Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis

Nat Rev Rheumatol. 2016 Jul;12(7):385-97. doi: 10.1038/nrrheum.2016.69. Epub 2016 May 26.


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.

Publication types

  • Review

MeSH terms

  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology*
  • Arthritis, Rheumatoid / physiopathology
  • Dendritic Cells / pathology
  • Fibroblasts / metabolism
  • Humans
  • Hypoxia / blood
  • Hypoxia / pathology*
  • Hypoxia / physiopathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inflammation / physiopathology
  • Janus Kinases / metabolism
  • Macrophages / pathology
  • Mitochondria / metabolism*
  • NF-kappa B / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor, Notch3 / metabolism
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology*
  • T-Lymphocytes / pathology


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NF-kappa B
  • Reactive Oxygen Species
  • Receptor, Notch3
  • Janus Kinases