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

PHILLIPS, Kate, JORDAN-MAHY, Nikki, NICKLIN, Martin J H and LE MAITRE, Christine (2013). Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration. Annals of the rheumatic diseases, 72 (11), 1860-7.

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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
Research Institute, Centre or Group - Does NOT include content added after October 2018: Biomedical Research Centre
Identification Number:
Page Range: 1860-7
Depositing User: Christine Le Maitre
Date Deposited: 04 Jun 2018 15:18
Last Modified: 18 Mar 2021 12:27

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