DNA Methylation of SPARC and Chronic Low Back Pain

Abstract

BackgroundThe extracellular matrix protein SPARC (Secreted Protein, Acidic, Rich in Cysteine) has been linked to degeneration of the intervertebral discs and chronic low back pain (LBP). In humans, SPARC protein expression is decreased as a function of age and disc degeneration. In mice, inactivation of the SPARC gene results in the development of accelerated age-dependent disc degeneration concurrent with age-dependent behavioral signs of chronic LBP.DNA methylation is the covalent modification of DNA by addition of methyl moieties to cytosines in DNA. DNA methylation plays an important role in programming of gene expression, including in the dynamic regulation of changes in gene expression in response to aging and environmental signals.We tested the hypothesis that DNA methylation down-regulates SPARC expression in chronic LBP in pre-clinical models and in patients with chronic LBP.ResultsOur data shows that aging mice develop anatomical and behavioral signs of disc degeneration and back pain, decreased SPARC expression and increased methylation of the SPARC promoter. In parallel, we show that human subjects with back pain exhibit signs of disc degeneration and increased methylation of the SPARC promoter. Methylation of either the human or mouse SPARC promoter silences its activity in transient transfection assays.ConclusionsThis study provides the first evidence that DNA methylation of a single gene plays a role in chronic pain in humans and animal models. This has important implications for understanding the mechanisms involved in chronic pain and for pain therapy.

Plasticity of DNA methylation in a nerve injury model of pain

“…Tajerian et al analyzed the methylation status of 6 CpGs located in the promoter region of the SPARC gene in mice. 5 The authors found that lumbar disc degeneration was associated with an increase of methylation at these sites, resulting in an increased expression of SPARC. In the present study, 9 CpGs were captured in the SPARC gene; yet, all were located in the gene body.…”

“…[1][2][3] Whether PNS injury leads to epigenetic remodeling on a grand scale has not been determined but candidate gene studies suggest the possibility. [4][5][6][7] Denk and McMahon 8 suggested in a recent review article that "direct evidence that epigenetic mechanisms could be involved in the development and/or maintenance of chronic pain conditions is only just beginning to surface, and [that] the field is in its infancy;" [that] "the currently available data suggest that epigenetic mechanisms may be important contributors to chronic pain states;" and that "descriptive studies, for instance examination of genome-wide . .…”

The role of the extracellular matrix in chronic pain following injury

“…54 Here, we review evidence for the role of the ECM in pain-related plasticity in the peripheral and central nervous systems, plasticity that may facilitate the transition of pain from an acute to a chronic form. It is important to note that, while there is a clear ECM contribution in the etiology of painful degenerative conditions such as back pain 44 and osteoarthritis, 28 this article explores the relationship between ECM proteins and nociception in conditions where the immediate source of the painful syndrome is not caused by ECM destruction.…”

Epigenetic regulation of persistent pain

“…In general, obtaining broader regions with higher resolution of methylation on individual CpGs consumes more resources and time. Yet a number of laboratories reported evidence showing the involvement of DNA methylation in persistent pain [85–91] (see Table 1 for summary).…”

“…Methylation states relevant to pain conditions have been examined by several laboratories from animals to human. Tajerian et al provided the first evidence that DNA methylation is indirectly correlated to persistent pain in mouse and human intervertebral discs [85]. They studied the transcriptional downregulation of SPARC (secreted protein, acidic, rich in cysteine) in the spinal discs of aging mice.…”