Role of Cytokines and Proteases in the Pathogenesis of Intervertebral Disc Degeneration

Abstract

The intact intervertebral disc (IVD) is considered an immune-privileged site with no inflammatory cells. Despite the lack of inflammatory cells, the IVD has been shown to be a source of a plethora of cytokines and chemokines, normally associated with inflammation. These cytokines are produced by the nucleus pulpous (NP) and annulus fibrous (AF) of the disc and their expression is increased during disc degeneration together with expression of their receptors. Whereas a plethora of cytokines have been identified during disc degeneration, the main research focus has been toward interleukin 1 (IL-1) and tumor necrosis factor α (TNFα) initially driven by their known roles in osteoarthritis. These cytokines have been shown to regulate several characteristic features of disc degeneration, including increased expression of matrix degrading enzymes: MMPs and ADAMTS, the main proteases produced within the degenerate disc. IL-1 and TNF have also been implicated in the down regulation of normal matrix synthesis, induction of factors which could lead to the ingrowth of blood vessels and nerves, and induction of cellular senescence and apoptosis. However, of these two cytokines, IL-1 appears to be the main regulator of the pathogenic events within the degenerate disc. IL-1 stimulation induces the expression of a plethora of cytokines and chemokines by NP cells and inhibition of IL-1 by the natural inhibitor of IL-1: IL-1Ra in ex vivo tissue explants obliterates all matrix degrading enzyme activity. Recent studies have shown that in a mouse model where the natural inhibitor of IL-1: IL-1Ra is knocked out the mice demonstrated spontaneous degeneration, associated with increased expression of matrix degrading enzymes, thus implicating IL-1 as a causative agent in disc degeneration. This is further supported by the numerous studies which link polymorphisms in the IL-1 gene family to increased risk of IVD degeneration and herniation in humans. This presentation will focus on the current understanding of the role of cytokines and chemokine's in the pathogenesis of disc degeneration and herniation, particularly on their role in regulating protease expression and other characteristic features of degeneration. Furthermore, the involvement of inflammation following herniation will be discussed, providing the distinction between true “inflammation” and “inflammatory cytokine” roles in the pathogenesis of disc degeneration and herniation, and how these can be targeted in therapeutic approaches. Disclosure of Interest None declared