Identifying Inflammatory Targets for Biologic Therapies for Spine Pain

Biologics Supplement

Identifying Inflammatory Targets for Biologic Therapies for Spine Pain Lloydine J. Jacobs, MD, Nam Vo, PhD, James D. Kang, MD Abstract: The costs associated with treating spine-related conditions are enormous and are trending upward. Current methods employed to treat inflammatory-mediated pain are targeted at alleviating symptoms, rather than correcting the underlying cause of disease. It is clear that a biochemical basis for inflammatory-mediated intervertebral disk, facet joint, and nerve pain exists. Biologic therapies that address the underlying cause of pain could potentially decrease the costs associated with treating spine pathology. MMPs, IL-1, TNF- ␣, IL-6, NGF, bradykinin, prostaglandins, and nitric oxide are implicated in much of the catabolic effects seen in the pathogenesis of inflammatory-mediated pain and are good targets for inhibition. The anticatabolic and anabolic effects of TIMPs, BMPs, TGF- ␤, and IGF-1 are targets already shown to favorably impact disk matrix homeostasis. With rapid advances in biomedical technology, these interventions may be available for clinical use in the near future. PM R 2011;3:S12-S17

INTRODUCTION: CLINICAL SIGNIFICANCE AND SOCIOECONOMIC IMPACT OF SPINE PAIN Spine-related conditions are among the most common causes of temporary and permanent disability among all workers aged 18 to 64 years. In particular, back pain, which includes conditions related to the cervical and lumbar spine, is the most common reason for an outpatient doctor’s visit among Americans today [1]. Statistics show that back pain is actually more commonly reported than migraine headaches or sinusitis. Approximately 60%-80% of adults are affected by back pain at least once in their life, which makes it an important public health issue [2]. At the time of final evaluation, intervertebral disk degeneration is reportedly one of the most prevalent contributors of back pain [3]. The National Center for Health Statistics reported the estimated annual cost for spinerelated medical care to be $190 billion dollars from 2000-2004, which represents an increase of $60 billion dollars from 1996-2000. These numbers reflect the cost of prescription drugs, ambulatory or inpatient care, imaging studies, and indirect costs, such as wages lost secondary to disability [4]. The costs expended in treating spine-related conditions are enormous and are trending upward. New biologic therapies that address the underlying cause of pain could potentially decrease the costs associated with treating spine pathology. A greater understanding of the biologic basis of spine pain is essential to identify potential targets for biologic therapies.

NEED FOR BIOLOGIC THERAPEUTIC INTERVENTIONS The current methods used to treat inflammatory-mediated pain are targeted at alleviating symptoms rather than correcting the underlying cause of disease. This commonly leads to recurrence of symptoms at the same or neighboring areas in the spine. Diskectomy procedures may relieve ridicular pain but do not completely restore the disk’s original load-bearing capacity. Spinal fusion procedures limit motion at the involved segments, which can induce disk degeneration at neighboring spinal levels. Facet injections with local injection of steroids and anesthetics potentiates the inflammatory response and may relieve pain for weeks to months but does not address the underlying cause of pathology. Physical PM&R

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L.J.J. Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. Address correspondence to: L.J.J.; e-mail: [email protected] Disclosure: nothing to disclose N.V. Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA Disclosure: nothing to disclose J.D.K. Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA Disclosure: nothing to disclose Disclosure Key can be found on the Table of Contents and at www.pmrjournal.org Submitted for publication January 19, 2011; accepted May 1.

© 2011 by the American Academy of Physical Medicine and Rehabilitation Vol. 3, S12-S17, June 2011 DOI: 10.1016/j.pmrj.2011.05.003

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therapy and analgesics also are helpful but still do not address the underlying biologic process. Kirkaldy-Willis [5] described the cascade of degenerative changes and its role in producing spine pain in the 1980s; there are 3 phases: dysfunction, instability, and stabilization. Optimal management of spine pain is dictated by the current phase of each patient. The dysfunction phase begins with the inciting traumatic event that can cause outer annular tears, endplate separation, cartilage destruction, or synovial reaction of the facet joints. An inflammatory response is initiated, and the patient displays local tenderness on examination, as well as hypomobility and pain. The dysfunction stage is followed by the instability stage in which the inflammatory state tips the homeostatic balance into net catabolism. Disk resorption with loss of disk height, and facet joint subluxation secondary to facet capsular laxity may result. Patients experience that their back “gives way,” “catches” with movement, or hurts with standing after flexion. The final stage of stabilization is characterized by osteophyte formation, with resultant canal and foraminal stenosis. Pain begins to decrease in severity, and the physical examination results show localized muscle tenderness, stiffness, and hypomobility. Efforts have been made toward treating the biologic derangements that lead to spine-related pain, but they are not yet clinically translatable. The field of regenerative medicine and tissue engineering has yielded 3 potential areas of focus for treating intervertebral disk degeneration (IDD): gene therapy, stem cell transplantation, and intervertebral disk transplantation [6]. Elucidation of the molecular pathways involved in inflammatory-mediated spine pain is central to the effective development of treatment modalities that can address the underlying causes of spine pathology and pain.

SOURCES OF INFLAMMATORY-MEDIATED SPINE PAIN Back pain can originate from pathologic changes in any of the structures within the spine and the surrounding musculoskeletal structures. These include the intervertebral disks, facet joints, nerve roots, vertebral bodies, ligaments, and the paraspinal muscles. Acute pain serves as the body’s alarm system in response to damage that may threaten the host. It results from physical stimulation of nociceptors and from cytokine signaling. Hyperalgesia, or peripheral nerve sensitization, is a central feature of inflammation. Mediators produced at the sites of inflammation have been known to produce pain through many different biochemical pathways. Increased tissue levels of tumor necrosis factor ␣ (TNF-␣) stimulates secretion of nerve growth factor through an interleukin (IL) 1␤ mediated pathway. The inflammatory markers seen in patients with diskogenic back pain usually are not found in patients with asymptomatic injured disks [7]. This supports the role of inflammation in spine pain. A thorough under-

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standing of the inflammatory response to injury is the first step toward identifying potential targets for biologic intervention.

Sources of Inflammatory-Mediated Spine Pain: Intervertebral Disk The primary function of the intervertebral disk is to serve as a shock absorber, transmitting compressive loads between vertebral bodies. Each disk is composed of 3 distinct regions: the cartilaginous endplates, the nucleus pulposus, and the annulus fibrosus. The annulus fibrosus is a tough, fibrous structure that surrounds the gelatinous nucleus pulposus. Compressive forces are transmitted through the superior vertebral body to the superior endplate, the nucleus pulposus, the annulus fibrosus, and finally to the inferior endplate and onto the subjacent vertebral body [8]. The major components of the disk matrix are water, collagen, proteoglycans, and elastin [9]. The annulus fibrosus has the highest collagen content overall, with collagen type I being more predominant in the outer layers. Collagen type II is highest in the nucleus pulposus and decreases toward the periphery of the disk. A variety of proteoglycans exist in the intervertebral disk, but aggrecan is the most prevalent proteoglycan in the disk and is heavily concentrated in the nucleus pulposus [10]. Aggrecan is responsible for creating and maintaining disk turgidity by forming aggregates that trap water inside the disk. Although proteolytic degradation of aggrecan plays a large role in matrix degradation and subsequent disk degeneration, matrix catabolism is necessary for ensuring cell survival, as well as disk tissue integrity and repair after injury. Proteoglycans that are not incorporated into aggregates can negatively impact disk swelling pressure [11]. Catabolic degradation of excess, unincorporated proteoglycan molecules is beneficial. It is a chronic imbalance in matrix homeostasis that leads to net loss of matrix, which results in premature disk degeneration and diskogenic pain. The major catabolic enzymes in the disk are matrix metalloproteinases (MMP) and ADAMTs (a disintegrin and metalloproteinase with thrombospondin motifs) [12]. MMPs and ADAMTs degrade the collagen and proteoglycan found in the disk. Disk catabolism is primarily balanced by specific tissue inhibitors called TIMPs (tissue inhibitors of metalloproteinases). Under inflammatory stress, gene expression of TIMPs is normally suppressed while MMP expression is enhanced [13], which leads to a net increase in proteolytic activity and matrix degradation. The abnormal matrix of degenerated disks triggers cell signaling that further promotes proinflammatory behavior. This behavior is modulated through a number of cytokines and growth factors, such as IL-1␤ and transforming growth factor ␤ (TGF-␤). IL-1␤ is one of the most important cytokines in the degenerative cascade [14] (Figure 1). IL-1␤ has

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Figure 1. In normal disk matrix homeostasis, matrix synthesis and breakdown are balanced. In degenerating disks, there is an increase in matrix breakdown mediated by MMPs, ADAMTS, TIMPs, prostaglandins, and various inflammatory cytokines. Matrix synthesis also is decreased.

been shown to decrease proteoglycan synthesis in disk matrix cells by regulating other cytokines, such as nitric oxide, IL-6, and prostaglandin E2 [15]. Ultimately, IL-1␤ triggers matrix catabolism and degeneration by stimulating MMP release and activation. The pain generated by symptomatic intervertebral disks results from the body’s attempt to heal the inciting injury via an inflammatory response [16]. Tears in the outer annulus fibrosus of the intervertebral disk initiate an inflammatory response mediated by markers such as fibroblast growth factor (FGF) and TGF-␤ [17]. These markers promote cellular proliferation, matrix deposition, and granulation tissue formation. They also attract inflammatory cells that play a role in the tissue degradation and fibrosis. Proinflammatory cells, such as macrophages and mast cells, have been shown to secrete nerve growth factor capable of inducing nerve

ingrowth into the inner layers of the disk. With time, the cells of the nucleus pulposus and annulus fibrosus also secrete nerve growth factor under inflammatory stimulation [18]. Irritating enzymes released from inflammatory cells sensitizes the newly synthesized nerve fibers, which may account for the pain experienced after annular injury in symptomatic patients. These changes are not observed in aging or asymptomatic “black” disks [17]. Nerve growth factor promotes nerve ingrowth into the inner annulus and also sensitizes nociceptors that lead to hyperalgesia [19]. Injury to the outer annulus of the disk initiates the production of proinflammatory agents in early and delayed phases. Increases in TNF-␣, IL-1␤, and IL-8 have been implicated in the early, transient inflammatory response in association with static loading of the disk [20]. Stab-induced annular degeneration in the rabbit model is

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associated with an early peak in expression of IL-1 and inducible nitric oxide synthase at 3 weeks [21]. It subsequently decreases then reproducibly peaks again at 12-24 weeks after injury. The second peak in cytokine production is conceivably triggered by the overall severity of disk degeneration and resultant altered biomechanics [22]. Targeting Biologic Therapies. The catabolic imbalance of disk matrix homeostasis present in inflammatory-mediated degeneration is where biologic intervention could conceivably be beneficial. Therapeutics that target the catabolic enzymes, such as the MMPs and ADAMTs, would inhibit excessive matrix degradation. The inhibitors of MMPs (TIMPs) are another area of potential focus. Safety of these interventions would need to be established, because MMPs have other important functions besides degrading matrix. Also, tipping the homeostatic balance into uncontrolled anabolism could have negative consequences because this may outpace the limit of nutrient diffusion into the degenerating disk.

Facet Joint The zygapophyseal joint, also known as the facet joint, is a synovial joint formed by the articulation of the inferior articular process of one vertebra with the superior articular process of the inferior vertebra. The facet joint is a load-bearing structure in the lumbar spine. With aging, the joint becomes more “C” shaped, or biplanar and forms coronally oriented joints [23]. Changes in normal joint angles can increase the biomechanical strain on the joint and induce degeneration [24]. The amount of load borne is dependent on the degree of degeneration of surrounding structures. These anatomic and biomechanical factors suggest an important role for facet joint degeneration in back pain. The facet joint is covered by hyaline articular cartilage, which is a glassy-appearing, relatively acellular structure that consists of chondrocytes and their extracellular matrix. The matrix secreted by chondrocytes consists of water, type II collagen, and proteoglycans. Similar to the intervertebral disk, proteoglycans such as aggrecan are important in maintaining the hydration of the matrix. Synovial cells line the articular cartilage and secrete synovial fluid, which maintains a frictionless environment within the joint during motion. Type A synovial cells are similar to macrophages in nature and are the cells that initiate the inflammatory response after phagocytosis of debris created within the joint [25]. Articular cartilage is avascular and has a limited capacity for regeneration after injury. IL-1 and TNF-␣ impair anabolic pathways in chondrocytes, further limiting their capacity for healing after injury [26]. The inflammatory response stimulated by cartilage degeneration causes local activation of MMPs and ADAMTs. As in the intervertebral disk, TIMPs are responsible for inhibiting these degradative enzymes.

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Although studies that specifically address the catabolic process in facet joints are limited, these joints are lined by articular cartilage and, therefore, should share much of the properties of articular cartilage elsewhere in the body. Under inflammatory conditions, gene expression of TIMPs is normally suppressed while MMP expression is enhanced, which leads to a net increase in proteolytic activity and matrix degradation. Injury to articular cartilage tends to result in fibrous scarring because of the decreased ability of chondrocytes to regenerate. The resultant fibrocartilage is biomechanically inferior to articular cartilage and degenerates more readily under loading [27]. IL-6 has been shown to potentiate the effects of IL-1 in stimulating MMP production, by inhibiting production of proteoglycan and recruiting inflammatory cells to synovial tissue [28]. Enzymatic degradation by MMPs and ADAMTs significantly outweighs the regenerative capabilities of chondrocytes in facet articular cartilage, which leads to net catabolic destruction with inadequate matrix production. IL-6 has been shown to modulate the inflammatory response, to some degree, by enhancing the production of TIMPs and not MMP by a negative feedback mechanism [29]. There are no nerve fibers in the cartilage of the facet joint, although that is the place where most of the inflammatorymediated matrix degeneration is focused. Nerve fibers are found in the joint capsule, synovium, subchondral bone, and even in the marrow cavities of osteophytes [30]. These fibers contain mechanosensitive afferents that mediate both nociception and proprioception [31]. Degeneration of the intervertebral disk can cause increased facet joint loading as the disk loses height [32]. Facet joint degeneration presents with progressive articular cartilage loss, capsular redundancy, and, finally, degenerative spondylolisthesis. The degenerative changes in the joint cartilage create debris that activates macrophages, which then initiate the inflammatory response. Patients with inflammation of the facet joint sense an exaggerated pain response to relatively normal stimuli, such as standing, walking, or sitting [33], which may relate to the changes in the nocioceptive system of the joint. Inflammatory cytokines, such as IL1-␤ and TNF-␣, stimulate the production of nerve growth factor from the synovial cells that line the facet joint [34]. Synovial cells express nerve growth factor receptors, which stimulates them to proliferate when activated, which further potentiates the role of inflammation in pain transmission and hyperalgesia. In addition, IL-1␤ levels have been found to be elevated in the articular cartilage and synovial membrane of the facet joint in patients with facet hypertrophy. Patients with higher levels of IL-1␤ also had more pain than those with lower levels of IL-1␤ [35]. Targeting Biologic Therapies. Modulation of the inflammatory effects of IL-1 and TNF-␣ has the potential to significantly decrease degradation of the facet joint and thereby lessen inflammatory-mediated facet joint pain. Re-

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combinant IL-1 receptor antagonists and soluble IL-1 receptor proteins have been shown to suppress MMPs in rabbit synovial cells [36]. Likewise, inhibiting TNF-␣ receptors or targeting TNF-␣ convertase enzyme are more targets for inhibition. Because inflammatory cytokines decrease the biosynthetic pathways in chondrocytes in the facet cartilage, which supplementation with TGF-␤ or insulin-like growth factor-1 may help to boost anabolism.

Nerve Pain Radiculopathic pain classically has been thought to result from disk herniation and impingement on the nerve roots. This concept was expanded upon in the early 20th century to include inflammatory mediators of nerve root irritation and pain in addition to mechanical compression alone. Several observations support an inflammatory component in the pathophysiology of radiculopathy. Not all patients with magnetic resonance imaging proven herniations with nerve root impingement are symptomatic, and not all symptomatic patients improve after decompression. Many patients with persistent herniations and compression improve after conservative management with nonsteroidal anti-inflammatories. There also are symptomatic patients without any radiographic evidence of impingement. These findings are best explained by an inflammatory-mediated mechanism, as opposed to a pure mechanical mechanism [37]. Results of studies specifically looking at the herniated nucleus pulposus suggest that it is a major source of TNF-␣, which initiates the inflammatory cascade [38]. The current thinking is that herniated material from the nucleus travels within the epidural space and leads to sensitization of different nerve roots through the action of bradykinin and prostaglandins [39], which may explain why some nerve roots are symptomatic in the absence of mechanical compression. Compression of sensitized nerve roots can lead to more severe pain. Herniation of the nucleus is also implicated in edema production, intravascular coagulation with resultant blood flow reduction, and in myelin splitting [40]. In addition, compression of the neuronal vascular supply causes hypoxia with resultant nitric oxide release. Neuronal vascular permeability is enhanced by nitric oxide release, which results in the breakdown of the blood-nerve barrier. The endoneurial pressure increases, which causes demyelination of the nerve root. T cells sense destruction of the myelin sheath and release inflammatory chemotactic agents, for example, macrophage activating factor. These agents stimulate macrophages to secrete IL-1␤ and more TNF- ␣, which acutely sensitize nerve roots and cause hyperalgesia [41]. Targeting Biologic Therapies. As discussed for inflammatory-mediated diskogenic and facet pain, IL-1, TNF- ␣, bradykinin, and prostaglandins are good targets for novel biologic intervention. Nitric oxide plays a role in dilatation of neuronal vasculature, which leads to demyelination, and,

therefore, is another potential target. Modulation of the effects of nerve growth factor may also be of benefit.

CONCLUSION It is clear that a biochemical basis for inflammatory-mediated intervertebral disk, facet joint, and nerve pain exists. A special emphasis was placed on inflammatory markers and their role in the pathogenesis of pain to identify potential targets for biologic intervention. The costs related to spine pain in our society are enormous and only expected to increase in the near future unless novel biologic methods are developed. Development of effective biologic therapeutics pose a challenge because the agent would need to single out pathologic processes while preserving the beneficial aspects of the inflammatory response. MMPs, IL-1, TNF-␣, IL-6, bradykinin, prostaglandins, and nitric oxide are implicated in much of the catabolic effects seen in the pathogenesis of inflammatory mediated pain and are good targets for inhibition. The anticatabolic and anabolic effects of TIMPs, BMPs, TGF-␤, and insulin-like growth factor-1 are targets already shown to favorably impact disk matrix homeostasis. With rapid advances in biomedical technology, these interventions may be available for clinical use in the near future.

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