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Extended report
Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease
  1. Jenny L Scott1,2,
  2. Christos Gabrielides1,
  3. Rose K Davidson3,
  4. Tracey E Swingler3,
  5. Ian M Clark3,
  6. Gillian A Wallis4,
  7. Raymond P Boot-Handford4,
  8. Tom B L Kirkwood5,
  9. Robert W Talyor5,
  10. David A Young1
  1. 1Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK
  2. 2Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, USA
  3. 3School of Biological Sciences, University of East Anglia, Norwich, UK
  4. 4Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK
  5. 5Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, UK
  1. Correspondence to Dr David Young, Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK; d.a.young{at}ncl.ac.uk

Abstract

Background Oxidative stress is proposed as an important factor in osteoarthritis (OA).

Objective To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA.

Methods SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin–Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression.

Results All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin–Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression.

Conclusion This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function.

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Footnotes

  • Competing interests None.

  • Ethics approval This study was performed with ethical committee approval from Norfolk and Norwich University Hospital Trust, Oxford Radcliffe Hospitals NHS Trust and Newcastle and North Tyneside Health Authority.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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