The prevalence of chronic pain in the general population is estimated at 15-40%. In addition to being a major health care problem, chronic pain has serious economic consequences, costing billions of dollars per year in lost productivity and medical expenses. Chronic pain is often resistant to therapeutic intervention, and individuals suffer for years without relief. New therapeutic strategies are desperately needed. Despite enormous efforts, significant advances in pain management continue to be elusive.
While a genetic basis for individual variations in the development of chronic pain is well established , genetics only accounts for approximately half of the inter-individual variability in chronic low back pain . One concept that is beginning to receive attention in pain research is the fact that gene function can be altered not only by differences in gene sequence but also by differences in epigenetic modification. Epigenetic modulation refers to chemical modifications of DNA including DNA methylation that produce long-term changes in gene expression. These changes can have long-lasting biological consequences and could become maladaptive, leading to chronic diseases such as obesity , fatigue  or neurological and mental disorders [19, 29].
In humans, decreased expression of SPARC is observed in painful, degenerating discs  and deletion of the SPARC gene triggers accelerated age-dependent disc degeneration  and chronic pain in mice . We therefore hypothesized that the SPARC gene may be silenced by DNA methylation as a function of aging in degenerating discs.
In the current study we show that disc degeneration is accompanied by signs of axial and radicular pain and physical impairment in mice (Figure 1) and with pain and physical disability in humans (Figure 4). Targeted inactivation of the SPARC gene results in early onset of both disc degeneration and behavioral indices of LBP in mice [12, 13]. Having established that deletion of SPARC increases chronic pain and disc generation, we determined whether this gene is commonly silenced by DNA methylation during normal aging. Increased disc degeneration and chronic pain are associated with age in rodents and humans.
There are multiple mechanisms by which IVD degeneration can result in chronic axial and/or radicular LBP. In the periphery, spinal instability due to disc degeneration could result in irritation of other structures such as the facet joints, muscles and ligaments. Increased innervation of degenerating discs by sensory neurons  is also thought to contribute to discogenic pain  and contact with the contents of the disc results in increased neuronal excitability and sensitization [32, 33]. In addition, disc degeneration may result in radicular pain following nerve compression due to disc bulging or herniation [34, 35].
Within the central nervous system, ongoing nociceptive input from peripheral structures may result in sensitization within the spinal cord or supraspinal structures, resulting in an exaggerated response to subsequent peripherally applied stimuli (for reviews see [36, 37]). Furthermore, chronic LBP results in changes in brain structure and function [38, 39]. Interestingly, therapeutic interventions that target the spinal column such as facet joint blocks or spinal surgery can reverse pain-related changes in the brain, suggesting that ongoing input from the periphery actively maintains pain-related CNS plasticity . While the current study is focused on the epigenetic modulation of the degeneration of a peripheral structure, studies examining the role of epigenetics in pain-related CNS plasticity are needed.
We provide several lines of evidence that support the hypothesis that DNA methylation occurs during aging and that it results in silencing of SPARC. First, the state of methylation of several CG sites in the promoter is increased with aging. Second, DNA methylation inhibitors resulted in demethylation of the SPARC promoter and increased expression of SPARC in vivo. Third, methylation of CG sites in the promoter lead to silencing of promoter activity. The combination of the genetic evidence for the role of SPARC in chronic pain and the DNA methylation analysis provide strong support for the idea that DNA methylation occurs during aging and that it is involved in disc degeneration and chronic LBP. Although it was not possible to provide direct evidence of SPARC mRNA expression in clinical samples, we tested whether the clinical situation is consistent with our hypothesis. We show that discs removed from patients that suffered from chronic LBP also exhibited increased methylation of the SPARC gene (Figure 4). The human promoter, like the mouse promoter, is silenced by DNA methylation (Figure 3).
Unlike the static genome, the epigenome is in dynamic equilibrium throughout our lifespan and DNA methylation is a bidirectional process that can be altered by pharmacological agents . Changes in methylation appear to be a common feature in aging cells and tissues. Epigenetics also plays a key role in the development of diseases associated with aging including cancer [41, 42], atherosclerosis, and neurodegenerative and autoimmune disorders . Interestingly, age itself is a risk factor for chronic pain in humans . Using the candidate gene approach, we demonstrate that aging is one physiological process that could lead to hypermethylation and silencing of SPARC. It is likely that aging results in silencing of additional genes that are involved in chronic pain either in the periphery or the central nervous system. Moreover, it stands to reason that other transient environmental exposures such as tissue injury could result in DNA methylation of many other genes, which could serve as a long-term memory of such exposures in the genome, resulting in chronic pain.