DNA methylation of SPARC and chronic low back pain
- Equal contributors
1 Alan Edwards Centre for Research on Pain, McGill University, 740 Dr. Penfield Avenue, Montreal, Quebec, H3A 1A4, Canada
2 McGill Scoliosis & Spine Research Group, McGill University Health Centre, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada
3 Department of Neurology and Neurosurgery, McGill University, Faculty of Medicine, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada
4 Department of Pharmacology and Therapeutics, McGill University, Faculty of Medicine, 3655 Promenade Sir William Osler, Montréal, Québec, H3G 1Y6, Canada
5 Sackler Program for Epigenetics & Developmental Psychobiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Québec H3G 1Y6, Canada
6 Faculty of Dentistry, McGill University, 3640 University Street, Montreal, Quebec, H3A 2B2, Canada
7 Department of Physical Medicine & Rehabilitation, University of Minnesota Medical School, 420 Delaware Street S.E., Minneapolis, MN, 55454, USA
8 Orthopaedics Research Laboratory, McGill University Health Centre, 687 Pine Avenue West, Montreal Quebec, H3A 1A1, Canada
9 Division of Orthopaedic Surgery, McGill University Health Centre, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada
10 Department of Anesthesiology, Anesthesia Research Unit, McGill University, Faculty of Medicine, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada
Molecular Pain 2011, 7:65 doi:10.1186/1744-8069-7-65Published: 25 August 2011
The 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.
Our 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.
This 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.