Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration

PHILLIPS, Kate Louise Eve, JORDAN-MAHY, Nikki, NICKLIN, Martin J. H. and LE MAITRE, Christine Lyn (2013). Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration. Annals of the Rheumatic Diseases, 72, 1860-1867.

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Official URL: http://dx.doi.org/10.1136/annrheumdis-2012-202266
Link to published version:: 10.1136/annrheumdis-2012-202266

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.

Item Type: Article
Additional Information: Accepted 20 January 2013
Research Institute, Centre or Group: Biomolecular Sciences Research Centre
Identification Number: 10.1136/annrheumdis-2012-202266
Depositing User: Marguerite Lyons
Date Deposited: 10 May 2013 10:00
Last Modified: 04 Mar 2015 10:30
URI: http://shura.shu.ac.uk/id/eprint/7023

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