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Upregulation of miR-221/222 expression in rheumatoid arthritis (RA) patients: correlation with disease activity

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Abstract

miRNAs are noncoding RNA that play a critical role as fine regulators of gene expression at the posttranscriptional level within cells in numerous autoimmune diseases. miR-221/222 play a role in cancer by regulating cell proliferation, invasion and apoptosis. However, there have been insufficient studies on their role in rheumatoid arthritis (RA). This work is designed to analyze the miR-221/222 expression patterns in peripheral blood mononuclear cells (PBMCs) of patients with RA in comparison with healthy controls using quantitative RT-PCR, in a group of 30 RA patients and 20 healthy controls. The fold change of miR-221/222 expression in PBMCs was significantly elevated (p < 0.01) in RA patients compared with healthy controls. A positive correlation between expression levels of miR-221 and miR-222 was recorded (r = 0.303; p < 0.05). High miR-221/222 expression levels appeared to be elevated with high activity. miR-222 expression in high activity group of RA patients was significantly increased in relation to moderate (p < 0.01) and low (p < 0.001) activity ones with positive correlation (r = 0.363; p < 0.05) between the progress of disease activity and change in miR-222 expression level. ROC analysis showed a sensitivity of 70% and specificity of 75% for miR-221. In miR-222, the sensitivity of 80% and specificity of 70% were recorded. Our data shed some light on the role of miR-221/222 expression in RA patients, and their great potential value as new novel noninvasive biomarkers for disease detection. Therefore; further investigations are warranted to fully elucidate their role in rheumatoid.

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References

  1. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358:903–11.

    Article  CAS  PubMed  Google Scholar 

  2. Sakr BR, Elfishawi MM, ElArousy MH, et al. Rheumatoid arthritis: a single center Egyptian experience. Immunol Invest. 2018;47(3):293–302.

    Article  CAS  PubMed  Google Scholar 

  3. Baillet A, Trocmé C, Berthier S. Synovial fluid proteomic fingerprint: S100A8, S100A9 and S100A12 proteins discriminate rheumatoid arthritis from other inflammatory joint diseases. Rheumatology. 2010;49(4):671–82.

    Article  CAS  PubMed  Google Scholar 

  4. Zendman AJ, van Venrooij WJ, Pruijn GJ. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology. 2006;45:20–5.

    Article  CAS  PubMed  Google Scholar 

  5. Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009;373:659–72.

    Article  CAS  PubMed  Google Scholar 

  6. Chekulaeva M, Filipowicz W. Mechanisms of miRNA-mediated posttranscriptional regulation in animal cells. Curr Opin Cell Biol. 2009;21:452–60.

    Article  CAS  PubMed  Google Scholar 

  7. Xu WD, Lu MM, Pan HF, et al. Association of microRNA-146a with autoimmune diseases. Inflammation. 2012;35:1525–9.

    Article  CAS  PubMed  Google Scholar 

  8. Wang Y, Li Z, He C, et al. MicroRNAs expression signatures are associated with lineage and survival in acute leukemias. Blood Cells Mol Dis. 2010;44:191–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li J, Wan Y, Guo Q, et al. Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res Ther. 2010;12:R81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Filková M, Aradi B, Senolt L, Ospelt C, Vettori S, Mann H, Gay S, et al. Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis. Ann Rheum Dis. 2014;73(10):1898–904.

    Article  CAS  PubMed  Google Scholar 

  11. Chen ZZ, Zhang XD, Chen Y, Wu YB. The role of circulating miR-146a in patients with rheumatoid arthritis treated by Tripterygium wilfordii Hook F. Medicine (Baltimore). 2017;96(20):e6775.

    Article  Google Scholar 

  12. Long L, Yu P, Liu Y, Wang S, Li R, et al. Upregulated microRNA-155 expression in peripheral blood mononuclear cells and fibroblast-like synoviocytes in rheumatoid arthritis. Clin Dev Immunol. 2013;2013:296139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Miao CG, Yang YY, He X, et al. New advances of microRNAs in the pathogenesis of rheumatoid arthritis, with a focus on the crosstalk between DNA methylation and the microRNA machinery. Cell Signal. 2013;25:1118–25.

    Article  CAS  PubMed  Google Scholar 

  14. Vicente R, Noel D, Pers YM, Apparailly F, Jorgensen C. Deregulation and therapeutic potential of microRNAs in arthritic diseases. Nat Rev Rheumatol. 2016;12:211–20.

    Article  CAS  PubMed  Google Scholar 

  15. Song Z, Li G. Role of specific microRNAs in regulation of vascular smooth muscle cell differentiation and the response to injury. J Cardiovasc Transl Res. 2010;3:246–50.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kuehbacher A, Urbich C, Dimmeler S. Targeting microRNA expression to regulate angiogenesis. Trends Pharmacol Sci. 2008;29:12–5.

    Article  CAS  PubMed  Google Scholar 

  17. Chistiakov DA, Sobenin IA, Orekhov AN, Bobryshev YV. Human miR-221/222 in physiological and atherosclerotic vascular remodeling. Biomed Res Int. 2015;2015:354517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rippe C, Blimline M, Magerko KA, et al. microRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation. Exp Gerontol. 2012;47:45–51.

    Article  CAS  PubMed  Google Scholar 

  19. Stenmark KR, Yeager ME, El Kasmi KC, et al. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol. 2013;75:23–47.

    Article  CAS  PubMed  Google Scholar 

  20. Yang S, Yang Y. Downregulation of microRNA221 decreases migration and invasion in fibroblast-like synoviocytes in rheumatoid arthritis. Mol Med Rep. 2015;12:2395–401.

    Article  CAS  PubMed  Google Scholar 

  21. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.

    Article  PubMed  Google Scholar 

  22. Prevoo ML, van ‘t Hof MA MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44–8.

    Article  CAS  PubMed  Google Scholar 

  23. Pincus T, Yazici Y. Bergman M. Development of a multi-dimensional health assessment questionnaire (MD-HAQ) for the infrastructure of standard clinical care. Clin Exp Rheumatol. 2005;23(Suppl 39):S19–28.

    CAS  PubMed  Google Scholar 

  24. Talaat RM, El-Bassiouny AI, Osman AM, Yossif M, Charmy R, Al-Sherbiny MM. Cytokine secretion profile associated with periportal fibrosis in S. mansoni-infected Egyptian patients. Parasitol Res. 2007;101:289–99.

    Article  PubMed  Google Scholar 

  25. Lian JB, Stein GS, van Wijnen AJ, et al. MicroRNA control of bone formation and homeostasis. Nat Rev Endocrinol. 2012;8(4):212–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Duroux-Richard I, Jorgensen C, Apparailly F. miRNAs and rheumatoid arthritis—promising novel biomarkers. Swiss Med Wkly. 2011;141:w13175.

    PubMed  Google Scholar 

  27. Zhu S, Pan W, Song X, et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB 2, TAB 3 and IKK-α. Nat Med. 2012;18(7):1077–86.

    Article  CAS  PubMed  Google Scholar 

  28. O’Connell RM, Kahn D, Gibson WS, et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010;33:607–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Baxter D, McInnes IB, Kurowska-Stolarska M. Novel regulatory mechanisms in inflammatory arthritis: a role for microRNA. Immunol Cell Biol. 2012;90:288–92.

    Article  CAS  PubMed  Google Scholar 

  30. Jimenez SA, Piera-Velazquez S. Potential role of human-specific genes, human specific microRNAs and human-specific non-coding regulatory RNAs in the pathogenesis of systemic sclerosis and Sjogren’s syndrome. Autoimmun Rev. 2013;12:1046–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bottini N, Firestein GS. Epigenetics in rheumatoid arthritis: a primer for rheumatologists. Curr Rheumatol Rep. 2013;15(11):372.

    Article  CAS  PubMed  Google Scholar 

  32. Viatte S, Plant D, Raychaudhuri S. Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol. 2013;9(3):141–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Glant TT, Mikecz K, Rauch TA. Epigenetics in the pathogenesis of rheumatoid arthritis. BMC Med. 2014;12:35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Reveille JD. Genetic studies in the rheumatic diseases: present status and implications for the future. J Rheumatol Suppl. 2005;72:10–3.

    PubMed  Google Scholar 

  35. Zhou Q, Haupt S, Kreuzer JT, et al. Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis. Ann Rheum Dis. 2015;74(6):1265–74.

    Article  CAS  PubMed  Google Scholar 

  36. Churov AV, Oleinik EK, Knip M. MicroRNAs in rheumatoid arthritis: altered expression and diagnostic potential. Autoimmun Rev. 2015;14(11):1029–37.

    Article  CAS  PubMed  Google Scholar 

  37. Kim T-H, Choi SJ, Lee YH, Song GG, Ji JD. Gene expression profile predicting the response to anti-TNF treatment in patients with rheumatoid arthritis; analysis of GEO datasets. Joint Bone Spine. 2014;81(4):325–30.

    Article  CAS  PubMed  Google Scholar 

  38. Park HJ, Kim DH, Lim SH, et al. Insights into the role of follicular helper T cells in autoimmunity. Immune Netw. 2014;14(1):21–9.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ruedel A, Dietrich P, Schubert T, Hofmeister S, Hellerbrand C, Bosserhoff AK. Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts. Int J Clin Exp Pathol. 2015;8(6):6607–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 2008;10:R101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pandis I, Ospelt C, Karagianni N, Denis MC, Reczko M, Camps C, et al. Identification of microRNA-221/222 and microRNA-323-3p association with rheumatoid arthritis via predictions using the human tumour necrosis factor transgenic mouse model. Ann Rheum Dis. 2012;71:1716–23. https://doi.org/10.1136/annrheumdis-2011-200803.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang X, Shao S, Geng H, et al. Expression profiles of six circulating microRNAs critical to atherosclerosis in patients with subclinical hypothyroidism: a clinical study. J Clin Endocrinol Metab. 2014;99:E766. https://doi.org/10.1210/jc.2013-1629

    Article  CAS  PubMed  Google Scholar 

  43. Minami Y, Satoh M, Maesawa C, et al. Effect of atorvastatin on microRNA 221/222 expression in endothelial progenitor cells obtained from patients with coronary artery disease. Eur J Clin Invest. 2009;39:359–67. https://doi.org/10.1111/j.1365-2362.2009.02110.x.

    Article  CAS  PubMed  Google Scholar 

  44. Chen CF, Huang J, Li H, Zhang C, Huang X, Tong G, et al. microRNA-221 regulates endothelial nitric oxide production and inflammatory response by targeting adiponectin receptor 1. Gene. 2015;565:246–51.

    Article  CAS  PubMed  Google Scholar 

  45. Migeon BR. Females are mosaics: X inactivation and sex differences in disease. New York: Oxford University Press, Inc.; 2007.

    Google Scholar 

  46. Ozcelik T. X chromosome inactivation and female predisposition to autoimmunity. Clin Rev Allergy Immunol. 2008;34:348–51.

    Article  PubMed  Google Scholar 

  47. Carmona L, Cross M, Williams B, Lassere M, March L. Rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2010;24:733–45.

    Article  PubMed  Google Scholar 

  48. Kukurba KR, Parsana P, Balliu B, Smith K, Zappala Z, Knowles DA, et al. Impact of the X Chromosome and sex on regulatory variation. Genome Res. 2016;26:768–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Khalifa O, Pers YM, Ferreira R, Sénéchal A, et al. X-linked miRNAs associated with gender differences in rheumatoid arthritis. Int J Mol Sci. 2016;17(11):1852.

    Article  CAS  PubMed Central  Google Scholar 

  50. Teixeira AL, Ferreira M, Silva J, Gomes M, et al. Higher circulating expression Levels of miR-221 associated with poor overall survival in renal cell carcinoma patients. Tumour Biol. 2014;35(5):4057–66.

    Article  CAS  PubMed  Google Scholar 

  51. El-Garem H, Ammer A, Shehab H, Shaker O, et al. Circulating microRNA, miR-122 and miR-221 signature in Egyptian patients with chronic hepatitis C related hepatocellular carcinoma. World J Hepatol. 2014;6(11):818–24.

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Roba M. Talaat.

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All patients and healthy controls agreed to be enrolled in this study, and informed consent was obtained from all participants.

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Abo ElAtta, A.S., Ali, Y.B.M., Bassyouni, I.H. et al. Upregulation of miR-221/222 expression in rheumatoid arthritis (RA) patients: correlation with disease activity. Clin Exp Med 19, 47–53 (2019). https://doi.org/10.1007/s10238-018-0524-3

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