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Hypoxia: a critical regulator of early human tendinopathy
  1. Neal L Millar1,
  2. James H Reilly1,
  3. Shauna C Kerr1,
  4. Abigail L Campbell1,
  5. Kevin J Little3,
  6. William J Leach3,
  7. Brian P Rooney3,
  8. George A C Murrell2,
  9. Iain B McInnes1
  1. 1Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
  2. 2Orthopaedic Research Institute, Department of Orthopaedic Surgery, St George Hospital Campus, University of New South Wales, Sydney, Australia
  3. 3Department of Orthopaedic Surgery, Western Infirmary, Glasgow, UK
  1. Correspondence to Neal L Millar, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, 120 University Avenue, Glasgow G12 8TA, UK; neal.millar{at}


Objectives To seek evidence for the role of hypoxia in early human tendinopathy, and thereafter to explore mechanisms whereby tissue hypoxia may regulate apoptosis, inflammatory mediator expression and matrix regulation in human tenocytes.

Methods Fifteen torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of the subscapularis tendon were collected from 10 patients undergoing arthroscopic stabilisation surgery. Markers of hypoxia were quantified by immunohistochemical methods. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon anterior cruciate ligament reconstruction. The impact of hypoxia upon tenocyte biology ex vivo was measured using quantitative real-time PCR, multiplex cytokine assays, apoptotic proteomic profiling, immunohistochemistry and annexin V fluorescence-activated cell sorter staining.

Results Increased expression of hypoxia-inducible factor 1α, Bcl-2 and clusterin was detected in subscapularis tendon samples compared with both matched torn samples and non-matched control samples (p<0.01). Hypoxic tenocytes exhibited increased production of proinflammatory cytokines (p<0.001), altered matrix regulation (p<0.01) with increased production of collagen type III operating through a mitogen-activated protein kinase-dependent pathway. Finally, hypoxia increased the expression of several mediators of apoptosis and thereby promoted tenocyte apoptosis.

Conclusion Hypoxia promotes the expression of proinflammatory cytokines, key apoptotic mediators and drives matrix component synthesis towards a collagen type III profile by human tenocytes. The authors propose hypoxic cell injury as a critical pathophysiological mechanism in early tendinopathy offering novel therapeutic opportunities in the management of tendon disorders.

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  • Competing interests None.

  • Funding This work was funded by grants from the Arthritis Research UK Orthopaedic Clinical Research Fellowship and the Royal College of Surgeons of Edinburgh Cutner Fellowship.

  • Ethics approval This study was conducted with the approval of the South East Sydney Ethics Board, NHS Greater Glasgow and Clyde Research and Ethics Committee (West Section).

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

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