SAT0050 TNF-α INDUCES MITOPHAGY FORMATION IN RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLAST AND INHIBITION OF MITOPHAGY AMELIORATES SYNOVITIS IN COLLAGEN ANTIBODY-INDUCED ARTHRITIS
Authors: sang youn jung
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Rheumatoid arthritis (RA) is a systemic and chronic autoimmune disease that primarily targets synovial membranes. Mitophagy is a selective form of autophagy which removes damaged mitochondria. When mitochondria become damaged, PINK1 (PTEN-induced putative kinase 1) is accumulated on the outer membrane of damaged mitochondria and induces mitophagy. The study of mitophagy in lung fibrosis and parkinson's diseases has recently been described. However, the role of mitophagy in RA has not been reported yet. <h3>Objectives:</h3> The aim of this study was to determine the roles of mitophagy in rheumatoid arthritis synovial fibroblast (RASF) and collagen antibody-induced arthritis (CAIA) mice model. <h3>Methods:</h3> We studied the mitophagy marker, PINK1, in RASF treated with TNF-a by western blotting and immunofluorescence. Arthritis was induced in PINK1 knockout mice by intraperitoneal (i.p.) injection of anti-type II collagen antibody cocktail, followed by i.p injection of lipopolysaccharide. The severity of rheumatoid arthritis was histopathologically assessed <h3>Results:</h3> PINK1 expression and damaged mitochondria increased in RASF treated with TNF-α. TNF-α produced Intracellular ROS in RASF and mitophagy was regulated by ROS. PINK1 knockdown RASF decreased migration and invasion function. Histopathological examination revealed that the paws from PINK1-knockout mice showed markedly reduced swelling and inflammation compared with those of wild type mice <h3>Conclusion:</h3> Taken together, the results suggest that regulation of PINK1 expression in RA may represent potential therapeutic and diagnostic targets for RA <h3>References</h3> [1] Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford). 2006;45(6):669-75. [2] Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. The New England journal of medicine. 2001;344(12):907-16. [3] McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. The New England journal of medicine. 2011;365(23):2205-19. [4] Connor AM, Mahomed N, Gandhi R, Keystone EC, Berger SA. TNFalpha modulates protein degradation pathways in rheumatoid arthritis synovial fibroblasts. Arthritis research &amp; therapy. 2012;14(2):R62. [5] Rinaldi N, Schwarz-Eywill M, Weis D, Leppelmann-Jansen P, Lukoschek M, Keilholz U, et al. Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. Annals of the rheumatic diseases. 1997;56(1):45-51. [6] Bueno M, Lai YC, Romero Y, Brands J, St Croix CM, Kamga C, et al. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. The Journal of clinical investigation. 2015;125(2):521-38. [7] Ding WX, Yin XM. Mitophagy: mechanisms, pathophysiological roles, and analysis. Biological chemistry. 2012;393(7):547-64. <h3>Acknowledgement:</h3> This research was supported by the Basic Research Program through the National Research Foundation of Korea (NRF) funded by the MSIP (2014R1A1A1004857) <h3>Disclosure of Interests:</h3> None declared