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Molecular Pain
Published in: Molecular Pain 1/2011

Open Access 01-12-2011 | Research

DNA methylation of SPARC and chronic low back pain

Published in: Molecular Pain | Issue 1/2011

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Abstract

Background

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.

Results

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.

Conclusions

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.
Appendix
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Literature
1.
Devereaux M: Low back pain. The Medical clinics of North America 2009, 93: 477–501. x 10.1016/j.mcna.2008.09.013PubMedCrossRef
2.
Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D, Ross JS: Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 1994, 331: 69–73. 10.1056/NEJM199407143310201PubMedCrossRef
3.
Boden SD, Davis DO, Dina TS, Patronas NJ, Wiesel SW: Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg Am 1990, 72: 403–408.PubMed
4.
Luoma K, Riihimaki H, Luukkonen R, Raininko R, Viikari-Juntura E, Lamminen A: Low back pain in relation to lumbar disc degeneration. Spine 2000, 25: 487–492. 10.1097/00007632-200002150-00016PubMedCrossRef
5.
Samartzis D, Karppinen J, Mok F, Fong DY, Luk KD, Cheung KM: A population-based study of juvenile disc degeneration and its association with overweight and obesity, low back pain, and diminished functional status. The Journal of bone and joint surgery American volume 2011, 93: 662–670. 10.2106/JBJS.I.01568PubMedCrossRef
6.
Nyman T, Mulder M, Iliadou A, Svartengren M, Wiktorin C: High heritability for concurrent low back and neck-shoulder pain - a study of twins. Spine (Phila Pa 1976) 2010.
7.
Costigan M, Belfer I, Griffin RS, Dai F, Barrett LB, Coppola G, Wu T, Kiselycznyk C, Poddar M, Lu Y, et al.: Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain 2010, 133: 2519–2527. 10.1093/brain/awq195PubMedCentralPubMedCrossRef
8.
Bovenzi M: A longitudinal study of low back pain and daily vibration exposure in professional drivers. Ind Health 2010, 48: 584–595. 10.2486/indhealth.MSWBVI-02PubMedCrossRef
9.
Chou R, Shekelle P: Will this patient develop persistent disabling low back pain? JAMA 2010, 303: 1295–1302. 10.1001/jama.2010.344PubMedCrossRef
10.
Brekken RA, Sage EH: SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol 2001, 19: 816–827.PubMedCrossRef
11.
Gruber HE, Ingram JA, Leslie K, Hanley EN Jr: Cellular, but not matrix, immunolocalization of SPARC in the human intervertebral disc: decreasing localization with aging and disc degeneration. Spine 2004, 29: 2223–2228. 10.1097/01.brs.0000142225.07927.29PubMedCrossRef
12.
Gruber HE, Sage EH, Norton HJ, Funk S, Ingram J, Hanley EN Jr: Targeted deletion of the SPARC gene accelerates disc degeneration in the aging mouse. J Histochem Cytochem 2005, 53: 1131–1138. 10.1369/jhc.5A6687.2005PubMedCrossRef
13.
Millecamps M, Tajerian M, Sage EH, Stone LS: Behavioral signs of chronic back pain in the SPARC-null mouse. Spine 2011, 36: 95–102. 10.1097/BRS.0b013e3181cd9d75PubMedCentralPubMedCrossRef
14.
Razin A, Szyf M: DNA methylation patterns. Formation and function. Biochim Biophys Acta 1984, 782: 331–342.PubMedCrossRef
15.
16.
17.
Razin A, Riggs AD: DNA methylation and gene function. Science 1980, 210: 604–610. 10.1126/science.6254144PubMedCrossRef
18.
Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ: Epigenetic programming by maternal behavior. Nature neuroscience 2004, 7: 847–854. 10.1038/nn1276PubMedCrossRef
19.
20.
Zhang YG, Sun ZM, Liu JT, Wang SJ, Ren FL, Guo X: Features of intervertebral disc degeneration in rat's aging process. J Zhejiang Univ Sci B 2009, 10: 522–527. 10.1631/jzus.B0820295PubMedCentralPubMedCrossRef
21.
Steru L, Chermat R, Thierry B, Simon P: The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 1985, 85: 367–370. 10.1007/BF00428203PubMedCrossRef
22.
Sova P, Feng Q, Geiss G, Wood T, Strauss R, Rudolf V, Lieber A, Kiviat N: Discovery of novel methylation biomarkers in cervical carcinoma by global demethylation and microarray analysis. Cancer Epidemiol Biomarkers Prev 2006, 15: 114–123. 10.1158/1055-9965.EPI-05-0323PubMedCrossRef
23.
Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP: Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 1998, 58: 5489–5494.PubMed
24.
Klug M, Rehli M: Functional analysis of promoter CpG methylation using a CpG-free luciferase reporter vector. Epigenetics: official journal of the DNA Methylation Society 2006, 1: 127–130.CrossRef
25.
Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, et al.: Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005, 14: 135–143.PubMedCrossRef
26.
MacGregor AJ, Andrew T, Sambrook PN, Spector TD: Structural, psychological, and genetic influences on low back and neck pain: a study of adult female twins. Arthritis and rheumatism 2004, 51: 160–167. 10.1002/art.20236PubMedCrossRef
27.
Vucetic Z, Kimmel J, Totoki K, Hollenbeck E, Reyes TM: Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology 2010, 151: 4756–4764. 10.1210/en.2010-0505PubMedCentralPubMedCrossRef
28.
Landmark-Hoyvik H, Reinertsen KV, Loge JH, Kristensen VN, Dumeaux V, Fossa SD, Borresen-Dale AL, Edvardsen H: The genetics and epigenetics of fatigue. PM R 2010, 2: 456–465.PubMedCrossRef
29.
Sweatt JD: Neuroscience. Epigenetics and cognitive aging. Science (New York, NY 2010, 328: 701–702. 10.1126/science.1189968CrossRef
30.
Freemont AJ, Peacock TE, Goupille P, Hoyland JA, O'Brien J, Jayson MI: Nerve ingrowth into diseased intervertebral disc in chronic back pain. Lancet 1997, 350: 178–181. 10.1016/S0140-6736(97)02135-1PubMedCrossRef
31.
Garcia-Cosamalon J, del Valle ME, Calavia MG, Garcia-Suarez O, Lopez-Muniz A, Otero J, Vega JA: Intervertebral disc, sensory nerves and neurotrophins: who is who in discogenic pain? Journal of anatomy 2010, 217: 1–15. 10.1111/j.1469-7580.2010.01227.xPubMedCentralPubMedCrossRef
32.
Inoue G, Ohtori S, Aoki Y, Ozawa T, Doya H, Saito T, Ito T, Akazawa T, Moriya H, Takahashi K: Exposure of the nucleus pulposus to the outside of the anulus fibrosus induces nerve injury and regeneration of the afferent fibers innervating the lumbar intervertebral discs in rats. Spine 2006, 31: 1433–1438. 10.1097/01.brs.0000219946.25103.dbPubMedCrossRef
33.
Kawakami M, Hashizume H, Nishi H, Matsumoto T, Tamaki T, Kuribayashi K: Comparison of neuropathic pain induced by the application of normal and mechanically compressed nucleus pulposus to lumbar nerve roots in the rat. Journal of orthopaedic research: official publication of the Orthopaedic Research Society 2003, 21: 535–539. 10.1016/S0736-0266(02)00192-4CrossRef
34.
Lacroix-Fralish ML, Tawfik VL, Tanga FY, Spratt KF, DeLeo JA: Differential spinal cord gene expression in rodent models of radicular and neuropathic pain. Anesthesiology 2006, 104: 1283–1292. 10.1097/00000542-200606000-00025PubMedCrossRef
35.
Song XJ, Hu SJ, Greenquist KW, Zhang JM, LaMotte RH: Mechanical and thermal hyperalgesia and ectopic neuronal discharge after chronic compression of dorsal root ganglia. J Neurophysiol 1999, 82: 3347–3358.PubMed
36.
37.
Ruscheweyh R, Wilder-Smith O, Drdla R, Liu XG, Sandkuhler J: Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Molecular pain 2011, 7: 20. 10.1186/1744-8069-7-20PubMedCentralPubMedCrossRef
38.
Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, Parrish TB, Gitelman DR: Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci 2004, 24: 10410–10415. 10.1523/JNEUROSCI.2541-04.2004PubMedCrossRef
39.
Seminowicz DA, Wideman TH, Naso L, Hatami-Khoroushahi Z, Fallatah S, Ware MA, Jarzem P, Bushnell MC, Shir Y, Ouellet JA, Stone LS: Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. The Journal of neuroscience: the official journal of the Society for Neuroscience 2011, 31: 7540–7550. 10.1523/JNEUROSCI.5280-10.2011CrossRef
40.
Szyf M: Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol 2009, 49: 243–263. 10.1146/annurev-pharmtox-061008-103102PubMedCrossRef
41.
Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP: Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 1998, 58: 5489–5494.PubMed
42.
Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB: Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 1994, 7: 536–540. 10.1038/ng0894-536PubMedCrossRef
43.
Rodriguez-Rodero S, Fernandez-Morera JL, Fernandez AF, Menendez-Torre E, Fraga MF: Epigenetic regulation of aging. Discov Med 2010, 10: 225–233.PubMed
44.
Thomas E, Silman AJ, Croft PR, Papageorgiou AC, Jayson MI, Macfarlane GJ: Predicting who develops chronic low back pain in primary care: a prospective study. BMJ Clinical research ed 1999, 318: 1662–1667.PubMedCentralPubMedCrossRef
45.
Norose K, Clark JI, Syed NA, Basu A, Heber-Katz E, Sage EH, Howe CC: SPARC deficiency leads to early-onset cataractogenesis. Invest Ophthalmol Vis Sci 1998,39(13):2674–2680.PubMed
46.
Brekken RA, Puolakkainen P, Graves DC, Workman G, Lubkin SR, Sage EH: Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. J Clin Invest 2003, 111: 487–495.PubMedCentralPubMedCrossRef
47.
Jones BJ, Roberts DJ: The quantiative measurement of motor inco-ordination in naive mice using an acelerating rotarod. J Pharm Pharmacol 1968, 20: 302–304.PubMedCrossRef
48.
Fairbank JC, Pynsent PB: The Oswestry Disability Index. Spine 2000, 25: 2940–2952. discussion 2952 10.1097/00007632-200011150-00017PubMedCrossRef
49.
Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N: Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976) 2001, 26: 1873–1878. 10.1097/00007632-200109010-00011CrossRef
50.
Colella S, Shen L, Baggerly KA, Issa JP, Krahe R: Sensitive and quantitative universal Pyrosequencing methylation analysis of CpG sites. Biotechniques 2003, 35: 146–150.PubMed
51.
Rouleau J, Tanigawa G, Szyf M: The mouse DNA methyltransferase 5'-region. A unique housekeeping gene promoter. J Biol Chem 1992, 267: 7368–7377.PubMed
Metadata
Title
DNA methylation of SPARC and chronic low back pain
Publication date
01-12-2011
Published in
Molecular Pain / Issue 1/2011
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-7-65

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