Original scientific article
Synovial Hypoxia as a Cause of Tendon Rupture in Rheumatoid Arthritis

https://doi.org/10.1016/j.jhsa.2007.09.002Get rights and content

Purpose

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-2α. Tissue was also cultured under either hypoxic (1% O2) or normoxic (21% O2) 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-2α. 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.

Section snippets

In Vivo Oxygen Tension Measurements

All of the patients had clinically apparent rheumatoid hand disease at the time of surgery and met the American College of Rheumatology (formerly the American Rheumatism Association) 1987 criteria for RA.29 Patients having elective hand surgery for indications other than inflammatory synovitis (eg, surgery for Dupuytren’s contracture and carpal tunnel release for median nerve compression) were recruited as non-RA controls. Patients with concurrent illnesses that could affect tissue oxygenation

Invasive RA Tenosynovium Is Significantly Hypoxic

Oxygen measurements were carried out in 21 patients with RA and in 10 patients without RA. The measurements were taken at the start of each surgical procedure, while each patient was under general anesthesia but before application of a tourniquet. The number of separate oxygen tension recordings taken from each area was dependent on the size of the tissue being sampled and the degree of trauma caused by insertion of the electrode into the tissues. Between 1 and 4 measurements were possible at

Discussion

Despite dramatic improvements in the medical treatment of RA, it has been our clinical experience that (for many patients) destructive changes in the hand continue even when patients are on maximum therapy. The cause of tendon rupture in RA has been variously attributed to attrition over bony prominences and/or invasion of the tendons by synovium.3 Looked at more closely, attrition over a bony prominence is probably an overly simplistic explanation. In our hands, inspection of the bed in which

References (38)

  • A.J. Lewis et al.

    New targets for anti-inflammatory drugs

    Curr Opin Chem Biol

    (1999)
  • T. Sokka

    Work disability in early rheumatoid arthritis

    Clin Exp Rheumatol

    (2003)
  • B. Sivakumar et al.

    Modulating angiogenesis: more vs less

    JAMA

    (2004)
  • P.J. Etherington et al.

    VEGF release is associated with reduced oxygen tensions in experimental inflammatory arthritis

    Clin Exp Rheumatol

    (2002)
  • A. Ceponis et al.

    Synovial lining, endothelial and inflammatory mononuclear cell proliferation in synovial membranes in psoriatic and reactive arthritis: a comparative quantitative morphometric study

    Br J Rheumatol

    (1998)
  • D.A. Walsh et al.

    Focally regulated endothelial proliferation and cell death in human synovium

    Am J Pathol

    (1998)
  • K. Lund-Olesen

    Oxygen tension in synovial fluids

    Arthritis Rheum

    (1970)
  • P.S. Treuhaft et al.

    Synovial fluid pH, lactate, oxygen and carbon dioxide partial pressure in various joint diseases

    Arthritis Rheum

    (1971)
  • T. Gaber et al.

    Hypoxia inducible factor (HIF) in rheumatology: low O2!See what HIF can do!

    Ann Rheum Dis

    (2005)
  • Cited by (0)

    The Kennedy Institute of Rheumatology receives a core grant from arc (Registered Charity No. 207711). The authors are grateful for the support of the Restoration of Appearance and Function Trust (B.S., M.A.A.) and the Royal College of Surgeons of England and The Dunhill Medical Trust (M.A.A.). B.S. was a recipient of a Research Fellowship from the Royal College of Surgeons of England. The authors are grateful to Dr. Serafim Kiriakidis (Faculty of Medicine, Imperial College London) for advice, to Mr. David Peston and Mr. David Essex (Department of Histopathology, Charing Cross Hospital, London) for immunohistochemistry expertise, and to Dr. R.E. Ellis (School of Physics, University of Exeter) for help in constructing the electrodes.

    No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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