THU0050 Hypoxia induces production of citrullinated proteins in human fibroblast-like synoviocytes through regulating hif1Α. (12th June 2018)

• Record Type: Journal Article
• Authors: Yu, R.; Li, C.; Sun, L.; Jian, L.; Ma, Z.; Zhao, J.; Liu, X.
• Is Part Of: Annals of the rheumatic diseases. Volume 77(2018)Supplement 2
• Page Start: 250
• Page End: 250
• Publication Date: 2018-06-12
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-eular.6626
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Hypoxia is a prominent microenvironment feature in a range of disorders including cancer, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel disease (IBD), infection and obesity. Hypoxia promotes biological functions of fibroblast-like synoviocytes via regulating hypoxia-inducible factor 1α (HIF1α). Dysregulated protein citrullination in RA drives the production of antibodies to citrullinated proteins, a highly specific biomarker of RA. However, the mechanisms promoting citrullination in RA are not yet fully elucidated. Objectives: In the present study, we investigated whether pathophysiological hypoxia as found in the rheumatoid synovium modulates the citrullination in human fibroblast-like synoviocytes (HFLS). Methods: HFLS were incubated in a hypoxic chamber (5% CO2 and 1% O2, balanced with N2 as indicated) or in a normal incubator containing 5% CO2 and approximately 20% O2 . The realtime quantitative PCR and western blotting were used to detect the expression of peptidylarginine deiminase 2, peptidylarginine deiminase 4 and citrullinated proteins. HFLS were transfected with HIF1α siRNA to block the HIF1α pathway. Results: In the present study, we found that peptidylarginine deiminase 2 (PAD2) and citrullinated proteins were increased in HFLS after exposed to hypoxia. Moreover, knocking down HIF1α by hif1α siRNA ameliorated the expression of PAD2 and citrullinated proteins. Conclusions: Collectively, the present study provide a new mechanism involved in generating citrullinated proteins: hypoxia promote citrullination and PAD production in HFLS. Concurrently, we also proposed a novel hypoxia involved mechanism in RA pathogenesis. The present study deepens our understanding of the role of hypoxia in the pathogenesis of RA and provides potential therapeutic strategy for RA. Acknowledgements: We thank Jiansheng Huang for providing language help and revising the manuscript. Disclosure of Interest: None declared