THU0081 MIR-17-5P REDUCES INFLAMMATION AND BONE EROSIONS IN COLLAGEN INDUCED ARTHRITIS MICE AND DIRECTLY TARGETS THE JAK-STAT PATHWAY IN RHEUMATOID ARTHRITIS FIBROBLAST-LIKE SYNOVIOCYTES
| Autor: | Ursula Fearon, Benjamin Ory, Frédéric Blanchard, P. Preuss, Steven Georges, B. Le Goff, DJ Veale, Thibaut Quillard, F. M. Masson, Aurélie Najm |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Immunology Arthritis Inflammation General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Rheumatology medicine Immunology and Allergy STAT3 Autocrine signalling Fibroblast 030203 arthritis & rheumatology biology business.industry JAK-STAT signaling pathway Transfection medicine.disease 030104 developmental biology medicine.anatomical_structure Rheumatoid arthritis Cancer research biology.protein medicine.symptom business |
| Zdroj: | Annals of the Rheumatic Diseases. 79:252.2-253 |
| ISSN: | 1468-2060 0003-4967 |
| Popis: | Background:micro-RNAs (miR) are strong regulators of gene expression. Their involvement in RA key cytokines pathway regulation entitles them as important players in RA pathophysiology. The miR 17-92 cluster has been widely studied in cancer as they regulate cell apoptosis.Objectives:The aims of this study were to screen miR 17-92 cluster’s expression in different RA phenotypes (erosive and non erosive), further elucidate the mechanisms and direct targets involved in miR-17-5p anti-inflammatory role and to investigate miR-17-5p therapeutic effect in arthritis.Methods:A miR array was performed in synovial tissue from naïve erosive and non-erosive RA patients. Intra-articular delivery of miR-17 lipoplex was performed in collagen induced arthritis model in mice. Clinical, histological and structural effects were studied over the course of arthritis. In depth studies of miR-17 mechanisms of action were performed in primary RA-FLS isolated from RA synovial tissue.Results:Among others, miR-17-5p expression was reduced in erosive RA. miR-17 transfection in arthritic paws significantly reduced clinical inflammation. Moreover, synovial B cells, T cells, macrophages and polynuclear neutrophils infiltrates were significantly reduced. Structural damage was also decreased as shown by a reduction in the number of osteoclasts and erosion score by CT analysis. Pro-inflammatory cytokines of the IL-6 family, STAT3 target genes and IL-1β expression were also significantly reduced, but not TNF-alpha. miR17 directly targeted the 3’-untranslated region of STAT3 and JAK1. STAT3 and JAK1 mRNA and protein expression were reduced in RA-FLS following miR-17 transfection. STAT3 and JAK1 mRNA and activation of STAT3 as assessed by immunohistochemistry were also reduced in injected paws.Conclusion:We demonstrate an anti-inflammatory and anti-erosive role of miR-17 in vivo. This effect involves the suppression of the IL-6 family autocrine amplifying loop through the direct targeting of JAK1 and STAT3 as shown in RA-FLS.FigureEffect of miR-17 lipoplex injection in Collagen induced arthritis (CIA) mice’s ankles.Disclosure of Interests:None declared |
| Databáze: | OpenAIRE |
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