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Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration
  1. Kate Louise Eve Phillips1,
  2. Nikki Jordan-Mahy1,
  3. Martin J H Nicklin2,
  4. Christine Lyn Le Maitre1
  1. 1Biomedical Research Centre, Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, UK
  2. 2Department of Infection and Immunity, University of Sheffield, Sheffield, UK
  1. Correspondence to Dr Christine Lyn Le Maitre, Biomedical Research Centre, Sheffield Hallam University, 730 Owen Building, Howard Street, Sheffield S1 1WB, UK; c.lemaitre{at}shu.ac.uk

Abstract

Objectives Interleukin 1 (IL-1) is potentially important in the pathogenesis of intervertebral disc (IVD) degeneration; increasing production of matrix degradation enzymes and inhibiting matrix synthesis. Although IL-1 polymorphisms have been linked to increased risk of IVD degeneration, it is still unclear whether IL-1 drives IVD degeneration in vivo or is a secondary feature of degeneration. Here, we investigated whether IVD degeneration could be induced spontaneously by the removal of the natural inhibitor of IL-1 (IL-1 receptor antagonist) in mice that lack a functional IL-1rn gene.

Methods Histological staining and immunohistochemistry was performed on BALB/c IL-1rn+/+ and IL-1rn−/− mice to examine degeneration and to localise and detect IL-1, matrix metalloproteinases (MMP)3, MMP7, a disintigrin and MMP with thrombospondin motifs (ADAMTS)4 protein production. In addition, IVD cells were isolated using collagenase and proliferation potential determined.

Results IL-1rn−/− knockout mice displayed typical features of human disc degeneration: loss of proteoglycan and normal collagen structure and increased expression of matrix degrading enzymes: MMP3; MMP7 and ADAMTS4. Histological grade of degeneration increased in IL-1rn−/− mice which was more evident within older mice. In addition IVD cells isolated from IL-1rn−/− mice displayed reduced proliferation potential.

Conclusions Here, we show that IL-1rn−/− mice develop spinal abnormalities that resemble characteristic features associated with human disc degeneration. The current evidence is consistent with a role for IL-1 in the pathogenesis of IVD degeneration. The imbalance between IL-1 and IL-1Ra which is observed during human IVD degeneration could therefore be a causative factor in the degeneration of the IVD, and as such, is an appropriate pharmaceutical target for inhibiting degeneration.

  • Low Back Pain
  • Cytokines
  • Disease Activity
  • Chondrocytes

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