Abstract
In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1α, IL-1β, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1β-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family.This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1β-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6).In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration.
Highlights
Low back pain is a common, debilitating, and economically important disorder
No significant difference was observed between the proportions of cells in the nucleus pulposus (NP) and inner annulus fibrosus (IAF) reacting for IL-1α, IL-1 receptor antagonist (IL-1Ra), and IL-1β-converting enzyme (ICE) (P = 1.525, 0.870, and 0.639, respectively)
No immunopositivity was observed in the matrix of the intervertebral disc (IVD) or in blood vessels, with the exception of immunopositivity for ICE, which showed some staining in the matrix and blood vessels of the most degenerate discs
Summary
Current evidence implicates loss of intervertebral disc (IVD) matrix consequent upon disc 'degeneration' as a major cause of low back pain [1]. Degeneration is characterized by increased degradation of the normal IVD matrix by locally produced matrix metalloproteinases (MMPs) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) [3,4,5,6]. The resultant changes within the ADAMTS = a disintegrin and metalloproteinase with thrombospondin motifs; AF = annulus fibrosus; DMEM + F12 = Dulbecco's modified Eagle's medium and Ham's F12 nutrient medium; EDTA = ethylenediaminetetraacetic acid; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; H&E = haematoxylin and eosin; IAF = inner annulus fibrosus; ICE = IL-1β-converting enzyme; IL-1 = interleukin-1; IL-1Ra = IL-1 receptor antagonist; IL-RI = IL-1 receptor, type I; IVD = intervertebral disc; MMP = matrix metalloproteinase; NP = nucleus pulposus; OAF = outer annulus fibrosus
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