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Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis

Nature Reviews Rheumatology volume 12, pages 385–397 (2016)Cite this article

Subjects

Key Points

  • Hypoxia, arising as a consequence of the increased cellular demand for oxygen during the inflammatory response, is a powerful trigger for the activation, proliferation and survival of endothelial cells and fibroblast-like synoviocytes

  • Impaired mitochondrial function and oxidative damage caused by hypoxia further exacerbate the inflammatory response through metabolic perturbation

  • Hypoxia induces immune cell dysfunction, resulting in an altered metabolic profile

  • The hypoxic environment induces activation of a complex crosstalk of signalling pathways, providing a feedback loop leading to further activation and inflammation

  • Targeting synovial metabolic pathways through inhibition of hypoxia-induced signalling pathways might have therapeutic benefit for rheumatoid arthritis and other inflammatory diseases

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.

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Figure 1: Blood vessel activation in the rheumatoid joint.
Figure 2: Hypoxia and mitochondrial dysfunction.
Figure 3: Acute and chronic hypoxia regulates dendritic cell function.
Figure 4: Hypoxia-induced signalling in the rheumatoid joint.
Figure 5: Interplay between HIF-1α, Notch and STAT3 signalling.

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Authors and Affiliations

  1. The Department of Molecular Rheumatology, Trinity College Dublin, The University of Dublin, College Green, Dublin, 2, Ireland

    Ursula Fearon

  2. The Centre for Arthritis and Rheumatic Disease, Dublin Academic Medical Centre, St. Vincent's University Hospital, Dublin, 4, Elm Park, Ireland

    Ursula Fearon, Mary Canavan, Monika Biniecka & Douglas J. Veale

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Fearon, U., Canavan, M., Biniecka, M. et al. Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat Rev Rheumatol 12, 385–397 (2016). https://doi.org/10.1038/nrrheum.2016.69

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