Disc in flames: Roles of TNF-α and IL-1β in intervertebral disc degeneration

Abstract

The intervertebral disc is an important mechanical structure that allows range of motion of the spinal column. Degeneration of the intervertebral disc--incited by aging, traumatic insult, genetic predisposition, or other factors--is often defined by functional and structural changes in the tissue, including excessive breakdown of the extracellular matrix, increased disc cell senescence and death, as well as compromised biomechanical function of the tissue. Intervertebral disc degeneration is strongly correlated with low back pain, which is a highly prevalent and costly condition, significantly contributing to loss in productivity and health care costs. Disc degeneration is a chronic, progressive condition, and current therapies are limited and often focused on symptomatic pain relief rather than curtailing the progression of the disease. Inflammatory processes exacerbated by cytokines tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are believed to be key mediators of disc degeneration and low back pain. In this review, we describe the contributions of TNF-α and IL-1β to changes seen during disc degeneration at both cellular and tissue level, as well as new evidence suggesting a link between infection of the spine and low back pain, and the emerging therapeutic modalities aimed at combating these processes.

Figure 1. TNF-α signaling pathway

Membrane-bound TNF (mTNF) is processed by the metalloproteinase TACE/ADAM-17 to the soluble form (sTNF). sTNF-α or mTNF-α may bind the transmembrane TNFR1 receptor, causing a conformational change that releases the inhibitory SODD protein. Binding results in the recruitment of several facors including TRADD, RIP1, TRAF2, and cIAP 1 and 2 resulting in formation of Complex I that signals through either the NF-κB or MAPK pathways to activate p65 or AP1, respectively. Complex I signaling results in transcription of inflammatory (chemokines, cytokines) and matrix catabolic genes (MMPs, ADAMTSs) as well as pro-survival genes (cIAP1 and 2, cFLIP, TRAF1, TRAF2). Alternatively, mTNF-α may activate the TNFR2 receptor to form a similar complex and downstream signaling cascade. In some instance, TNFR1 bound to sTNF-α may be internalized initiating Complex II or DISC formation that leads to cleavage of procaspase 8 and finally cell apoptosis. Abbreviations: TNF-α, tumor necrosis factor α ; TACE, TNF-α converting enzyme; ADAM-17, a disintegrin and metalloproteinase domain containing protein 17; TNFR1, TNF receptor 1; SODD, silencer of death domains; TNFR2, TNF receptor 2; TRADD, TNFR1-assoicated death domain protein; RIP1, receptor-interacting protein 1; TRAF2, TNF-receptor-associated factor 2; cIAP, baculoviral IAP repeat containing; DISC, death-inducing signaling complex; NF-κB, nuclear factor κB; MAPK, mitogen-activated protein kinase; DD, death domain.

Figure 2. Schematic showing the major phases of intervertebral disc degeneration and discogenic back pain

Potential triggering events include overt trauma to the disc, altered loading, genetic predisposition and spinal infection. These triggers result in NP and AF cell-mediated synthesis of cytokines such as TNF-α, IL-1β, and IL-6. These cytokines have at least three major effects: increased matrix breakdown through production of SDC4, ADAMTS4/5, and MMPs, activation and chemotaxis of immune cells to the disc, induction of neurotrophins (NGF, BDNF) by disc cells and immunocytes. NGF and BDNF induce production of pain-associated channels ASIC3 and Trpv1 in the DRG. Presence of these factors in the inflammatory microenvironment of the degenerated disc is thought to promote DRG sensitization and pain. Blocking of cytokine production in Phases 1 and 2 may have most the profound positive effect on disease progression and back pain. Red blocking symbols indicate possible areas for clinical intervention. Abbreviations: ADAMTS4/5, a disintegrin and metalloproteinase with thrombospondin motifs 4/5; ASIC3, acid-sensing ion channel 3; BDNF, brain-derived neurotrophic factor; β-NGF, β-nerve growth factor; DRG, dorsal root ganglion; IFN-γ, interferon-γ; MMPs, matrix metalloproteinases; SDC4, Syndecan-4; TrpV1, transient receptor potential cation channel subfamily V member 1. Adapted from Risbud and Shapiro, 2014.