Pathophysiology of Disc Disease: Disc Degeneration

Fig. 2.1 Degenerative disc disease is a complicated process with many factors interacting to lead to the disc pathology that presents in the clinic. This figure demonstrates many of those factors and their interactions.

Several risk factors have been associated with disc degeneration and include genetic predisposition, decreased nutrient transport, abnormal biomechanics, smoking, and the normal wear and tear of the IVD associated with aging.⁵^,⁶^,⁷^,⁸^,⁹ Although the relative importance of each risk factor in initiating DDD is uncertain, these factors initiate a known cascade of molecular mechanisms, described below, leading to the pathological breakdown of the IVD. This chapter discusses the key changes observed in the degenerative disc and the known underlying biological processes that drive those changes.

2.1.1 Composition Changes

Degeneration of the IVD varies with severity¹⁰ and is typically diagnosed via magnetic resonance imaging (MRI),¹¹ utilizing the Thompson criteria,¹² to grade degeneration based on disc water content, bulging and narrowing of the disc, end plate sclerosis, and osteophyte formation (▶ Fig. 2.2 and ▶ Table 2.1).

Fig. 2.2 Macroscopic images of the intervertebral disc (IVD) demonstrating multiple grades of disc degeneration.¹⁰ (a) Healthy young adult disc with a defined nucleus pulposus (NP). (b) Middle age adult disc that is slightly aged but not yet degenerated. (c) Moderately degenerated young adult disc. (d) Severely degenerated young adult disc. (e) Prolapsed middle age adult disc.

Degenerative IVDs exhibit a loss of the transition zone between the nucleus pulposus (NP) and annulus fibrosus (AF) tissue partially caused by changes in collagen expression and synthesis within the disc. Early-stage disc degeneration can induce transient increases in expression of collagen type II,¹³ but ultimately shifts to decreased collagen type II and increased collagen type I synthesis in the NP and the inner AF¹⁴^,¹⁵ as degeneration progresses. In addition to changes in collagen content, there are also changes in proteoglycan (PG) content that occur with DDD.¹⁶^,¹⁷^,¹⁸ PG content in the NP decreases as DDD progresses and results in the dehydration of the NP and formation of fissures beginning in the NP that extend into the AF. Furthermore, the AF of a degenerative IVD is characterized by collagen fiber reorganization,¹⁹ scar/granulation tissue, fissure formation, neovascularization, and neoinnervation.²⁰^,²¹^,²² In addition to a general loss of PG content, there is a shift in the types of PGs found in the disc. Degenerative discs demonstrate increased synthesis of small PGs including versican, biglycan, and decorin,¹⁵^,¹⁹^,²³ along with increased degradation of aggrecan and versican, and decreased sulfation. The loss of PG and a shift toward expression of small PGs is linked to decreased hydrostatic pressure observed in degenerated discs. Additionally, the extracellular matrix (ECM) of degenerative discs exhibit increased fibronectin, increased elastin, collagen types X, VI, III, and amyloid.²⁴ Overall, these changes in matrix components in degenerative discs have deleterious effects on the discs’ mechanical properties and ability to properly transmit load. These changes also alter the loads the encapsulated cells experience and have negative effects on the balance of ECM anabolism/catabolism.

2.1.2 Architectural and Mechanical Changes

The unique structure of the NP, AF, and end plates are adapted to perform specific mechanical functions. The interaction between these disc components allows the IVD to transmit mechanical loads while providing constrained flexibility between vertebrae. The NP of the healthy IVD is a hydrated, gel-like core that is constrained radially by the AF tissue and axially by the cartilaginous end plates (▶ Fig. 2.3). The NP is primarily composed of water, PGs, collagen type II, and other minor proteins.²⁵ The most abundant PG in the IVD, aggrecan,²⁶ contains keratin sulfate and chondroitin sulfate glycosaminoglycan (GAG) chains that are bound to the aggrecan core protein. This complex binds hyaluronic acid via a link protein to form large molecules that are contained within the type II collagen-rich network.²⁷ The negatively charged GAG chains of these molecules bind counter-ions, creating an imbalance of ions between the IVD and the surrounding tissue resulting in a large osmotic swelling pressure in the NP, which contributes 70 to 80% of the compressive strength of the IVD.²⁸ When the disc is compressed axially, water in the NP tissue pressurizes, resulting in a swelling of the NP that is contained axially by the end plates and radially by tension in fibers of the AF tissue²⁹ (▶ Fig. 2.3). In disc degeneration, aggrecan content in the NP is decreased and compromises the compressive properties of the NP.¹⁸ These changes diminish the ability of the disc to hold water,³⁰ swell,⁹ and subsequently results in reduced disc height. This loss in disc height results in increased strains in the axial direction and causes the compressive load to shift from the NP to the AF, which leads to buckling of the lamellae, an increased bulging of the AF tissue, and a loss of lamellae organization.³¹ Furthermore, the loss of osmotic pressure leads to hypermobility of the IVD.³²

Fig. 2.3 The intervertebral disc (IVD) is a mechanical organ that must resist complex loading in compression, torsion, flexion, and bending. Here we demonstrate how the annulus fibrosus (AF) and nucleus pulposus (NP) interact in the IVD to provide the disc with its compressive mechanical function. When compressive forces are applied to the IVD, the NP becomes pressurized and bulges vertically and radially. This pressurization of the NP results in tensile stresses in the AF in the direction of the collagen organization, which is responsible for containing the NP during this pressurization.

AF tissue composition is similar to that of NP tissue in that its primary components are collagen and PGs; however, the percentage and organization of components differ.³³ The collagen fibers of the AF are organized into concentric lamellae that consist mainly of collagen type I. Moving toward the NP, collagen type II and PG increase in content with collagen type I decreasing. During physiological loading, the AF tissue is subjected to both compressive and tensile stresses, with more compressive loading toward the inner AF and more tensile loading toward the outer AF.³³ Both the collagen content, and the collagen architecture and lamellar organization allow the AF to handle the hoop stresses generated by the bulging of the NP tissue under loading. Collagen fibers of concentric lamellae surrounding the bulging NP are stretched and subjected to tension during loading. In degenerative discs, fissures, replacement of AF tissue with granulation and scar tissue, and loss of fiber orientation decrease the ability of the AF to resist tensile loading.³⁴^,³⁵ In addition, the loss of osmotic pressure, increased collagen cross-linking, and increased collagen type I levels³⁴ leads to stiffening of the AF. Furthermore, the changes in the NP leads to decreased disc height, a shift of compressive load to the AF, subsequent inward and outward buckling of the lamellae, and increased axial and tensile strains, which increases the likelihood of the AF tearing or rupturing. Overall, the hypermobility of the disc and propensity for herniation during the degenerative process provide a key component to pathology of the IVD and its role in back pain. A more in-depth look at the mechanics of healthy and degenerative IVD can be seen in Chapter 4.

2.1.3 Innervation

The healthy IVD is innervated primarily by afferent nerve fibers limited to the external lamellae³⁶ of the AF and consist primarily of small myelinated (A-δ) and unmyelinated (C) fibers³⁶ that are positive for the neuropeptides substance P and calcitonin gene-related peptide (CGRP), indicating that the disc is primarily innervated by small nociceptive fibers.³⁶ In the degenerative IVD, nerve fibers extend into typically aneural regions of the inner AF and NP tissue and, in some cases, are accompanied by neovascularization and granulation tissue.³⁷^,³⁸ In the degenerative disc, the increased expression of nerve growth factor (NGF) and loss of chondroitin sulfate create an environment conducive to neoinnervation.³⁹ Furthermore, degenerative discs exhibit increased levels of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which have been shown to sensitize nociceptive neurons to noxious stimuli including heating⁴⁰ and mechanical loading⁴¹ in radiculopathy models. Furthermore, recent reports demonstrate that IL-6 released from degenerative discs sensitizes neurons to noxious stimuli,⁴² suggesting cytokines from degenerative IVD may contribute to back pain by sensitizing nociceptive neurons to noxious stimuli. Overall, the interactions between these nociceptive neurons and the degenerative IVD are a key component for the development of discogenic back pain but are currently poorly understood and are a major area of ongoing research.

2.2 Underlying Biological Processes

2.2.1 IVD Cell Metabolism

The structural, mechanical, and morphological changes that result due to disc degeneration are regulated by cells in the disc, which respond to their environment to mediate the structural and compositional changes that are observed during disc degeneration. At birth, cells within the IVD are composed of fibroblast-like cells in the AF, chondrocyte-like cells in the end plate, and a mix of notochordal and chondrocyte-like cells in the NP.⁴³ As the disc matures over the first 10 years of life, the notochordal cells within the NP disappear and leave only chondrocyte-like cells.⁴⁴ This loss of notochordal cells has been speculated to have direct consequences on the ECM composition of the IVD. These notochordal cells have been linked to a number of anabolic activities, which include the synthesis of growth factors, the stimulation of IVD cell proliferation, the elevated synthesis of collagen type II and aggrecan,⁴⁵ and the decrease in matrix metalloproteinases (MMP)-3 and MMP-13 expression.⁴⁶^,⁴⁷ It has been hypothesized that the loss of notochordal cells leads to decreased cell proliferation, decreased production of PGs, decreased collagen type II production, and increased tissue catabolism.

The alterations in the PG and collagen content in the NP, that occur with aging and degeneration, lead to changes in the osmotic and hydrostatic pressure, which can have deleterious effects on cell function. For example, decreased hydrostatic pressure observed in the degenerative IVD leads to decreased (20–40%) NP PG production, increased MMP-3 production, and upregulated tissue inhibitors of matrix metalloproteinase (TIMP) production.⁴⁸ Similarly, the decreased osmotic pressure of degenerative IVDs leads to decreased PG production by NP cells.⁴⁹ The end plates respond to low hydrostatic pressure by entering hypertrophic conversion, which leads to type X collagen production and eventually end plate calcification.⁵⁰ This calcification can lead to a decreased supply of oxygen and nutrients to the NP and produce an increase in NP acidity, and ultimately a decrease in viable cells.⁵¹ In addition to a decrease in cell viability being associated with DDD, an increase in the number of senescent cells has been found in the degenerative disc.⁵² These senescent cells show a decrease in anabolism and no longer divide to replace the cells lost to apoptosis. Additionally, these senescent cells produce increased levels of cytokines and matrix-degrading enzymes.⁵³ Overall, changes that move the IVD away from its healthy state tend to decrease anabolism and increase catabolism in the IVD cell population.

2.2.2 Immune Cells and Inflammatory Cytokines

It has been well established that there is an elevated level of pro-inflammatory cytokines in degenerative and herniated discs.³⁸ These increased cytokine levels are a cellular response to decreased nutrient availability and the presence of invading immune cells.³⁷ The cells involved with the production and secretion of these pro-inflammatory molecules include NP cells, AF cells, macrophages, T cells, and neutrophils.³⁸ The proinflammatory molecules they secrete result in numerous pathological changes in the IVD, including cell senescence/apoptosis of IVD cells,⁵⁴^,⁵⁵ breakdown of ECM,⁵⁶ increased expression of cytokines, increased expression of neurotrophic factors,²¹ recruitment of immune cells,⁵⁷ angiogenesis, neoinnervation of the disc, and sensitization of neurons to noxious stimuli.⁴²

Many of these pathological changes are induced by the presence of immune cells in the IVD. Studies done on degenerative or herniated discs from patient samples have shown that there is a presence of invading CD 68 + macrophages, neutrophils, and T cells (CD 4+and CD 8+) within the degenerative disc.³⁷^,⁵⁸ Concurrent with immune cell invasion, degenerative IVDs exhibit increased levels of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL13, CXCL10, and IL-8,³⁸^,⁵⁷ which promote recruitment of macrophages, neutrophils, and T cells. The accompaniment of invading immune cells by angiogenesis suggests macrophages enter the herniated or degenerative IVD via blood vessels in an attempted healing response.³⁷^,⁵⁹ Consequently, these immune cells stimulate the expression of pro-inflammatory cytokines and NGF by NP cells.⁶⁰ NGF expression can lead to dorsal root ganglion (DRG) neurons expressing neuronal pain–associated cation channels, which may provide a link to disc degeneration and low back pain.⁶¹^,⁶² Overall, once these immune cells are recruited to the degenerative disc, they further elevate the level of inflammatory cytokines, which propagates a catabolic environment in the disc.

There are multiple cytokines that have been shown to propagate the inflammatory environment in the degenerative disc. The inflammatory cytokines that have been studied and associated with disc degeneration include TNF-α, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17, and interferon-γ (IFN-γ).³⁸ The two most commonly studied cytokines are TNF-α, and IL-1β, which both induce inflammatory signaling and cell apoptosis through their respective receptors, TNFR1 and IL1R1. Signaling through both of these receptors is known to cause activation of the transcription factor NF-KB, which induces the expression of a number of pro-inflammatory and catabolic target genes involved with the breakdown of IVD tissue (▶ Fig. 2.4).⁶³^,⁶⁴ It is believed that TNF-α and IL-1β play important roles in tissue breakdown mediated by NF-KB activity as these cytokines have been linked to IVD degradation in numerous studies and blocking NF-KB activity has been shown to reduce degradation in rodent models of disc degeneration.⁶⁵^,⁶⁶^,⁶⁷ Although TNF-α and IL-1β have been heavily associated with disc degeneration in one study increased levels of TNFR1 expression was only found in herniated discs which indicates disease-specific roles for TNF-α and IL-1β in the degenerative process.⁶⁶ Additionally this indicates that inflammatory signaling is being regulated by both the specific expression of cytokines and the expression of specific receptors. In addition to mediating tissue breakdown TNF-α and IL-1β are also involved with production of chemokines that promote recruitment of immune cells. IVD cells cultured with these two cytokines exhibit increased expression of pro-inflammatory chemokines (i.e. CCL3 and CCL5) shown to be elevated in degenerate discs.⁵⁷^,⁶⁸ Overall the body of literature implicates TNF-α and IL-1β in the processes of catabolism inflammation angiogenesis and neoinnervation that characterize DDD.

Fig. 2.4 Signaling pathway of TNFR1 and IL1R1 demonstrating how activation of NF-KB occurs through the proteasomal degradation of IKB. This allows NF-KB to translocate to the nucleus where it activates catabolic target genes, which include inflammatory cytokines, aggrecanases, and proteases. (Adapted with permission from Macmillan Publishers Ltd: [Nat Immunol]⁶³ copyright [2011].)

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