of CD4 + T cells obtained from RA patients. Mechanistically, we found that the DNA hypermethylation in the Smad7 promoter of CD4 + T cells was associated with decreased Smad7 expression in RA patients. This was associated with overreactive DNA methyltransferase (DMNT1) and downregulation of the methyl-CpG binding domain proteins (MBD4). Inhibition of DNA methylation by treating CD4 + T cells from RA patients with 5-AzaC significantly increased Smad7 mRNA expression along with the increased MBD4 but reduced DNMT1 expression, which was associated with the rebalance in the Th17/Treg response., Conclusion: DNA hypermethylation at the Smad7 promoter regions may cause a loss of Smad7 in CD4 + T cells of RA patients, which may contribute to the RA activity by disrupting the Th17/Treg balance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hu, Xu, He, Shan, Zhou, Wang, Bai, Shang, Nie, Pan, Lan and Wang.)

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease. We previously revealed that the natural compound artemisitene (ATT) exhibits excellent broad anticancer activities without toxicity on normal tissues. Nevertheless, the effect of ATT on RA is undiscovered. Herein, we aim to study the effect and potential mechanism of ATT on RA management., Methods: A collagen-induced arthritis (CIA) mouse model was employed to confirm the anti-RA potential of ATT. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, cell cycle and apoptosis analysis, immunofluorescence, migration and invasion assays, quantitative real-time PCR (RT-qPCR), Western blot, RNA-sequencing (RNA-seq) analysis, plasmid construction and lentivirus infection, and methylated RNA immunoprecipitation and chromatin immunoprecipitation assays, were carried out to confirm the effect and potential mechanism of ATT on RA management., Results: ATT relieved CIA in mice. ATT inhibited proliferation and induced apoptosis of RA-fibroblast-like synoviocytes (FLSs). ATT restrained RA-FLSs migration and invasion via suppressing epithelial-mesenchymal transition. RNA-sequencing analysis and bioinformatics analysis identified intercellular adhesion molecule 2 (ICAM2) as a promoter of RA progression in RA-FLSs. ATT inhibits RA progression by suppressing ICAM2/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/p300 pathway in RA-FLSs. Moreover, ATT inhibited methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine methylation of ICAM2 mRNA in RA-FLSs. Interestingly, p300 directly facilitated METTL3 transcription, which could be restrained by ATT in RA-FLSs. Importantly, METTL3, ICAM2 and p300 expressions in synovium tissues of RA patients were related to clinical characteristics and therapy response., Conclusions: We provided strong evidence that ATT has therapeutic potential for RA management by suppressing proliferation, migration and invasion, in addition to inducing apoptosis of RA-FLSs through modulating METTL3/ICAM2/PI3K/AKT/p300 feedback loop, supplying the fundamental basis for the clinical application of ATT in RA therapy. Moreover, METTL3, ICAM2 and p300 might serve as biomarkers for the therapy response of RA patients., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Rheumatoid arthritis (RA) is a common disease worldwide and is treated commonly with methotrexate (MTX). CS12192 is a novel JAK3 inhibitor discovered by Chipscreen Biosciences for the treatment of autoimmune diseases. In the present study, we examined the therapeutic effect of CS12192 against RA and explored if the combinational therapy of CS12192 and MTX produced a synergistic effect against RA in rat collagen-induced arthritis (CIA). Arthritis was induced in male Sprague-Dawley rats by two intradermal injections of bovine type II collagen (CII) and treated with MTX, CS12192, or the combination of CS12192 and MTX daily for two weeks. Effects of different treatments on arthritis score, X-ray score, pathology, and expression of inflammatory cytokines and biomarkers were examined. We found that treatment with either CS12192 or MTX produced a comparable therapeutic effect on CIA including: (1) significantly lowering the arthritis score, X-ray score, serum levels of rheumatic factor (RF), C-reactive protein (CRP), and anti-nuclear antibodies (ANA); (2) largely alleviating histopathological damage, reducing infiltration of Th17 cells while promoting Treg cells; (3) inhibiting the expression of inflammatory cytokines and chemokines such as IL-1β, TNF-α, IL-6, CCL2, and CXCL1. All these inhibitory effects were further improved by the combinational therapy with MTX and CS12192. Of importance, the combinational treatment also resulted in a marked switching of the Th17 to Treg and the M1 to M2 immune responses in synovial tissues of CIA. Thus, when compared to the monotherapy, the combination treatment with CS12192 and MTX produces a better therapeutic effect against CIA with a greater suppressive effect on T cells and macrophage-mediated joint inflammation.

This research was designed to investigate the fracture healing pattern in a rheumatoid arthritis (RA) rat model. A mid-shaft femur fracture (RA + F) model and normal fracture (NF) model as control were established. Micro-CT, H&E staining, TB staining, SO staining, tartrate-resistant acid phosphates, and immunohistochemistry test were performed. In the micro-CT images and H&E stains, fracture gaps were evident in the RA + F group 4 and 8 weeks after fracture. In detail, the bone mineral density, the ratio of bone volume to tissue volume, and trabecular thickness of the RA + F group were significantly lower than those of the NF group at all time points. Trabecular number value was significantly lower in the RA + F group 4 weeks after surgery in comparison with that of the NF group. Furthermore, the structure model index test result of the RA + F group was significantly higher than that of the NF group at all time points. TB staining and SO staining test results showed that the NF group had more cartilaginous callus in the earlier stage of bone healing process (4 weeks), and less cartilage callus formation in the later stage (8 weeks) in comparison with that of the RA + F group. Osteoclasts statistics score in the NF group were obviously lower than that of the RA + F group at all time points. MMP-3 and OPN protein levels of the fracture area in the RA + F group were significantly higher than those in the NF group. This study improves the understanding of the bone healing characteristics in patients with RA. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2876-2885, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

The hypoxic microenvironment is a clinicopathological characteristic of many diseases, such as rheumatoid arthritis (RA). As a transcription factor activating the gene expression involved in processes such as cell metabolism and angiogenesis, hypoxia-inducible factor (HIF) has a central function in adaption to altered oxygen tension and even contributes to the progression of related diseases. In RA, HIF induces angiogenesis, cell migration, and cartilage destruction, inhibits the apoptosis of synovial cells and inflammatory cells and initiates glycolysis for energy supply by upregulating specific protein levels. HIF expression in RA can be regulated in both oxygen-dependent and independent fashions, leading to the aggravation of this disease. Therefore, HIF is one of the vital RA mediators. Based on the application of HIF-targeted drug research and development in tumors, HIF is a potential therapeutic target for treating RA.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs. Without treatment, inflammation leads to cartilage damage, bone erosions, joint destruction, and impaired movement. Because of the limited success of disease-modifying anti-rheumatic drugs, the exploration of new anti-rheumatic drugs with high efficacy and less toxicity is eagerly needed. Genistein, the major active compound from soybean, has received much attention due to its potential beneficial effects on some of the degenerative diseases. It has been found that genistein has anti-inflammatory, antiangiogenesis, antiproliferative, antioxidant, immunomodulatory, pain relief, and joint protection properties. Hence, significant advances have been made, both by in vitro and in vivo studies showing that genistein is a promising agent for RA treatment.

At present, rheumatoid arthritis (RA) is considered a type of autoimmune disease. Its pathology is not certain, and effective drugs with less toxicity have not been established. The establishment and application of animal models are effective methods for RA research, especially using animal models similar to humans. Arthritis is more heterogeneous, and this is an important starting point when discussing animal models for arthritis. Animal models are instrumental in understanding the etiology and pathogenetic mechanisms of RA. Appropriate animal models should be selected according to experiments because they have different traits. Various methods have been applied to induce arthritis in animal experimental models, which have provided important insights into the etiopathogenetic mechanisms of human RA. This review was written to give a broad introduction of the current stage of RA model and hope to offer beneficial help for RA-related research.