- » Etiology of Disc Degeneration
The lumbar spine is composed of the five caudal-most fully segmented vertebrae of the spine. Each vertebra is a complex bone composed of several parts (Fig. 1.1). The vertebral body serves as the primary weight-bearing structure of the spine. The lamina and pedicles form the spinal canal that contains and protects the neural elements. A central spinous process and two lateral transverse processes protrude from the vertebrae and serve as attachment points for the paravertebral muscles and ligaments. The superior and inferior articular processes form synovial joints with the adjacent vertebrae known as the facet joints. Multiaxial motion between the vertebrae is achieved through a three-joint complex composed of an anterior intervertebral disc (IVD) separating two vertebral bodies and two posterior facet joints.
The facet joints are lined with articular cartilage and are surrounded by a capsule, typical of synovial joints elsewhere in the body. The IVD, however, has a unique structure consisting of an inner proteoglycan-rich gelatinous nucleus pulposus (NP), surrounded by the annulus fibrosus (AF), an organized fibrous ring with abundant type I collagen content. The entire structure is confined cranially and caudally by cartilaginous end plates.
With age, both the IVD and facet joints can degenerate displaying morphologic changes similar to other articulations in the skeleton, including joint space narrowing, subchondral sclerosis, and osteophyte formation (Figs. 1.2A and B).1 In a segment of the population, this process can lead to a variety of clinical presentations including debilitating back pain, a common condition with enormous psychosocial and economic ramifications. It has been estimated that approximately 85% of individuals in the United States suffer from back pain at some point in their lifetime, with an annual prevalence of 15–45%.2 The resulting direct and indirect economic costs have been estimated to be between 14 and 90 billion dollars per year.3 Despite the enormous clinical problem it represents, there is a lack of consensus as to how lumbar degeneration should be defined and which changes, particularly within the IVD, should be considered pathologic or just a normal part of aging.
Fig. 1.1: Mid-sagittal crytome section of the caudal lumbar spine demonstrating the relationship between the vertebrae, intervertebral discs, and the spinal canal.
Figs. 1.2A and B: Lateral X-ray of a normal lumbar spine (A) and a lumbar spine with advanced degenerative changes (B) including disc space narrowing (arrowheads), osteophyte formation (arrow), and spondylolisthesis (*).
Fig. 1.3: Histologic section of rabbit intervertebral disc demonstrating migration of chondrocytes from the end plate into the nucleus pulposus (arrows). The pyknotic nuclei of notochordal cells undergoing apoptosis are visible in the center of the nucleus.
This chapter will describe the development of the lumbar spine, the morphologic and biochemical features of the normal IVD and vertebrae, as well as the changes that occur with aging and pathologic degeneration. A better understanding of these processes is the first essential step in the development of novel therapies to treat and even potentially reverse the degenerative process and its consequence.
Development of the Spine
The axial skeleton is formed by condensation of mesenchymal cells in somites and their aggregation around the notochord. The segmentation of this perichordal tube results in condensed regions that form the vertebral bodies and noncondensed regions that form the IVDs.4,5 The notochordal cells proliferate within the IVD and synthesize an extracellular matrix rich in glycosaminoglycans, forming the original embryonic structure of the NP. The AF, on the other hand, is derived from the surrounding mesenchymal tissue. This gives rise to a distinct border between these two IVD components as well as very different tissue composition and properties.6,7 In the NP, the negatively charged aggregating proteoglycans produced by the notochordal cells generate an osmotic gradient that both attracts and holds waters within the IVD. At birth, the population of notochordal cells within the IVD is estimated to be 2,000 cells/mm3.8 Shortly afterward, Fas-mediated mitochondrial caspase-9 activation9 results in notochordal cell apoptosis with a resulting cell density of 100 cells/mm3 at 1 year of age and almost none identifiable by late childhood. As the notochordal cell population dwindles, chondrocytic cells migrate from the cartilaginous end plate to repopulate the NP (Fig. 1.3). These cells synthesize both proteoglycan and type II collagen in an effort to maintain extracellular matrix homeostasis.10 Since these migrated chondrocytes are believed to be the major NP cell type in the adult IVD, NP and articular cartilage biology share many similar features.
The AF, derived from the mesoderm, is composed primarily of type I collagen organized into concentric lamellae synthesized by a fibrocyte-like cell population (Fig. 1.4). The collagen fibrils within the annulus are oriented approximately 30° from the long axis of the spine. Fibrils within each layer are parallel and run in opposing directions to adjacent layers. This organization confers significant tensile strength to AF tissue, which is responsible for resistance to tensile and shearing loads placed on the IVD. Only a small percentage of the dry weight of the AF is made up of proteoglycans. With aging, the distinct border characteristic of the developing NP and AF is lost, resulting in fibrous and highly organized outer AF, and an inner AF with mixed fibrocartilaginous characteristics.
Fig. 1.4: The intervertebral disc composed of a gelatinous nucleus pulposus, surrounded by a fibrous annulus fibrosus. The annulus is composed of concentric lamellae with collagen fibers running in alternating directions, angles approximately 30° from the vertical axis of the spine.
The bony vertebral bodies and cartilaginous end plates are formed by mesenchymal cells above and below the IVD. In early life, blood vessels permeate through these structures providing the disc with nutrients.11
By the third decade of life, the blood vessels that supply the center of the disc have receded. As a result, nutritional support to the IVD comes from diffusion through the end plate and outer AF.12 The cell density within the IVD decreases to a level lower than almost any other tissue in the body as the disc grows with age and more extracellular matrix (ECM) is laid down.13 Much of this sparse cell population is found in the regions closest to the source of nutrition near the periphery of the IVD.
When development is complete, the IVD is a relatively acellular, avascular tissue with little potential for self-repair. As a consequence of this process and the constant biomechanical demands placed on the spine, the balance in production and degradation of extracellular matrix components within the NP and AF becomes disturbed with aging. This can give rise to the morphologic appearance of IVD degeneration, and sometimes, symptomatic discogenic low back pain (LBP).
Biochemistry of the Intervertebral Disc
The biochemical composition of the individual components of the spine dictates the biomechanical behavior of the various structures of the spinal motion segment. Biochemical changes within the IVD are considered the primary drivers of the degenerative process and therefore will be the focus in this section.
Fig. 1.5: Schematic drawing of the major extracellular matrix component of the nucleus pulposus. Large, predominantly type 2 collagen fibers (pink) are randomly arranged throughout the matrix. Aggrecan molecules (circular inset), composed of highly charged chondroitin sulfate and keratin sulfate monomers connected to a core protein, surround the collagen fibers. Multiple aggrecan molecules are connected to long hyaluronan backbones (green) via link protein to form large proteoglycan aggregates.
The IVD and hyaline cartilage share a similar extracellular matrix molecule profile, likely due to the similar cell type populating both tissues (Fig. 1.5). It is estimated that 60% of the dry weight of the AF and 20% of the dry weight of the NP is made up of various collagen types, making it the most abundant protein in the disc. Both fibril forming (collagen I, II, III, V, XI) and short helical forming (collagen VI, IX, XII) collagen types are present in the disc.14 Type II collagen is the predominant type within the NP, creating a disordered fibrillar framework for other matrix molecules and cell attachment. There is a shift to a predominance of organized type I collagen with progression from the center of the NP toward the AF. Approximately 80% of the collagen molecules in the outer AF are type I.
The structure and distribution of collagen molecules within the IVD change in at least three significant ways as degeneration progresses.1 The AF and the NP become more fibrous tissues as a result of an increase in the ratio of type I to type II collagen in both structures. Advanced glycation end products are formed and accumulate due to the nonenzymatic cross-linking of collagen molecules. Production of collagenases by disc cells is also augmented, leading to enzyme-mediated proteolytic cleavage of collagen fibers. The consequence of these events is a buildup of incompetent fibrous collagen that decreases the compliance of the NP, limits its overall swelling ability, and impairs resistance to compressive loading.15
Up to 50% of the dry weight of the NP and 20% of the dry weight of the AF is made up of proteoglycans. After collagen, these are the second most abundant group of extracellular matrix molecules within the IVD. Versican, lumican, decorin, biglycan, and fibromodulin are all found in measurable quantities within the IVD; however, aggrecan is by far the most abundant proteoglycan.1 The NP's ability to attract and bind water is largely due to the highly charged nature of this molecule consisting of chondroitin-6 sulfate and keratin sulfate side chains bound to a core protein. The aggrecan of the IVD also forms large proteoglycan aggregates by binding to hyaluronan through interaction with link protein, further augmenting its ability of attracting water and maintaining disc hydration.
As the disc ages, there is a change in both the amount and character of aggrecan within the IVD. A reduction in both cell numbers and the rate of proteoglycan synthesis per cell leads to a decrease in overall aggrecan production. At birth, chondroitin sulfate is the most abundant glycosaminoglycan side chain present within aggrecan molecules. With age, however, there is a shift to a predominance of keratin sulfate side chains.16 Water-binding capacity and efficiency is diminished as both aggrecan and aggrecan-hyaluronan aggregates are subject to proteolytic degradation. Additionally, due to the large size of these molecules, the partially digested proteoglycans are not easily scavenged from the disc. Similar to the collagens, these molecules amass within the IVD and are subject to nonenzymatic cross-linking further contributing to the accumulation of advanced glycation end products.15
The principal proteolytic enzymes produced by native disc cells are a disintegrin and metalloprotease with thrombospondin motifs and matrix metalloproteinases (MMPs).17 The cells also produce natural antagonists to MMPs, namely, tissue inhibitors of metalloproteinases. These enzymes and enzymatic inhibitors, which are modulated by a number of biochemical stimuli including expression of growth factors and cytokines, are responsible for remodeling and maintenance of IVD matrix homeostasis. Clearly, a certain amount of tissue turnover is required to clear damaged molecules. However, the balance between anabolic and catabolic metabolism within the IVD can be altered due to age-related metabolic changes, genetic predisposition, and biomechanical dysfunction. This balance is generally shifted toward intensified catabolism, thus producing the biochemical changes typical of degeneration.
The consequence of these biochemical changes in collagen and proteoglycan content and enzymatic activity within the disc is a limited ability to adequately dissipate both compressive loads and progressive mechanical incompetence. Additionally, the impaired swelling pressure within the degenerated disc leads to a reduction in exchange of waste and nutrients, further starving the few remaining disc cells, which are diffusion dependent. The progressively fibrous matrix also places increased stress on the mechanically sensitive disc cells. The intracellular response to this microenvironment can lead to increased cell death and/or further upregulation of type I collagen and proteolytic enzyme synthesis, possibly contributing to downward degenerative spiral.18
Two adjacent vertebrae, the facets joints, an intervening IVD, and the various connecting ligaments form the functional spinal unit. The AF and end plates enclose the relatively incompressible hydrated NP. Both axial compression and eccentric loading result in even stress distribution across the cartilaginous end plate in nondegenerated IVD.19 In the unloaded condition, proteoglycans attract and hold water within the NP generating positive intradiscal hydrostatic pressure. When the spine is loaded, stress is transmitted through the compact subchondral bone of the end plate to the NP. This leads to an increase in pressure within the NP that, in turn, is transmitted to the organized lamellar structure of the AF and converted into tensile hoop stress resulting in altered spatial arrangement of the collagen network and a small amount of immediate decrease in disc height. If the load applied to the spine remains constant, slow outflow of fluid through the AF and end plates results in a viscoelastic creep phenomenon with the IVD continuing to lose height over time. When the load is eventually removed, the osmotic pressure generated by the proteoglycans within the healthy NP will cause an influx of fluid from the surrounding tissue to slowly recover the lost height.20 There is, therefore, a regular diurnal variation in IVD height with progressive loss of height during the day when upright, and recovery when supine at night.
Many rehabilitation regimes designed for patients with discogenic back pain are based on the in vivo intradiscal pressure measurements in various functional positions reported by Nachemson and Morris.21 In their study of undegenerated human discs, the unsupported sitting position resulted in the highest recorded intradiscal pressure (0.8–1.5 MPa). Conversely, the lowest pressures were measured in the discs of relaxed, supine subjects (0.1–0.2 MPa). Lifting, especially with an anterior positioned load, and other strenuous activities resulted in a significant increase in intradiscal pressure. These general trends observed by Nachemson were confirmed in two more recent studies.22,23 These studies also found a significant decrease in intradiscal pressure in degenerated IVDs (see Fig. 1.3).
The mechanical properties of the IVD change from those of a viscous semi-fluid to properties closer to those of a solid as the nucleus degenerates and becomes fibrous with decreased proteoglycan and increased collagen content.1 Stress distribution across the spinal motion segment becomes uneven as the more fibrous NP has a diminished overall swelling capacity and is unable to adequately conform to and transmit applied loads.24 The AF becomes overloaded and structurally damaged, especially when eccentric loads are applied to the IVD. Nucleus pulposus containment eventually fails, often through the development of fissures within the AF, as the degenerative process proceeds. Degenerated IVDs demonstrate altered creep characteristics with larger and more rapid deformation with any given load, and slower recovery when the load is removed.25 As the main load-bearing structure of the functional spinal unit fails, a higher portion of load bearing is transferred to the posterior elements. Osteoarthritic changes similar to other cartilaginous synovial articulations begin to manifest within the overloaded facet joints. While facet joint degeneration does not always progress in parallel to IVD degeneration, facet degeneration is not found in the absence of a degenerated IVD.26
The degenerative cascade proposed by Kirkaldy-Willis and Farfan explains the pathogenesis of spinal motion segment degeneration through three progressive phases.27 In the first “dysfunctional” stage, acute or repetitive injury can lead to the accumulation of microscopic damage within the disc and synovitis within facet joint. In the second “unstable” phase, diminished IVD height, in addition to facet capsule laxity and subluxation, leads to pathologic and potentially painful hypermobility of the degenerated spinal motion segment. Eventually, severe degenerative changes inducing disc osteophyte formation and facet enlargement lead to the third “stabilization” phase with resolution of the hypermobility present in stage two. The majority of back pain episodes are thought to occur during the first two stages of degeneration. In the third stage, discogenic back pain is relatively uncommon; however, patients may remain or become symptomatic from spinal stenosis due to hypertrophy of the facet joint and disc bulging. Recent cadaveric studies in both the lumbar28 and cervical spine29 have supported this observation, reaffirming the relationship between spinal motion and disc degeneration.
Macroscopic and Radiographic Changes
The biochemical and biomechanical alterations within the IVD result in well-described macroscopic changes. This progressive deterioration is the basis of the grading system proposed by Thompson et al. based on gross pathologic changes visible as the disc degenerates.30
As pathologic examination is not usually practical, clinicians rely on radiographic imaging to diagnose degenerative disc disease. On plain X-ray, disc space narrowing, end plate sclerosis, and osteophyte formation at the margins of the affected level characterize degeneration. In more severe cases, gas collections can be visible within the disc. Degenerative changes on magnetic resonance imaging (MRI) provide a more detailed assessment of the state of the IVD. However, clinical correlation with the radiologic finding is always important, as MRI abnormalities are found in a large percentage of asymptomatic individuals.31,32 On T2-weighted sequences, loss of NP hydration results in progressive loss of signal intensity. Pfirrmann et al.33 described an MRI grading scale of degenerative changes, similar to the pathologic Thompson scale (Table 1.1 and Fig. 1.6). Tears within the AF are often visible,34 as well as end plate signal changes, both of which can be indicative of degenerative disc disease (DDD). Modic et al.35 classified end plate signal changes into two types: Modic type I changes, indicative of augmented marrow fibrovascularity, demonstrate decreased signal intensity on T1-weighted sequences and increased signal intensity on T2-weighted sequences; whereas, Modic type II changes are characterized by increased signal intensity on T1-weighted sequences and isointense or slightly increased signal on T2-weighted sequence. The correlation of these changes with back pain is still the subject of debate.36–39
As degeneration within the disc progresses, arthritic changes in other parts of the spinal motion segment become evident on imaging. Degenerative changes within the facet joint can become clinically important, and severity can be graded with either computed tomography scans or MRI.26,40
Fig. 1.6: Grading disc degeneration: T2-weighted magnetic resonance images (left panel) and gross pathology mid-sagittal sections (right panel) of intervertebral discs demonstrating progression of degenerative changes from Pfirmmann/Thompson Grade I, with no degeneration to Pfirmmann/Thompson Grade V, with severe degeneration and disc space collapse.
The combination of both IVD and facet degeneration can lead to spinal stenosis and segmental instability, known as spondylolisthesis (Fig. 1.7). If degeneration progresses over multiple levels, alteration in both coronal and sagittal alignment can occur resulting in degenerative lumbar scoliosis or kyphosis. When asymmetric degeneration of the IVD and/or the facet joints occurs, the spinal motion segment is loaded unevenly. Over several years, an asymmetric deformity (i.e. scoliosis and/or kyphosis) can develop. The developing deformity further alters the load distribution, setting up a cycle, with the deformity again triggering additional asymmetric degeneration and inducing more asymmetric loading.41 These changes often occur in postmenopausal females or older men who have altered bone metabolism and some osteopenia.42 These patients may experience collapse of weak osteoporotic vertebrae and develop asymmetric bony deformity, which can contribute to further progression of either scoliosis or kyphosis. At each level, translational dislocations in either the coronal plane alone or three-dimensionally can occur in addition to spondylolisthesis, leading to rotational subluxation.43
The degenerative changes not only lead to spinal deformity, but are also likely to result in the development of spinal canal narrowing, known as spinal stenosis. This stenosis, a result of disc narrowing, disc bulging, facet hypertrophy, and vertebral translation, can impinge on the neural elements in the spinal canal or neural foramen. Clinically, patients with stenosis can experience back pain and/or leg pain in the form of radiculopathy or neurogenic claudication.
ETIOLOGY OF DISC DEGENERATION
Lumbar spine degeneration is considered an unavoidable consequence of aging. In one anatomic study, macroscopic disc degeneration was found in 98% of specimens above the age of 70 years, and in only 16% of specimens below the age 20 years.44 Fortunately, while extremely common on pathologic examination and imaging, spinal degeneration is frequently asymptomatic.31,32 In patients with back pain, it can be a clinical challenge to determine which degenerated structures are the pain generators and which are incidental findings.
Fig. 1.7: Mid-sagittal (left panel) and axial (right panel) T2-weighted magnetic resonance imaging of the lumbar spine of a 64-year-old woman who presented with both low back and bilateral leg pain. The hallmarks of disc degeneration are apparent at the L4-5 level (arrow head) on the sagittal including loss of nucleus pulposus hydration and disc space narrowing. Facet joint hypertrophic osteophyte formation is evident on the axial images (arrows). These degenerative changes have resulted in spondylolisthesis, with L4 slipped forward on L5 (left panel), and severe spinal stenosis (*, right panel).
There are many etiologic factors that have been linked to the development of spinal degeneration. As discussed previously, the disc cells are responsible for maintenance of homeostasis within the IVD. Therefore, anything that impacts the microenvironment within the NP or alters disc cell metabolism and synthetic rate can accelerate the degenerative process. These factors can be environmental, mechanical, and/or genetic.
Intervertebral disc nutrition has been implicated as a major contributor to degeneration.45 As detailed above, the blood vessels supplying the NP recede in the first two decades of life leaving the disc cells largely dependent on diffusion through the end plates and outer AF for nutrition.12 As the end plates calcify with age, diffusion into the IVD is impeded further. The cells at the center of the mature NP can be several millimeters from the nearest blood supply, severely limiting nutrient diffusion.12 Viability of these cells is significantly impacted by the loss of nutritional support, leading to a decreased number of cells over time.46 Lack of nutrients and low oxygen tension shift the metabolism of the remaining cells to the anaerobic pathway, leading to lactate production and lowered tissue pH. In these conditions, the rate of matrix synthesis by disc cells drops off further.47,48 The combination of a low number of viable cells and less matrix synthesis per cell shifts the balance of homeostasis within the disc to one of net catabolism. Systemic diseases that can alter vertebral blood supply, such as atherosclerosis,49 have been associated with higher rates of disc degeneration. Smoking has also been linked to the development disc degeneration and back pain in several epidemiologic studies.50,51 The negative effects of smoking on the disc are thought to be mediated both through nutritional restriction52,53 and direct nicotine toxicity to disc cells.54,55
Alteration in mechanical loading has also been implicated as a cause of disc degeneration, with changes in the biomechanical environment leading to biochemical changes within the tissue.56,57 Excess, or asymmetric mechanical loading of the disc can lead to localized tissue trauma. Tissue repair will be minimal due to slow turnover of the disc matrix.58 Prolonged mechanical loading can lead to a higher rate of apoptosis of IVD cells.59 Additionally, excessive hydration or dehydration of the disc has been shown to significantly decrease the rate of matrix synthesis.60,61 The combination of repetitive microtraumas and the decreased turnover and synthetic rate of disc cells and matrix, ultimately leads to progressive structural failure of the disc, making it more susceptible to further injury.
Genetic susceptibility has also been implicated as major contributing factor to disc degeneration. The so-called “Twin Spine Study”62 compared the rates of IVD degenerative changes in monozygotic twins in three countries with discordant exposure to occupational or sport-related spinal loading. The data demonstrated that genetic factors are the primary predictor of disc degeneration, with heredity accounting for up to 74% of the variance present in the adult population. This dispelled the previously held belief that mechanical injury was the strongest driver of degeneration. Further work by Videman et al.63 demonstrated that polymorphism within vitamin D receptor gene was associated with disc degeneration. Other gene polymorphisms including aggrecan,63 interleukin-1 and COL9A3,64,65 COL9A2,66 collagen IX and XI,67 and MMPs-368 have been linked to the development of disc degeneration.
Chronic low-grade infection has recently received some attention as a potential contributor to disc degeneration and LBP. Albert et al.64 cultured herniated disc material from patients undergoing discectomy. The study found microorganisms to be present in 46% of herniations, with the anaerobic bacteria Propionibacterium acnes being the most common isolate detected. The study further demonstrated a statistically significant higher rate of type 1 Modic changes in patients with disc material infected with anaerobic bacteria. A follow-up randomized controlled trial demonstrated improved clinical outcomes in patients with chronic back and previous herniated discs after 100 days of antibiotic therapy.65 The generalizability of these exciting findings to the general population of LBP patients has yet to be determined.
An understanding of the biomechanical and biochemical processes as well as the etiologic factors leading to spinal degeneration is important. However, from a clinical perspective, an essential question remains to be answered—what is the source of pain in the degenerating spinal motion segment? This is especially relevant as there is a poor correlation between the morphologic signs of degeneration and back pain.66 No single answer to these questions has emerged; however, it has become clear that several sources of pain exist.
Pain originating from the IVD, termed discogenic pain, has long been implicated as a major player in the process; however, its etiology is not well understood. The central end plate and the periannular tissues have the most abundant nerve supply of the IVD.67 The outer rim of the AF is thought to contain the bulk of IVD nociceptive fibers arising from the sinuvertebral nerve, a meningeal branch of the spinal nerve originating from the dorsal root ganglia (Figs. 1.8A and B). It has been demonstrated in animal models that the caudal IVDs may be innervated by the L1 or L2 dorsal root ganglia through the sympathetic trunk.68–71 Thus, discogenic back pain may be referred to the groin (i.e. the L2 dermatome). There is currently debate in the literature as to whether or not this finding may be of diagnostic or therapeutic value.72,73
Discography, injection of fluid into the IVD, has been used as a provocative test for discogenic pain; however, its accuracy in predicting the source of pain in response to treatment is still quite controversial.74 Stretch of an abnormal AF, extravasation of foreign tissue into the peridural space, and pressure on adjacent nervous structures are thought to be mechanism for pain generation. In vitro experiments have demonstrated that human IVD cells increase production of nerve growth factor when exposed to interleukin-1β and tumor necrosis factor-α, both important proinflammatory cytokines.75 This may promote infiltration of nociceptive nerve fibers into the disc and lead to back pain. Other authors have attempted to find differences in morphologically degenerate discs with varying degrees of clinical symptoms. Keshari et al. found that proteoglycan, lactic acid, and collagen ratio as measured by nuclear magnetic resonance spectroscopy differed in symptomatic and nonsymptomatic abnormal IVDs.66 These findings may serve as the basis for a diagnostic test at some point in the future.
The facet joints have been noted to be a major source of pain since early in the 20th century.76,77 The load to the facets is maximal with lumbar hyperextension, and is further increased when disc height is lost as a result of degeneration.78 Experiments using both provocative and therapeutic intra-articular injections confirmed the facets joints to be a significant pain generator in patients with LBP.79,80
Figs. 1.8A and B: Innervation of the intervertebral disc. (A) Ascending and descending branch of the sinuvertebral nerve shown arising from the dorsal root ganglion (DRG). (B) Course of the recurrent sinuvertebral nerve from the DRG through the vertebral foramen innervating the outer annulus fibrosus.Source: Raj PP. Intervertebral disc: anatomy-physiology-pathophysiology-treatment. Pain Pract. 2008;8(1):18-44.
Additionally, both sensory and autonomic nerve fibers as well as neurotransmitters have been shown to be present in the facet capsule.81 The lumbar facet joints are segmentally innervated by the medial branch of the dorsal rami.82 Thus, intra-articular facet joint injections, and medial branch block or ablation is a commonly employed treatment for chronic LBP. Evidence for the efficacy of these treatments remains unclear, especially in the long term.83–85
Nerve root compression or irritation can also be a mechanism for pain production in lumbar degeneration. While this most often presents as radiculopathy, with pain radiation to the dermatomes of the lower extremities, nerve compression can also cause isolated back pain. The pathophysiologic basis for neurogenic pain is a subject of debate; however, recent studies have demonstrated increased neuropathy, ectopic discharge, and mechano-sensitization of nerve roots when exposed to NP tissue, a situation commonly found in the degenerated lumbar spine.86
As more information emerges in the literature, it is clear that the area of pain generation deserves further study both mechanistically and diagnostically in order to enable researchers and clinicians to develop and plan appropriate therapies.
Biologic Therapy for Lumbar Degeneration
Although our understanding of the mechanisms of spinal degeneration has advanced significantly, the current standard of care for patients with lumbar degeneration is aimed at symptomatic control rather than reversal of the disease process. Nonsurgical therapeutic modalities including patient education, medications, exercise therapy, and occasionally various types of injections are commonly employed. In a small number of patients with unrelenting symptoms, surgical intervention to decompress, stabilize, or even replace the affected motion segments is recommended. While these interventions can be effective, they come at a high cost and put patients at risk of complications. As discussed previously, spinal degeneration is believed to begin with changes in the NP of the IVD. Thus, biologic repair to slow or reverse the early nucleus degenerative process is an attractive alternative to the current end-stage mechanical treatment approaches. Successful biologic repair strategies require a consideration of one or all of the following components: delivery of cells, the application of therapeutic molecules, and the supplementation of matrix.11
The density of cells present in the NP decreases significantly with aging and degeneration.13 In order for tissue repair to be possible, a new population of cells is necessary to produce appropriate extracellular matrix molecules and supplement the existing population. This can be achieved by implantation of new healthy cells into the disc, and/or by stimulation of native cell proliferation with bioactive molecules. A small clinical study examined the utility of autologous disc cell harvest, followed by ex vivo expansion and subsequent reimplantation.87 While the possibility of supplementation with autologous cells is attractive, concerns with the practical application of this strategy and the infrastructure necessary to harvest and expand the cells ex-vivo have prompted the investigation of other source of cells. Pluripotent cells, such as mesenchymal stem cells, are interesting candidates for cell supplementation as they can be harvested from several sources and are highly metabolically active in the proper environment. They have thus become the focus of many studies. Experiments conducted both in vitro and in vivo have demonstrated that mesenchymal stem cells can be successfully differentiated into chondrocyte-like cell populations. Under appropriate conditions, these cells can express IVD matrix proteins and cell surface markers.88–99 Based on successful recent in vivo work with an ovine model of disc degeneration,100 a phase 2 human clinical trial using cell-based therapy is currently underway. The study is designed to determine the safety and initial efficacy of injecting mesenchymal precursor cells in a hyaluronic acid carrier into the degenerating IVDs. Results of this study have yet to be released; however, this represents an important step in the translation of this technology from the laboratory to clinical application.
The delivery of bioactive molecules to alter the catabolic environment of the degenerating NP is another cornerstone of a successful regenerative strategy. There are four basic categories of potentially therapeutic bioactive molecules: anticatabolics, mitogens, chondrogenic morphogens, and intracellular regulators.11 The chondrogenic morphogens, which include transforming growth factor-β and the bone morphogenetic protein (BMP) family, have been the focus of much investigation in this field. Proteoglycan and collagen synthesis is increased in response to transforming growth factor-β treatment of both healthy and degenerated IVD cells in vitro.101–103 The BMP family of growth factors is currently used clinically to promote fracture healing and spinal fusion as they have been shown to induce osteogenesis. Interestingly, disc cells treated with BMP-2 and BMP-7 (osteogenic protein-1) show increased production of collagen type II and proteoglycans, without osteogenic effects seen in other environments.104–107 In preclinical animal experiments, direct injection of a single dose of BMP-7 into degenerating discs resulted in improved disc height, restoration of viscoelastic biomechanical properties, and healthier functional metabolism.108,109 Another member of the BMP family, growth differentiation factor-5, was found to improve IVD cell viability and extracellular matrix production in vitro, and to curb progression of degeneration in a preclinical model.110 Several other potentially therapeutic molecules, including interleukin-1 receptor antagonist, platelet-derived growth factor, and insulin growth factor-1, are currently being investigated for their effects on IVD cells and disc degeneration.
Despite encouraging in vitro and in vivo studies, there is some concern that a single direct injection of a therapeutic molecule into the IVD may not be sufficient to stimulate and maintain the repair process. Gene therapy has been proposed as a method to achieve long-term sustained expression of stimulatory molecules from cells within the IVD. The potential for immune reaction and the spread of disease have raised safety concerns with the employment of viral vectors to deliver gene therapy elsewhere in the body. Due to its relative avascularity, cells of the immune system have limited access to the IVD and it is considered to be an immune-privileged environment. Thus, viral transfection of both native disc cells and exogenous chondrocytes with vectors to promote expression of several therapeutic factors has been attempted. The genes of interest include both intracellular regulatory proteins and growth factors. Both cell culture work and in vivo experiments examining the delivery of the transcription factor Sox-9, known to be an important regulator of the chondrocytic phenotype, to nucleus cells via a recombinant adenovirus have demonstrated upregulation of proteoglycan synthesis and reversal of early degeneration.111,112 Increased cell viability and augmented production of extracellular matrix molecules have also been demonstrated with adenoviral transfection of both animal and human NP cells with several growth factors including transforming growth factor-β1, BMP-2, BMP-7, and insulin growth factor-1.112–114 Data from these experiments have served as a proof of principle that transfections of cells with stimulatory genes and subsequent implantation of these altered cells into the degenerating disc may represent an effective strategy for cell therapy and the delivery therapeutic molecules in a single treatment.
Scaffolds to serve as cell or drug carriers and supplement the degenerating extracellular matrix are the final component of a successful IVD tissue-engineering strategy. A wide variety of candidate materials have been investigated. A scaffold must provide a favorable microenvironment for cell growth, migration, and synthesis of extracellular matrix in order to be successful. Ideally, constructs must have mechanical properties capable of withstanding the loads within the IVD in the short term, and then incorporate and remodel as the disc regenerates.115 Many of the scaffolds studied are designed by combining fibrillar molecules and glycosaminoglycans in an attempt to re-create the normal matrix components of the IVD.116–120 This aspect of regenerative therapies continues to be the subject of active investigation.
The lumbar spine is a complex structure elegantly designed to support upright posture and protect the neural elements. Lumbar degeneration occurs as an inevitable part of aging and results in altered biochemical and biomechanical function as well as anatomic abnormalities. These changes result in a wide spectrum of symptoms, from completely asymptomatic to debilitating pain and functional decline. As our understanding of the makeup and function of the various components of the lumbar spine advances, opportunities for interventions to halt or reverse this process at early stages are evolving. In the future, these interventions may allow the next generation of physicians to change, for the better, the way we treat the aging lumbar spine.
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