Structure and Biology of the Intervertebral Disk in Health and Disease
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Structure and Biology of the Intervertebral Disk in Health and Disease Wilson C.W. Chan, PhDa, Kit Ling Sze, PhDa, Dino Samartzis, DScb, Victor Y.L. Leung, PhDc, Danny Chan, PhDa,* KEYWORDS Intervertebral disk Degeneration Extracellular matrix Development Biology Low back pain is a leading debilitating condition sixth and seventh decade of life.24,25 However, that affects every population worldwide,1 and the development or, rather, severity of IVD degen- can lead to diminished physical function, loss of eration is not linearly based on age; degenerative wages, decreased quality of life, and psycholog- changes can be noted in young children and not ical distress.1–4 In fact, chronic low back pain yet be manifested in other adults.19,24 Overall, the may also lead to brain tissue destruction.5–8 As true prevalence of IVD degeneration in populations a consequence, low back pain is one of the most has yet to be determined, due to improper surveil- common conditions for which to seek medical lance methods (ie, patient-based versus consultation and one of those preeminent for anal- population-based), sampling issues, heterogeneity gesic use in the United States.3,4 Furthermore, the in the operational definition and imaging modalities management of patients with low back pain can be in assessing the phenotype of disk changes, and an a challenge, often requiring a multidisciplinary incomplete understanding of the risk-factor profile approach to treatment (see the article by Karppi- and its interaction effects that may affect degener- nen and colleagues elsewhere in this issue).9–13 ative changes and their manifestation in different Although low back pain is a multifactorial condi- age, gender, and ethnic groups.14,15,26 Along these tion (eg, biopsychological, muscular, socioeco- lines, the incidence rates of annular tears, disk nomic), intervertebral disk (IVD) degeneration has bulging, and endplate defects/abnormalities are been indicated to be a strong etiologic factor also not conclusive, and vary between studies. (Fig. 1).14–24 Intervertebral disk degeneration The development of IVD degeneration is a com- occurs in every population worldwide, mainly plex, multifaceted condition. Various studies have involving the lower lumbar segments (L4 to S1) suggested that, age, male gender, abnormal phys- where disk height narrowing also commonly occurs ical loading, trauma, infection, hormonal, over- and generally affects almost all individuals by the weight and obesity, altered metabolism, Schmorl’s This work was supported by an Area of Excellence grant from the University Grants Committee of Hong Kong (AoE/M-04/04). a Department of Biochemistry, The University of Hong Kong, LKS Faculty of Medicine, Laboratory Block, 3rd Floor, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China b Department of Orthopaedics and Traumatology, Division of Spine Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Professorial Block, 5th Floor, 102 Pokfulam Road, Pokfulam, Hong Kong SAR, China c Department of Orthopaedics & Traumatology, The University of Hong Kong, Professorial Block, 5th Floor, 102 Pokfulam Road, Pokfulam, Hong Kong SAR, China * Corresponding author. E-mail address: [email protected] Orthop Clin N Am 42 (2011) 447–464 doi:10.1016/j.ocl.2011.07.012 0030-5898/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved. orthopedic.theclinics.com 448 Chan et al Fig. 1. Illustration of the different stages of intervertebral disk degeneration. Note the normal disk on the left and the progression of degenerative changes from left to right, which are characterized as chemical and struc- tural changes of the disk (eg, dehydration of the nucleus pulposus, disruption of the annulus fibrosus, decreased disk height, and endplate changes). IVD, intervertebral disk. nodes, cigarette smoking, and occupation are INTERVERTEBRAL DISK risk factors related to the development of IVD degeneration.20,27–41 Several investigators have The IVD is a functional unit connecting the verte- also noted that systemic conditions, such as athero- bral bodies of the spine. In humans there are sclerosis, may contribute to IVD degeneration, due 25 IVDs interposed from the axis to the sacrum. to the “vascular insufficiency” provided to the verte- Each IVD consists of 3 structural components: bral body that may affect diffusion of metabolites a soft gelatinous nucleus pulposus (NP) in the and nutrients into the disk necessary to maintain center surrounded by a tough peripheral lamellar a healthy environment.42–46 Furthermore, it has annulus fibrosus (AF), sandwiched between 2 been strongly suggested that IVD degeneration cartilaginous endplates (EP) (Fig. 2). The com- may be attributed to genetic factors. Familial aggre- ponents of the disk act synergistically, facilitating motions of the spine and acting as shock ab- gation studies have indicated that individuals with 60–62 severe forms of IVD degeneration that are often sorbers between vertebral bodies. symptomatic have family members with a history Traditional concepts on the function of the disk of disk-related problems, often seeking medical relate to specific ECM proteins that assemble attention themselves.47–51 Twin studies have also and interact to form the 3 distinct structures. While noted that more than 70% of variability of IVD one can describe the NP, AF, and EP separately degeneration may be attributed to genetics.52–55 with distinct functions, the homeostasis of the Moreover, observational cohort studies have identi- IVD as a unit must have optimal function from all fied specific genes that may play a role in the devel- 3 structures. The impairment of one or more of opment of IVD degeneration, some of which may these structures can lead to dire consequences have a synergistic effect with environmental expo- with IVD degeneration. The ECM is produced sures and perhaps be age dependent (see the article and maintained by resident cells, and there are by Kao and colleagues elsewhere in this issue).56–59 feedback mechanisms for cells to sense the As such, understanding the genetic epidemiology of ECM, while the ECM regulates extrinsic signals IVD degeneration is imperative in comprehending to cells for disk homeostasis. the scope of the degenerative condition, why degenerative changes occur in certain individuals DEVELOPMENT OF THE INTERVERTEBRAL rather than others, and in developing a better under- DISK standing of the use of biological therapies for the prevention or regeneration of the disease process The notochord is central to the development of IVD. (see the articles by Sakai, Woods and colleagues, The notochord is a rod-shaped midline structure of Leung and colleagues, and Bae and Masuda else- mesodermal origin found in chordate embryos where in this issue). However, at a more basic level, during gastrulation, and represents a primitive axial understanding the structure and biology of the IVD skeleton.63,64 As a structure that is recognized in in health and disease, in particular the develop- all vertebrate embryos, its development has been mental process, cellular origin, changes in the well studied and described since the nineteenth extracellular matrix (ECM) components, and mainte- century.65 It is composed of cells derived from the nance in adult life, is essential. organizer tissue at different stages of development. Structure and Biology of Intervertebral Disk 449 Fig. 2. Development of the intervertebral disk. (A) In early development, the notochord is localized adjacent to pairs of paraxial somites containing sclerotome cells. (B) Sclerotome cells migrate and condense around the noto- chord forming the perinotochordal sheath, with a metameric pattern of condensed and uncondensed regions (C) The notochord contracts within the developing vertebral bodies and expands within the future nucleus pulposus regions of the intervertebral disk. (D) Establishment of the basic structure of the intervertebral disk with forma- tion of the cartilage endplate and the lamellar structures of the annulus fibrosus. EP, endplate; IAF, inner annulus fibrosus; NP, nucleus pulposus; OAF, outer annulus fibrosus; VB, vertebral body. The contribution of the organizer to different regions Although this notion remains controversial, cell- of the notochord along the anterior-posterior axis is tracking analysis of notochordal cells in the mouse complex, but has been studied using cell-mapping suggests this may be the case, with perhaps tools and live time-lapse imaging.66,67 In principle, subsequent differentiation to mature NP cells.70 the anterior notochord is formed by direct conver- To date, no cell-tracking data are available to gence of the anterior dispersed cells, the trunk noto- confirm the origin of the AF cells, but it is thought chord is formed by convergent extension of the to originate from the somites. Little is known node-derived cells, and the tail notochord is formed regarding the origin of the cells in the EP and its by posterior migration of the node-derived progeni- formation. It was first postulated that the NP is tors. The notochord is important not only as not derived from the side of the vertebral body a signaling center but also as a structure that gives but from undifferentiated cells, which accumulate rise to the future NP. in early development and develop into an orga- In early gestation stages (30 days in human, 12 nized structure under mechanical influences. This days in mouse), the notochord is located adjacent hypothesis was later refined to suggest induction to the paraxial somites