Monocyte-related biomarkers of rheumatoid arthritis development in undifferentiated arthritis patients – a pilot study
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Submission date: 2018-01-08
Final revision date: 2018-02-14
Acceptance date: 2018-02-21
Online publication date: 2018-02-28
Publication date: 2018-02-28
Reumatologia 2018;56(1):10–16
Enhanced/disturbed activities of monocytes are crucial for perpetuation and for development of rheumatoid arthritis (RA). Therefore, knowledge about monocyte activities and regulation of molecular pathways operating within monocytes early in the course of RA development may help to predict the progression to the full-blown disease. We aimed to investigate the profile of miRNAs expression in circulating monocytes and monocyte-related cytokines in sera of individuals at undifferentiated arthritis (UA) stage, wich could serve as new biomarkers for RA development.

Material and methods:
Magnetically sorted monocytes from peripheral blood of 20 UA patients served for total RNA isolation. RNA samples were used for microRNA profiling. Concentrations of CCL3/MIP-1α, M-CSF, CCL2/MCP-1, IL-6, TNF-α and IL-15 in sera of UA patients were measured using ELISA assays. Verification of diagnosis after 4 years of follow-up led to the identification of patients who developed RA (UA -> RA patients) and patients who remained still in UA phase (UA -> UA patients). Comparisons between patients groups were performed using two-tailed Mann-Whitney U test.

We identified 50 miRNAs in monocytes with the largest variation of expression across all patients samples. From these selected miRNAs, expression of miR-642b-5p, miR-483-3p, miR-371b-5p were significantly up-regulated and miR-25-3p and miR-378d were significantly down-regulated in UA -> RA vs. UA -> UA patients. This specific pattern of miRNAs expression in circulating monocytes paralleled elevated IL-15 and M-CSF concentrations in sera of UA patients who progressed to RA.

Results of our pilot study indicate that altered activity of monocytes can be detected at early stages of RA. We found new miRNA candidates differentially expressed in peripheral blood monocytes and elevated concentrations of IL-15 and M-CSF involved in monocyte activity and differentiation in patients with UA who subsequently developed RA, in comparison to UA patients who did not progress to RA after 4 years follow-up.

Macfarlane LA, Murphy PR. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics 2010; 11: 537-561.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215-233.
Ghosh S, Hayden MS. New regulators of NF-kappaB in inflammation. Nat Rev Immunol 2008; 8: 837-848.
Wang J, Chen J, Sen S. MicroRNA as Biomarkers and Diagnostics. J Cell Physiol 2016; 231: 25-30.
Salehi E, Eftekhari R, Oraei M, et al. MicroRNAs in rheumatoid arthritis. Clin Rheumatol 2015; 34: 615-628.
Akhtar N, Singh AK, Ahmed S. MicroRNA-17 Suppresses TNF-signaling by interfering with TRAF2 and cIAP2 association in rheumatoid arthritis synovial fibroblasts. J Immunol 2016; 197: 2219-2228.
Shi DL, Shi GR, Xie J, et al. MicroRNA-27a Inhibits Cell Migration and Invasion of Fibroblast-Like Synoviocytes by Targeting Follistatin-Like Protein 1 in Rheumatoid Arthritis. Mol Cells 2016; 39: 611-618.
Long L, Yu P, Liu Y, et al. Upregulated microRNA-155 expression in peripheral blood mononuclear cells and fibroblast-like synoviocytes in rheumatoid arthritis. Clin Dev Immunol 2013; 2013: ID 296139.
Pauley KM, Satoh M, Chan AL, et al. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther 2008; 10: R101.
Sebastiani GD, Fulci V, Niccolini S, et al. Over-expression of miR-223 in T-lymphocytes of early rheumatoid arthritis patients. Clin Exp Rheumatol 2011; 29: 1058-1059.
Alivernini S, Kurowska-Stolarska M, Tolusso B, et al. MicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis. Nat Commun 2016; 7: 12970.
Kurowska-Stolarska M, Alivernini S, Ballantine LE, et al. Micro-RNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci U S A 2011; 108: 11193-11198.
Rajasekhar M, Olsson AM, Steel KJ, et al. MicroRNA-155 contributes to enhanced resistance to apoptosis in monocytes from patients with rheumatoid arthritis. J Autoimmun 2017; 79: 53-62.
Elmesmari A, Fraser AR, Wood C, Gilchrist D, et al. MicroRNA-155 regulates monocyte chemokine and chemokine receptor expression in Rheumatoid Arthritis. Rheumatology (Oxford) 2016; 55: 2056-2065.
Davignon JL, Hayder M, Baron M, et al. Targeting monocytes/macrophages in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2013; 52: 590-598.
Bresnihan B, Gerlag DM, Rooney T, et al. Synovial macrophages as a biomarker of response to therapeutic intervention in rheumatoid arthritis: standardization and consistency across centers. J Rheumatol 2007; 34: 620-622.
Lioté F, Boval-Boizard B, Weill D, et al. Blood monocyte activation in rheumatoid arthritis: increased monocyte adhesiveness, integrin expression, and cytokine release. Clin Exp Immunol 1996; 106: 13-19.
Coulthard LR, Geiler J, Mathews R, et al. Differential effects of infliximab on absolute circulating blood leucocyte counts of innate immune cells in early and late rheumatoid arthritis patients. J Clin Exp Immunol 2012; 170: 36-46.
Pacurari M, Tchounwou PB. Role of MicroRNAs in renin-angiotensin-aldosterone system-mediated cardiovascular inflammation and remodeling. Int J Inflam 2015; 2015: 101527.
Valmiki S, Ahuja V, Paul J, et al. MicroRNA exhibit altered expression in the inflamed colonic mucosa of ulcerative colitis patients. World J Gastroenterol 2017; 23: 5324-5332.
Lv Z, Shi Q, Huang W at al. MicroRNA expression profiling in Guillain-Barré syndrome. J Neuroimmunol 2016; 301: 12-15.
Liguori M, Nuzziello N, Licciulli F, et al. Combined microRNAs and mRNAs expression analysis in Pediatric Multiple Sclerosis: an integrated approach to uncover novel pathogenic mechanisms of the disease. Hum Mol Genet 2017; 27: 66-79.
Grabstein KH, Eisenman J, Shanebeck K, et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science 1994; 264: 965-968.
Ortiz AM, Laffon A, Gonzalez-Alvaro I. CD69 expression on lymphocytes and interleukin-15 levels in synovial fluids from different inflammatory arthropathies. Rheumatol Int 2002; 21: 182-188.
Ogata Y, Kukita A, Kukita T, et al. A novel role of IL-15 in the development of osteoclasts: inability to replace its activity with IL-2. J Immunol 1999; 162: 2754-2760.
Knevel R, Krabben A, Brouwer E, et al. Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study. Ann Rheum Dis 2012; 71: 1651-1657.
Xiao-KeYang, Wang-DongXu, Rui-Xue Leng, et al. Therapeutic potential of IL-15 in rheumatoid arthritis. Human Immunology 2015; 76: 812-818.
González-Álvaro I, Ortiz AM, Alvaro-Gracia JM, et al. Interleukin 15 levels in serum may predict a severe disease course in patients with early arthritis. PLoS One 2011; 6: e29492.
Deane KD, O’Donnell CI, Hueber W, et al. The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthritis Rheum 2010; 62: 3161-3172.
Smiljanovic B, Radzikowska A, Kuca-Warnawin E, et. al. Increased turnover of monocytes in patients with rheumatoid arthritis identified by transcriptome and cytometric prifiling. Ann Rheu Dis 2017; 76: A1-A55.
McQueen FM. Bone marrow edema and osteitis in rheumatoid arthritis: the imaging perspective. Arthritis Res Ther 2012; 14: 224.
Tamai M, Kawakami A, Uetani M, et al. A prediction rule for disease outcome in patients with undifferentiated arthritis using magnetic resonance imaging of the wrists and finger joints and serologic autoantibodies. Arthritis Rheum 2009; 61: 772-778.
Leng SX, McElhaney JE, Walston JD, et al. ELISA and multiplex technologies for cytokine measurement in inflammation and aging research. J Gerontol A Biol Sci Med Sci 2008; 63: 879-884.
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