MicroRNA modulation in complex regional pain syndrome

Journal of Translational Medicine

Seena K Ajit³  Robert J Schwartzman¹  James E Barrett³  Alessandro Graziano³  Ahmet Sacan²  Rehman A Qureshi²  Guillermo M Alexander¹  Irina A Orlova³ 

[1] Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA;School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA 19104, USA;Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA

关键词: CRPS;    pain;    biomarker;    MicroRNA;   

Others  :  1207823
DOI  :  10.1186/1479-5876-9-195

 received in 2011-09-07, accepted in 2011-11-10,  发布年份 2011

【 摘 要 】

Background

Aberrant expression of small noncoding RNAs called microRNAs (miRNAs) is a common feature of several human diseases. The objective of the study was to identify miRNA modulation in patients with complex regional pain syndrome (CRPS) a chronic pain condition resulting from dysfunction in the central and/or peripheral nervous systems. Due to a multitude of inciting pathologies, symptoms and treatment conditions, the CRPS patient population is very heterogeneous. Our goal was to identify differentially expressed miRNAs in blood and explore their utility in patient stratification.

Methods

We profiled miRNAs in whole blood from 41 patients with CRPS and 20 controls using TaqMan low density array cards. Since neurogenic inflammation is known to play a significant role in CRPS we measured inflammatory markers including chemokines, cytokines, and their soluble receptors in blood from the same individuals. Correlation analyses were performed for miRNAs, inflammatory markers and other parameters including disease symptoms, medication, and comorbid conditions.

Results

Three different groups emerged from miRNA profiling. One group was comprised of 60% of CRPS patients and contained no control subjects. miRNA profiles from the remaining patients were interspersed among control samples in the other two groups. We identified differential expression of 18 miRNAs in CRPS patients. Analysis of inflammatory markers showed that vascular endothelial growth factor (VEGF), interleukin1 receptor antagonist (IL1Ra) and monocyte chemotactic protein-1 (MCP1) were significantly elevated in CRPS patients. VEGF and IL1Ra showed significant correlation with the patients reported pain levels. Analysis of the patients who were clustered according to their miRNA profile revealed correlations that were not significant in the total patient population. Correlation analysis of miRNAs detected in blood with additional parameters identified miRNAs associated with comorbidities such as headache, thyroid disorder and use of narcotics and antiepileptic drugs.

Conclusions

miRNA profiles can be useful in patient stratification and have utility as potential biomarkers for pain. Differentially expressed miRNAs can provide molecular insights into gene regulation and could lead to new therapeutic intervention strategies for CRPS.

【 授权许可】

   
2011 Orlova et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Schwartzman RJ, Alexander GM, Grothusen J: Pathophysiology of complex regional pain syndrome. Expert Rev Neurother 2006, 6:669-681.
• [2]Schwartzman RJ, Erwin KL, Alexander GM: The natural history of complex regional pain syndrome. Clin J Pain 2009, 25:273-280.
• [3]Costigan M, Scholz J, Woolf CJ: Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009, 32:1-32.
• [4]Maihofner C, Seifert F, Markovic K: Complex regional pain syndromes: new pathophysiological concepts and therapies. Eur J Neurol 2010, 17:649-660.
• [5]Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR: Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med 2007, 8:326-331.
• [6]Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell 2009, 136:215-233.
• [7]Ceman S, Saugstad J: MicroRNAs: Meta-controllers of gene expression in synaptic activity emerge as genetic and diagnostic markers of human disease. Pharmacol Ther 2011, 130:26-37.
• [8]Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, et al.: Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 2008, 18:997-1006.
• [9]Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, et al.: Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 2008, 105:10513-10518.
• [10]Cortez MA, Calin GA: MicroRNA identification in plasma and serum: a new tool to diagnose and monitor diseases. Expert Opin Biol Ther 2009, 9:703-711.
• [11]Park NJ, Zhou H, Elashoff D, Henson BS, Kastratovic DA, Abemayor E, Wong DT: Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res 2009, 15:5473-5477.
• [12]Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi N, Benjamin H, Kushnir M, Cholakh H, Melamed N, et al.: Serum microRNAs are promising novel biomarkers. PLoS One 2008, 3:e3148.
• [13]Hanke M, Hoefig K, Merz H, Feller AC, Kausch I, Jocham D, Warnecke JM, Sczakiel G: A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. Urol Oncol 2009.
• [14]Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ, Wang K: The microRNA spectrum in 12 body fluids. Clin Chem 2010, 56:1733-1741.
• [15]Etheridge A, Lee I, Hood L, Galas D, Wang K: Extracellular microRNA: A new source of biomarkers. Mutat Res 2011.
• [16]Scholer N, Langer C, Dohner H, Buske C, Kuchenbauer F: Serum microRNAs as a novel class of biomarkers: a comprehensive review of the literature. Exp Hematol 2010, 38:1126-1130.
• [17]Wehling M: Translational medicine: can it really facilitate the transition of research "from bench to bedside"? Eur J Clin Pharmacol 2006, 62:91-95.
• [18]Frank R, Hargreaves R: Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2003, 2:566-580.
• [19]Bai G, Ambalavanar R, Wei D, Dessem D: Downregulation of selective microRNAs in trigeminal ganglion neurons following inflammatory muscle pain. Mol Pain 2007, 3:15. BioMed Central Full Text
• [20]Kusuda R, Cadetti F, Ravanelli MI, Sousa TA, Zanon S, De Lucca FL, Lucas G: Differential expression of microRNAs in mouse pain models. Mol Pain 2011, 7:17. BioMed Central Full Text
• [21]Poh KW, Yeo JF, Ong WY: MicroRNA changes in the mouse prefrontal cortex after inflammatory pain. Eur J Pain 2011, 15:801. e801-812.
• [22]Aldrich BT, Frakes EP, Kasuya J, Hammond DL, Kitamoto T: Changes in expression of sensory organ-specific microRNAs in rat dorsal root ganglia in association with mechanical hypersensitivity induced by spinal nerve ligation. Neuroscience 2009, 164:711-723.
• [23]von Schack D, Agostino MJ, Murray BS, Li Y, Reddy PS, Chen J, Choe SE, Strassle BW, Li C, Bates B, et al.: Dynamic changes in the microRNA expression profile reveal multiple regulatory mechanisms in the spinal nerve ligation model of neuropathic pain. PLoS One 2011, 6:e17670.
• [24]Zhao J, Lee MC, Momin A, Cendan CM, Shepherd ST, Baker MD, Asante C, Bee L, Bethry A, Perkins JR, et al.: Small RNAs control sodium channel expression, nociceptor excitability, and pain thresholds. J Neurosci 2010, 30:10860-10871.
• [25]Favereaux A, Thoumine O, Bouali-Benazzouz R, Roques V, Papon MA, Salam SA, Drutel G, Leger C, Calas A, Nagy F, Landry M: Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: role in pain. EMBO J 2011, 30:3830-3841.
• [26]Li X, Gibson G, Kim JS, Kroin J, Xu S, van Wijnen AJ, Im HJ: MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis. Gene 2011, 480:34-41.
• [27]Schmittgen TD, Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008, 3:1101-1108.
• [28]Hochberg YBaY: Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society 1995, 57:289-300.
• [29]Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D, Jones SJ, Marra MA: Circos: an information aesthetic for comparative genomics. Genome Res 2009, 19:1639-1645.
• [30]Sethupathy P, Megraw M, Hatzigeorgiou AG: A guide through present computational approaches for the identification of mammalian microRNA targets. Nat Methods 2006, 3:881-886.
• [31]Lewis BP, Burge CB, Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120:15-20.
• [32]Gee HE, Buffa FM, Camps C, Ramachandran A, Leek R, Taylor M, Patil M, Sheldon H, Betts G, Homer J, et al.: The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis. Br J Cancer 2011, 104:1168-1177.
• [33]Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT: GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene 2009, 28:195-208.
• [34]Williams GT, Mourtada-Maarabouni M, Farzaneh F: A critical role for non-coding RNA GAS5 in growth arrest and rapamycin inhibition in human T-lymphocytes. Biochem Soc Trans 2011, 39:482-486.
• [35]Schinkel C, Gaertner A, Zaspel J, Zedler S, Faist E, Schuermann M: Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome. Clin J Pain 2006, 22:235-239.
• [36]Huygen FJ, De Bruijn AG, De Bruin MT, Groeneweg JG, Klein J, Zijlstra FJ: Evidence for local inflammation in complex regional pain syndrome type 1. Mediators Inflamm 2002, 11:47-51.
• [37]Marchand F, Perretti M, McMahon SB: Role of the immune system in chronic pain. Nat Rev Neurosci 2005, 6:521-532.
• [38]Abbadie C: Chemokines, chemokine receptors and pain. Trends Immunol 2005, 26:529-534.
• [39]Watkins LR, Maier SF: Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003, 2:973-985.
• [40]DeLeo JA, Yezierski RP: The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 2001, 90:1-6.
• [41]Austin PJ, Moalem-Taylor G: The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 2010, 229:26-50.
• [42]Uceyler N, Eberle T, Rolke R, Birklein F, Sommer C: Differential expression patterns of cytokines in complex regional pain syndrome. Pain 2007, 132:195-205.
• [43]Uceyler N, Rogausch JP, Toyka KV, Sommer C: Differential expression of cytokines in painful and painless neuropathies. Neurology 2007, 69:42-49.
• [44]Ritz BW, Alexander GM, Nogusa S, Perreault MJ, Peterlin BL, Grothusen JR, Schwartzman RJ: Elevated blood levels of inflammatory monocytes (CD14+ CD16+) in patients with complex regional pain syndrome. Clin Exp Immunol 2011, 164:108-117.
• [45]Alexander GM, Peterlin LB, Perreault MJ, Grothusen JR, Schwartzman RJ: Changes in plasma cytokines and their soluble receptors in complex regional pain syndrome. J Pain 2011, in press.
• [46]Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT: MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 2011, 13:423-433.