title: Synovial hypoxia as a cause of tendon rupture in rheumatoid arthritis.
abstract: OBJECTIVE
  Hypoxia and angiogenesis are now recognized as being important events in the perpetuation of joint destruction in rheumatoid arthritis (RA). In 50% of patients with RA, however, the disease also involves inflammation of the synovial tissue surrounding the tendons, which is associated with multiple ruptures and poor prognosis for long-term hand function. The aim of this study was to determine whether hypoxia and angiogenesis may also play a role in RA tendon disease.
  
  
  METHODS
  Matched in vivo synovial oxygen measurements (invasive and encapsulating tenosynovium and joint synovium) were taken intraoperatively using a microelectrode technique in patients having elective hand surgery for RA. Patients having elective hand surgery for indications other than inflammatory synovitis were recruited as controls. In parallel, RA synovial tissue was harvested and stained for vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-2alpha. Tissue was also cultured under either hypoxic (1% O(2)) or normoxic (21% O(2)) conditions to investigate the effect of hypoxia on the expression of VEGF and its soluble receptor, as well as on the key cytokines interleukin (IL)-6, IL-8, IL-10 and the chemokine monocyte chemoattractant protein-1.
  
  
  RESULTS
  Invasive tenosynovium was observed to be significantly more hypoxic than either noninvasive tenosynovium or joint synovium in the same patients. Furthermore, RA tenosynovium was shown to be more hypoxic than tenosynovium in patients without RA. This hypoxia was accompanied by expression of VEGF and hypoxia-inducible factor-2alpha. Using in vitro joint synovial cell cultures, upregulation of VEGF expression was shown to be a consequence of this in vivo hypoxia. Furthermore, hypoxia downregulated release of monocyte chemoattractant protein-1 and the immunoregulatory cytokine IL-10.
  
  
  CONCLUSIONS
  These data demonstrate that hypoxia is a feature of rheumatoid tendon disease and differentially regulates angiogenesis and the inflammatory cascade in RA.
authors.affiliation: Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Branavan
authors.initials: B
authors.lastname: Sivakumar
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Akhavani
authors.forename: C Peter
authors.initials: CP
authors.lastname: Winlove
authors.forename: Peter C
authors.initials: PC
authors.lastname: Taylor
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Paleolog
authors.forename: Norbert
authors.initials: N
authors.lastname: Kang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism*; D052256:Tendinopathy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D010100:Oxygen; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C467484:VEGFA protein, human