title: Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration.
abstract: OBJECTIVE
  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.
authors: Biomedical Research Centre, Faculty of Health and Wellbeing, Sheffield Hallam University, , Sheffield, UK.
authors: Kate Louise Eve
authors: KL
authors: Phillips
authors: Nikki
authors: N
authors: Jordan-Mahy
authors: Martin J H
authors: MJ
authors: Nicklin
authors: Christine Lyn
authors: CL
authors: Le Maitre
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000818:Animals; D004195:Disease Models, Animal; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D007375:Interleukin-1 / Q000378:metabolism; D055959:Intervertebral Disc Degeneration / Q000209:etiology* / Q000473:pathology; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011348:Procollagen N-Endopeptidase / Q000378:metabolism; D013131:Spine / Q000473:pathology*
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D020783:Matrix Metalloproteinase 7; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse
keywords: Chondrocytes; Cytokines; Disease Activity; Low Back Pain