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MicroRNA-340-5p suppressed rheumatoid arthritis synovial fibroblast proliferation and induces apoptotic cell number by targeting signal transducers and activators of transcription 3. Zhang Shibin,Meng Tingting,Tang Chunzhi,Li Shengdong,Cai Xudong,Wang Dawei,Chen Min Autoimmunity Rheumatoid arthritis is a chronic systemic autoimmune disease. In this study, the role of microRNA-340-5p in rheumatoid arthritis was investigated. qRT-PCR was used to detect the expression of microRNA-340-5p in serums, synovial tissues, and fibroblast-like synoviocytes from patients and healthy participants. Cell proliferation rate, cell cycle and apoptotic cell numbers were measured by CCK-8 and flow cytometry assays. The expression of pro-inflammation factors was determined by ELISA. Our data showed that the expression of microRNA-340-5p was greatly suppressed in rheumatoid arthritis serums, synovial tissues and rheumatoid arthritis-fibroblast-like synoviocytes compared to that in healthy controls. Over-expression of microRNA-340-5p greatly suppressed cell proliferation, promoted cell apoptosis, and suppressed the expression of inflammation factors in rheumatoid arthritis fibroblast-like synoviocytes. Additionally, STAT3 was a target of microRNA-340-5. Overexpression of STAT3 could reverse the outcome of microRNA-340-5p on cell proliferation and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes. The findings in our study demonstrated that microRNA-340-5p may serve as a potential target for therapeutic direction for patients with rheumatoid arthritis. 10.1080/08916934.2020.1793134
Differential DNA methylation correlates with response to methotrexate in rheumatoid arthritis. Nair Nisha,Plant Darren,Verstappen Suzanne M,Isaacs John D,Morgan Ann W,Hyrich Kimme L,Barton Anne,Wilson Anthony G, Rheumatology (Oxford, England) OBJECTIVES:Identifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX. METHODS:DNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study. RESULTS:In the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study. CONCLUSION:These data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks. 10.1093/rheumatology/kez411
Depletion of activated macrophages with a folate receptor-beta-specific antibody improves symptoms in mouse models of rheumatoid arthritis. Hu Yingwen,Wang Bingbing,Shen Jiayin,Low Stewart A,Putt Karson S,Niessen Hans W M,Matteson Eric L,Murphy Linda,Ruppert Clemens,Jansen Gerrit,Oliver Stephen J,Feng Yang,Dimitrov Dimiter S,Nickerson-Nutter Cheryl,Low Philip S Arthritis research & therapy OBJECTIVES:Most therapies for autoimmune and inflammatory diseases either neutralize or suppress production of inflammatory cytokines produced by activated macrophages (e.g., TNFα, IL-1, IL-6, IL-17, GM-CSF). However, no approved therapies directly target this activated subset of macrophages. METHODS:First, we undertook to examine whether the folate receptor beta (FR-β) positive subpopulation of macrophages, which marks the inflammatory subset in animal models of rheumatoid arthritis, might constitute the prominent population of macrophages in inflamed lesions in humans. Next, we utilized anti-FR-β monoclonal antibodies capable of mediating antibody-dependent cell cytotoxicity (ADCC) to treat animal models of rheumatoid arthritis and peritonitis. RESULTS:Human tissue samples of rheumatoid arthritis, Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, and scleroderma are all characterized by dramatic accumulation of macrophages that express FR-β, a protein not expressed on resting macrophages or any other healthy tissues. A monoclonal antibody to FR-β accumulates specifically in inflamed lesions of murine inflammatory disease models and successfully treats such models of rheumatoid arthritis and peritonitis. More importantly, elimination of FR-β-positive macrophages upon treatment with an anti-FR-β monoclonal antibody promotes the departure of other immune cells, including T cells, B cells, neutrophils, and dendritic cells from the inflamed lesions. CONCLUSIONS:These data suggest that specific elimination of FR-β-expressing macrophages may constitute a highly specific therapy for multiple autoimmune and inflammatory diseases and that a recently developed human anti-human FR-β monoclonal antibody (m909) might contribute to suppression of this subpopulation of macrophages. 10.1186/s13075-019-1912-0