Abstract
Degeneration of the intervertebral discs, a process characterized by a cascade of cellular, biochemical, structural and functional changes, is strongly implicated as a cause of low back pain. Current treatment strategies for disc degeneration typically address the symptoms of low back pain without treating the underlying cause or restoring mechanical function. A more in-depth understanding of disc degeneration, as well as opportunities for therapeutic intervention, can be obtained by considering aspects of intervertebral disc development. Development of the intervertebral disc involves the coalescence of several different cell types through highly orchestrated and complex molecular interactions. The resulting structures must function synergistically in an environment that is subjected to continuous mechanical perturbation throughout the life of an individual. Early postnatal changes, including altered cellularity, vascular regression and altered extracellular matrix composition, might set the disc on a slow course towards symptomatic degeneration. In this Perspective, we review the pathogenesis and treatment of intervertebral disc degeneration in the context of disc development. Within this scope, we examine how model systems have advanced our understanding of embryonic morphogenesis and associated molecular signaling pathways, in addition to the postnatal changes to the cellular, nutritional and mechanical microenvironment. We also discuss the current status of biological therapeutic strategies that promote disc regeneration and repair, and how lessons from development might provide clues for their refinement.
Highlights
Low back pain affects up to 85% of people at some point during their lives, resulting in healthcare and related costs in the United States of $100 billion every year (Andersson, 1999; Katz, 2006)
Disc degeneration is perhaps best defined as a cascade that begins with changes to the cellular microenvironment within the substructures of the disc that progresses over decades to structural breakdown and functional impairment (Freemont, 2009; Urban and Roberts, 2003)
Noggin is initially expressed by cells of the notochord (McMahon et al, 1998) before becoming localized to the developing annulus fibrosus (AF) where it remains until birth, potentially acting to block BMP signaling that originates from the vertebral bodies (DiPaola et al, 2005)
Summary
Low back pain affects up to 85% of people at some point during their lives, resulting in healthcare and related costs in the United States of $100 billion every year (Andersson, 1999; Katz, 2006). Model systems have been used to uncover multiple postnatal changes within the disc microenvironment, including a transition in cell phenotype (Peacock, 1952; Trout et al, 1982a; Hunter et al, 2004), vascular regression (Nerlich et al, 2007) and altered matrix synthesis (Cappello et al, 2006; Aguiar et al, 1999; Erwin et al, 2006; Erwin and Inman, 2006), which, by altering the mechanical and nutritional microenvironment, might together predispose the disc to degenerative changes later in life.
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