Open AccessThe transcriptional response of normal and rheumatoid arthritis synovial fibroblasts to hypoxia
Author(s) -
Del Rey Manuel J.,
Izquierdo Elena,
Usategui Alicia,
Gonzalo Elena,
Blanco Francisco J.,
Acquadro Francesco,
Pablos José L.
Publication year - 2010
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.27750
Subject(s) - hypoxia (environmental) , microarray analysis techniques , gene expression , angiogenesis , biology , gene expression profiling , arthritis , pathogenesis , rheumatoid arthritis , transcription factor , microarray , proinflammatory cytokine , hypoxia inducible factors , gene , inflammation , cancer research , immunology , chemistry , genetics , organic chemistry , oxygen
Objective Hypoxia is a prominent feature in rheumatoid arthritis (RA) synovium. However, its contribution to the pathogenesis of RA remains unclear. We undertook this study to systematically characterize the changes in gene expression induced by hypoxia in synovial fibroblasts. Methods We used microarray expression profiling in paired normoxic and hypoxic cultures of healthy synovial fibroblasts (HSFs) and RA synovial fibroblasts (RASFs). We used Student's paired t ‐test with Benjamini and Hochberg multiple testing correction to determine statistical significance. Validation of microarray data was performed by quantitative real‐time reverse transcription–polymerase chain reaction analysis of selected genes. Biologic pathways differentially modulated by hypoxia in RASFs or HSFs were identified using unsupervised Ingenuity Pathways Analysis. Results Hypoxia induced significant changes in the expression of a large group of genes in both HSFs and RASFs. In RASFs, we observed a lower number of hypoxia‐regulated genes and partial differences in their functional categories. The number of differentially expressed genes in RASFs compared with HSFs was significantly increased by hypoxia. Multiple gene sets involved in energy metabolism, intracellular signal transduction, angiogenesis, and immune and inflammatory pathways were significantly modified, the last in both proinflammatory and antiinflammatory directions. Conclusion These data demonstrate that hypoxia induces significant changes in gene expression in HSFs and RASFs and identify differences between RASF and HSF profiles. The hypoxia‐induced gene expression program in synovial fibroblasts identifies new factors and pathways relevant to understanding their contribution to the pathogenesis of chronic arthritis.