Pathophysiology of Intervertebral Disc Degeneration and Pain

Anatomy

The IVD has a complex structural organization that has evolved to have unique biomechanical properties. The healthy IVD consists of three primary structures: the central gelatinous nucleus pulposus (NP), the collagenous annulus fibrosus (AF) ( Fig. 31.1 ), which surrounds the NP circumferentially, and the end plates (EPs), which are layered composites of cartilage and bone that separate the AF and NP from the vertebral bodies. The outer AF is integrated with the vertebral rim via a fibrocartilage enthesis, that consists of a thin layer of calcified cartilage, or “tidemark” ( Fig. 31.2 ). These disc substructures are distinct at birth, but become progressively indistinct with age.

The bone marrow compartment adjacent to the EP is important for disc biological homeostasis, and consists of hematopoietic cells, fat cells, sinusoids (thin-walled capillaries), and nerves. Vertebral blood vessels and nerves enter via the basivertebral foramen at the posterior vertebral cortex and small pores in the cortical shell, form an “arterial grid” at the vertebral centrum, then branch and terminate just adjacent to the EPs. EP sinusoids and nerves provide a continuous bed across the bone–disc interface.

Extracellular Matrix

The IVD is comprised of an extensive extracellular matrix (ECM), which is maintained by cells with tissue-specific phenotypes (these cells occupy <0.5% of the tissue volume ). The biochemical components throughout the disc are primarily water, proteoglycan (PG), and collagen, with the relative proportions varying spatially ( Table 31.1 ). The ECM composition changes gradually along the transverse plane, with the central NP having the highest water/PG and lowest collagen/PG content, and the outer AF having the lowest water/PG and highest collagen/PG content.

Disc PG serve as an osmotic stimulus to maintain disc hydration. The major PG is aggrecan, a large molecule with a molecular weight ranging from 3 to 7 million Daltons. Aggrecan consists of a linear protein core to which large numbers of the negatively-charged sulfated glycosaminoglycan (GAG) side chains are attached, mostly chondroitin and keratin sulfate. Many aggrecan chains can bind to hyaluronic acids via link proteins to form large aggregates (up to 10 μm long). In the NP, about 25% of the PGs are aggregated, whereas 50% to 60% are in the AF. Importantly, the negatively-charged GAG side chains bind mobile ions (mostly sodium), and thereby generate a concentration gradient relative to outside the disc. This concentration gradient serves to attract water to the NP via osmotic mechanisms, thereby producing a physical “swelling” pressure that supports spinal compression forces.

Collagen type I and II make up approximately 90% of total IVD collagen. The NP, cartilaginous EP (CEP), and inner AF consist almost exclusively of type II collagen, which is very fine (10–100 nm in diameter) in comparison to the larger type I fibrils (100–200 nm in diameter) that predominate in the AF and increase in relative proportion peripherally. In the NP, collagen fibers are irregularly oriented; in the AF, they are organized into 10 to 25 unidirectionally aligned lamellae, which encircle the NP and attach to the cartilaginous EP in the inner zone and to the vertebral EPs in the outer zone (see Fig. 31.1A and D). Alignment alternates between +30 degrees and –30 degrees with respect to the circumferential direction of the IVD.

In the healthy disc, the cartilaginous EP PG content is approximately 300 μg/mg, with water and type I collagen contents being 78% and 0.9 ng/mg, respectively. The CEP is typically between 0.1 and 2.0 mm thick ^, ; however, its thickness is known to vary with position and level, being thinner centrally and in the upper levels of the spine than peripherally and in the lower levels of the spine. The nature of the structural integration between the EP and the surrounding tissues also varies with position. Peripherally, the collagen fibers in the lamellae of the AF are continuous with the collagen fibers in the EP, whereas centrally, the integration between collagen fibers in the NP and the EP is more convoluted. ^, The collagen fibers of the cartilaginous and bony components of the EP are completely separate.

The most abundant nonstructural proteins in the IVD are the matrix metalloproteinases, tissue inhibitors of metalloproteinases, and a disintegrin and metalloproteinase with thrombospondin motif metalloproteinases. These are zinc-dependent proteinases, which can cleave almost all components of the ECM.

Cells

IVD cells synthesize and maintain the ECM. Because IVD cells are relatively quiescent and make up such a small fraction of the disc volume, ECM turnover takes years.

There are three main types of disc cells: notochordal cells (NCs), NP cells, and AF cells. NCs are remnants from the embryonic notochord and form the postnatal NP. NCs are significantly larger than NP and AF cells, and contain vacuole-like cytoplasmic structures. In early childhood, NCs begin to be replaced by NP cells. According to their gene expression profile, AF cells are fibrocytic (synthesize collagen I as the main structural protein), and NP cells are chondrocytic (synthesize primarily aggrecan and collagen II). Morphologically, NP cells are spherical, and AF cells are elongated and aligned with the AF collagen fibers. The CEP consists mainly of chondrocyte-like cells.

Nutrition

The IVD is the largest avascular tissue in the human body, with a distance of 6 to 8 mm between the center of an adult lumbar IVD and blood vessels at the IVD periphery. Therefore, nutrient supply and cell metabolite drainage rely primarily on diffusion over long distances. The diffusion rate depends strongly on the microstructure and composition of tissues along the transport route, particularly the EP. The EP has a higher permeability in its central NP zone, which is essential to sustaining metabolite transport to and from NP cells ( Fig. 31.3 ).

Innervation

The nerve supply to a healthy IVD is restricted to the three outermost lamellae of the AF and to the CEP. ^, These nerve fibers primarily consist of small myelinated and unmyelinated fibers, ^, and are afferent axons whose cell bodies reside within the dorsal root ganglia. There are two paths between the annulus and dorsal root ganglia—one from the sinuvertebral nerve, and another along the paravertebral sympathetic trunk. The sinuvertebral nerve is a recurrent branch of the ventral primary ramus of the spinal nerve, that is, a portion of the spinal nerve at each spinal level connects back to the posterior disc. The sympathetic trunk is a paired chain of ganglia that run along the anterolateral borders of the spine. Axons from the sympathetic trunk course through the gray rami communicans to the spinal nerve.

The EP is innervated by basivertebral nerve (BVN), the fibers of which reach the bone marrow along with the nutrient arteries that enter the vertebra through the posterior basivertebral foramen. ^{, , ,} EP innervation is comparable to that of the peripheral annulus. ^{, ,}

Function

The primary IVD function is mechanical. The spinal column supports the torso mass and facilitates trunk movement. By itself, the spinal column is inherently unstable, and will buckle under axial compressive loading. The physical stability of the spinal column is determined by the synergy between passive constraints (defined by osteoligamentous tissues such as the vertebra, facet joints, IVDs, and intervertebral ligaments) and active constraints (defined by the paraspinal muscles). The paraspinal muscles include: the erector spinae that runs longitudinally on the dorsal surface of the spinal column and functions to extend the spine; the psoas that runs longitudinally on the ventrolateral surface of the spinal column and serves to flex the hip (bilateral contraction) or laterally bend the trunk (unilateral contraction); and the multifidus that connects intersegmentally to stabilize the spine by acting like a bowstring to maintain lordosis. The contributions of passive and active constraints to spinal stability vary at each spinal level.

Muscle plus gravity loads cause the lumbar disc to be one of the most highly loaded tissues in the body. It routinely experiences compressive pressures in the 2-MPa range and as high as 3 MPa during extreme activities. ^, Diurnal fluctuations can be significant: during sleep, pressures decrease to 0.1 MPa, and during quiet standing are 0.5 MPa. The disc supports these forces by the combined actions of nuclear osmotic swelling and, in reaction, annular fiber biaxial tension. The extent of annular stretch generated in response to in vivo compression loading conditions is near 4% strain, and as high as 6% during flexion and extension. Deflection of the EP into the underlying vertebral bodies may also occur in response to compressive loading; these deformations create a multiaxial stress state in the EP that involves biaxial tensile stretching in the transverse plane.

Together, nuclear pressure, annular tension, and facet compression support spinal compression, bending, torsion, and shear. Yet, the loading balance between these subtissues is time-dependent because the EP is semipermeable and allows water to move out of the disc when spinal stress exceeds NP osmotic pressure, and vice versa. Additionally, the disc’s solid–fluid interactions contribute to a viscoelastic behavior that contributes to diurnal variations in disc water content, disc height, and spinal flexibility. For example, sustained compression over the course of a day results in loss of stature, owing to the accumulated disc height loss over the length of the spine. ^, Even low-impact activities, such as gentle walking, have been shown to decrease stature significantly, and more strenuous exercise, work-related activities, and high body mass exacerbate this loss.