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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis is a progressive and systemic autoimmune disease seriously compromises human health. Fibroblast like synoviocytes are the major effectors of proliferation and inflammation in rheumatoid arthritis synovial tissue. Shikonin has anti-inflammatory and immunomodulatory activities. But, its role on synovitis of rheumatoid arthritis is unknown. Methods: The DBA/1 male mice were randomly divided into the following three groups (n = 6): (1) the normal control group of mice, (2) the CIA (collagen-induced arthritis) group in which mice suffered from arthritis induced by collagen, (3) the SKN (shikonin) group of mice which got arthritis and given intragastrically with shikonin 4 mg/kg per day continuously for 20 days,(4) the MTX (methotrexate) group of mice which got arthritis and orally administration with shikonin 0.5 mg/kg once two days continuously for 20 days. The therapeutic effect of shikonin on collagen induced arthritis mice was tested by arthritis incidence rate, arthritis score and inflammatory joint histopathology. The invasion, adhesion and migration of fibroblast like synoviocytes induced by tumor necrosis factor-α were applied to measure the anti-synovitis role of shikonin. The effect of shikonin on expression of interleukin-6, interleukin-1β and tumor necrosis factor-α was measured by enzyme linked immunosorbent assay. The interaction between shikonin and suppressor of cytokine signaling 1 was verified by molecular docking. The signaling pathways activated by shikonin were measured by western blot. Results: Shikonin decreased the arthritis score and arthritis incidence, and inhibited inflammation of inflamed joints in collagen induced arthritis mice. And shikonin reduced the number of vimentin+cells in collagen induced arthritis mice inflamed joints. Meanwhile, shikonin suppressed tumor necrosis factor-α-induced invasion, adhesion and migration of fibroblast like synoviocytes and reduced the expression of interleukin-6, interleukin-1β and tumor necrosis factor-α. And we found that shikonin targeted suppressor of cytokine signaling 1. More interestingly, shikonin blocked the phosphorylation of Janus kinase 1/signal transducer andactivator of transcription 1/signal transducer andactivator of transcription 6 in synovial tissues and in fibroblast like synoviocytes. Conclusion: Shikonin represents a promising new anti-rheumatoid arthritis drug candidate that has anti-synovitis effect in collagen induced arthritis mice and inhibits tumor necrosis factor-α-induced fibroblast like synoviocytes by targeting suppressor of cytokine signaling 1/ Janus kinase/signal transducer andactivator of transcription signaling pathway. These findings demonstrate that shikonin has anti-synovitis effect and has great potential to be a new drug for the treatment of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]