title: Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis.
abstract: Synovial proliferation, neovascularization and leukocyte extravasation transform the normally acellular synovium into an invasive tumour-like 'pannus'. The highly dysregulated architecture of the microvasculature creates a poor oxygen supply to the synovium, which, along with the increased metabolic turnover of the expanding synovial pannus, creates a hypoxic microenvironment. Abnormal cellular metabolism and mitochondrial dysfunction thus ensue and, in turn, through the increased production of reactive oxygen species, actively induce inflammation. When exposed to hypoxia in the inflamed joint, immune-inflammatory cells show adaptive survival reactions by activating key proinflammatory signalling pathways, including those mediated by hypoxia-inducible factor-1α (HIF-1α), nuclear factor κB (NF-κB), Janus kinase-signal transducer and activator of transcription (JAK-STAT) and Notch, which contribute to synovial invasiveness. The reprogramming of hypoxia-mediated pathways in synovial cells, such as fibroblasts, dendritic cells, macrophages and T cells, is implicated in the pathogenesis of rheumatoid arthritis and other inflammatory conditions, and might therefore provide an opportunity for therapeutic intervention.
authors.affiliation: The Department of Molecular Rheumatology, Trinity College Dublin, The University of Dublin, College Green, Dublin 2, Ireland.|The Centre for Arthritis and Rheumatic Disease, Dublin Academic Medical Centre, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
authors.affiliation: The Centre for Arthritis and Rheumatic Disease, Dublin Academic Medical Centre, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: Canavan
authors.affiliation: The Centre for Arthritis and Rheumatic Disease, Dublin Academic Medical Centre, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
authors.forename: Monika
authors.initials: M
authors.lastname: Biniecka
authors.affiliation: The Centre for Arthritis and Rheumatic Disease, Dublin Academic Medical Centre, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003713:Dendritic Cells / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology; D053612:Janus Kinases / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071656:Receptor, Notch3 / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000473:pathology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000071656:Receptor, Notch3; D053612:Janus Kinases