Original Articles
25 September 2025
Early Access
The diagnostic utility of miRNA21 in systemic sclerosis
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
256
Views
35
Downloads
Authors
Objective. Systemic sclerosis (SSc) is a multisystem autoimmune disease of heterogeneous pathogenesis, including vascular, immunologic, genetic, epigenetic, and environmental factors. Progressive fibrosis is the hallmark of SSc. Intense research has been conducted to unveil new tools for early diagnosis and management, thus reducing morbidity and mortality. miR-21 has recently been considered to play an important role in the fibrosis of SSc. The objective of this study was to evaluate miR-21 levels in SSc patients and study its correlation to the extent of skin fibrosis and association with various clinical characteristics.
Methods. A total of 25 patients with SSc who fulfilled the American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 classification criteria, as well as 25 controls, were enrolled in a cross-sectional study. The extent of skin fibrosis was evaluated using the modified Rodnan skin score, and disease severity was assessed using the Medsger severity score. The levels of miR-21 were measured by quantitative real-time polymerase chain reaction. The 2-ΔΔCt method was used for analysis. SSc patients affected by diabetes mellitus, hypertension, renal impairment, heart disease, malignancy, other autoimmune diseases, or a history of serious acute infection within 6 weeks were excluded.
Results. There was a high statistically significant difference in miR-21 levels between cases and controls (p<0.001). At a cut-off level of 2.55, miR21 could discriminate between SSc patients and controls with sensitivity and specificity. There was no significant correlation between miR-21 levels and the degree of skin fibrosis. There was a significant positive association between miR-21 levels and the presence of arthritis in SSc patients (p=0.007).
Conclusions. miR-21 was suggested as a robust diagnostic biomarker in SSc with exceptional superiority over the traditionally utilized antibodies. Additionally, due to its association with arthritis, it is supposed to play a proinflammatory role in addition to its pronounced profibrotic effects. Interestingly, the profibrotic miR-21 may not reflect the extent of skin fibrosis.
Altmetrics
Downloads
Download data is not yet available.
Citations
Ingegnoli F, Ughi N, Mihai C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Pract Res Clin Rheumatol 2018; 32: 223-40. DOI: https://doi.org/10.1016/j.berh.2018.08.005
Van Den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 2013; 65: 2737-47. DOI: https://doi.org/10.1002/art.38098
Yang M, Goh V, Lee J, Espinoza M, Yuan Y, Carns M, et al. Clinical phenotypes of patients with systemic sclerosis with distinct molecular signatures in skin. Arthritis Care Res 2023; 75: 1469-80. DOI: https://doi.org/10.1002/acr.24998
Satoh T, Ishikawa O, Ihn H, Endo H, Kawaguchi Y, Sasaki T, et al. Clinical usefulness of anti-RNA polymerase III antibody measurement by enzyme-linked immunosorbent assay. Rheumatology 2009; 48: 1570-4. DOI: https://doi.org/10.1093/rheumatology/kep290
Spencer-Green G, Alter D, Welch HG. Test performance in systemic sclerosis: anti-centromere and anti-Scl-70 antibodies. Am J Med 1997; 103: 242-8. DOI: https://doi.org/10.1016/S0002-9343(97)00023-5
Merkel PA, Silliman NP, Clements PJ, Denton CP, Furst DE, Mayes MD, et al. Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2012; 64: 3420-9. DOI: https://doi.org/10.1002/art.34427
Sierra-Sepúlveda A, Esquinca-González A, Benavides-Suárez SA, Sordo-Lima DE, Caballero-Islas AE, Cabral-Castañeda AR, et al. Systemic sclerosis pathogenesis and emerging therapies, beyond the fibroblast. Biomed Res Int 2019; 2019: 4569826. DOI: https://doi.org/10.1155/2019/4569826
Lu Q. The critical importance of epigenetics in autoimmunity. J Autoimmun 2013; 41: 1-5. DOI: https://doi.org/10.1016/j.jaut.2013.01.010
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281-97. DOI: https://doi.org/10.1016/S0092-8674(04)00045-5
Makarova JA, Shkurnikov MU, Wicklein D, Lange T, Samatov TR, Turchinovich AA, et al. Intracellular and extracellular microRNA: An update on localization and biological role. Prog Histochem Cytochem 2016; 51: 33-49. DOI: https://doi.org/10.1016/j.proghi.2016.06.001
Pekow JR, Dougherty U, Mustafi R, Zhu H, Kocherginsky M, Rubin DT, et al. miR-143 and miR-145 are downregulated in ulcerative colitis: putative regulators of inflammation and protooncogenes. Inflamm Bowel Dis 2012; 18: 94-100. DOI: https://doi.org/10.1002/ibd.21742
Fasseu M, Tréton X, Guichard C, Pedruzzi E, Cazals-Hatem D, Richard C, et al. Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease. PloS One 2010; 5: e13160. DOI: https://doi.org/10.1371/journal.pone.0013160
Murugaiyan G, Da Cunha AP, Ajay AK, Joller N, Garo LP, Kumaradevan S, et al. MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest 2015; 125: 1069-80. DOI: https://doi.org/10.1172/JCI74347
Ma X, Zhou J, Zhong Y, Jiang L, Mu P, Li Y, et al. Expression, regulation and function of microRNAs in multiple sclerosis. Int J Med Sci 2014; 11: 810-8. DOI: https://doi.org/10.7150/ijms.8647
Fenoglio C, Cantoni C, De Riz M, Ridolfi E, Cortini F, Serpente M, et al. Expression and genetic analysis of miRNAs involved in CD4+ cell activation in patients with multiple sclerosis. Neurosci Lett 2011; 504: 9-12. DOI: https://doi.org/10.1016/j.neulet.2011.08.021
Smigielska-Czepiel K, van den Berg A, Jellema P, van der Lei RJ, Bijzet J, Kluiver J, et al. Comprehensive analysis of miRNA expression in T-cell subsets of rheumatoid arthritis patients reveals defined signatures of naive and memory Tregs. Genes Immun 2014; 15: 115-25. DOI: https://doi.org/10.1038/gene.2013.69
Dong L, Wang X, Tan J, Li H, Qian W, Chen J, et al. Decreased expression of micro RNA‐21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis. J Cell Mol Med 2014; 18: 2213-24. DOI: https://doi.org/10.1111/jcmm.12353
Tang ZM, Fang M, Wang JP, Cai PC, Wang P, Hu LH. Clinical relevance of plasma miR‐21 in new‐onset systemic lupus erythematosus patients. J Clin Lab Anal 2014; 28: 446-51. DOI: https://doi.org/10.1002/jcla.21708
Stagakis E, Bertsias G, Verginis P, Nakou M, Hatziapostolou M, Kritikos H, et al. Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. Ann Rheum Dis 2011; 70: 1496-506. DOI: https://doi.org/10.1136/ard.2010.139857
Zhang L, Wu H, Zhao M, Lu Q. Meta‐analysis of differentially expressed microRNAs in systemic sclerosis. Int J Rheum Dis 2020; 23: 1297-304. DOI: https://doi.org/10.1111/1756-185X.13924
Zhu H, Luo H, Li Y, Zhou Y, Jiang Y, Chai J, et al. MicroRNA-21 in scleroderma fibrosis and its function in TGF-β-regulated fibrosis-related genes expression. J Clin Immunol 2013; 33: 1100-9. DOI: https://doi.org/10.1007/s10875-013-9896-z
Meng X-M, Huang XR, Xiao J, Chung AC, Qin W, Chen H-y, et al. Disruption of Smad4 impairs TGF-β/Smad3 and Smad7 transcriptional regulation during renal inflammation and fibrosis in vivo and in vitro. Kidney Int 2012; 81: 266-79. DOI: https://doi.org/10.1038/ki.2011.327
Chung AC, Dong Y, Yang W, Zhong X, Li R, Lan HY. Smad7 suppresses renal fibrosis via altering expression of TGF-β/Smad3-regulated microRNAs. Mol Ther 2013; 21: 388-98. DOI: https://doi.org/10.1038/mt.2012.251
Chen B, Liu J, Chang Q, Beezhold K, Lu Y, Chen F. JNK and STAT3 signaling pathways converge on Akt-mediated phosphorylation of EZH2 in bronchial epithelial cells induced by arsenic. Cell Cycle 2013; 12: 112-21. DOI: https://doi.org/10.4161/cc.23030
Meng F, Henson R, Wehbe–Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007; 133: 647-58. DOI: https://doi.org/10.1053/j.gastro.2007.05.022
Zhou B, Zuo XX, Li YS, Gao SM, Dai XD, Zhu HL, et al. Integration of microRNA and mRNA expression profiles in the skin of systemic sclerosis patients. Sci Rep 2017; 7: 42899. DOI: https://doi.org/10.1038/srep42899
Jafarinejad-Farsangi S, Gharibdoost F, Farazmand A, Kavosi H, Jamshidi A, Karimizadeh E, et al. MicroRNA-21 and microRNA-29a modulate the expression of collagen in dermal fibroblasts of patients with systemic sclerosis. Autoimmunity 2019; 52: 108-16. DOI: https://doi.org/10.1080/08916934.2019.1621856
Park J-S, Kim C, Choi J, Jeong HY, Moon Y-M, Kang H, et al. MicroRNA-21a-5p inhibition alleviates systemic sclerosis by targeting STAT3 signaling. J Transl Med 2024; 22: 323. DOI: https://doi.org/10.1186/s12967-024-05056-3
Khanna D, Furst DE, Clements PJ, Allanore Y, Baron M, Czirjak L, et al. Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. J Scleroderma Relat Disord 2017; 2: 11-8. DOI: https://doi.org/10.5301/jsrd.5000231
Medsger TA, Bombardieri S, Czirják L, Scorza R, Rossa AD, Bencivelli W. Assessment of disease severity and prognosis. Clin Exp Rheumatol 2003; 21: S42-6.
Shumnalieva R, Kachakova D, Kaneva R, Kolarov Z, Monov S. Serum miR-21 and miR-29a expression in systemic sclerosis patients. Clin Exp Rheumatol 2023; 41: 1688-94. DOI: https://doi.org/10.55563/clinexprheumatol/165gj5
Mohammed MH, Shaker OG, Abd El-Raheem TA, Abdulkhaleq A, Khatery BH. Transforming growth factor-beta and microRNA-21, microRNA-29b, microRNA-92, and microRNA-129 in systemic sclerosis patients: a case–control study. JEWDS 2022; 19: 44-50. DOI: https://doi.org/10.4103/jewd.jewd_50_21
Wermuth PJ, Piera-Velazquez S, Jimenez SA. Exosomes isolated from serum of systemic sclerosis patients display alterations in their content of profibrotic and antifibrotic microRNA and induce a profibrotic phenotype in cultured normal dermal fibroblasts. Clin Exp Rheumatol 2017; 35: 21-30.
Motawi TK, Mohsen DA, El-Maraghy SA, Kortam MA. MicroRNA-21, microRNA-181a and microRNA-196a as potential biomarkers in adult Egyptian patients with systemic lupus erythematosus. Chem Biol Interact 2016; 260: 110-6. DOI: https://doi.org/10.1016/j.cbi.2016.11.001
Broen JC, Radstake TR. How birds of a feather flock together: genetics in autoimmune diseases. Expert Rev Clin Immunol 2011; 7: 127-8. DOI: https://doi.org/10.1586/eci.11.2
Santiago T, Santos EJF, Ruaro B, Lepri G, Green L, Wildt M, et al. Recommendations for the execution and reporting of skin ultrasound in systemic sclerosis: an international collaboration under the WSF skin ultrasound group. RMD Open 2022; 8: e002371. DOI: https://doi.org/10.1136/rmdopen-2022-002371
Yang J, Wang S, Liu L, Wang J, Shao Y. Long non-coding RNA NEAT1 and its targets (microRNA-21 and microRNA-125a) in rheumatoid arthritis: altered expression and potential to monitor disease activity and treatment outcome. J Clin Lab Anal 2021; 35: e24076. DOI: https://doi.org/10.1002/jcla.24076
Haschka J, Simon D, Bayat S, Messner Z, Kampylafka E, Fagni F, et al. Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis. Rheumatology 2023; 62: 3448-58. DOI: https://doi.org/10.1093/rheumatology/kead059
Suo QF, Sheng J, Qiang FY, Tang ZS, Yang YY. Association of long non‑coding RNA GAS5 and miR‑21 levels in CD4+ T cells with clinical features of systemic lupus erythematosus. Exp Ther Med 2018; 15: 345-50. DOI: https://doi.org/10.3892/etm.2017.5429
van der Fits L, van Kester MS, Qin Y, Out-Luiting JJ, Smit F, Zoutman WH, et al. MicroRNA-21 expression in CD4+ T cells is regulated by STAT3 and is pathologically involved in Sezary syndrome. J Invest Dermatol 2011; 131: 762-8. DOI: https://doi.org/10.1038/jid.2010.349
Chen Y, Xian PF, Yang L, Wang SX. MicroRNA-21 promotes proliferation of fibroblast-like synoviocytes through mediation of NF-kappaB nuclear translocation in a rat model of collagen-induced rheumatoid arthritis. Biomed Res Int 2016; 2016: 9279078. DOI: https://doi.org/10.1155/2016/9279078
Koba S, Jinnin M, Inoue K, Nakayama W, Honda N, Makino K, et al. Expression analysis of multiple micro RNA s in each patient with scleroderma. Exp Dermatol 2013; 22: 489-91. DOI: https://doi.org/10.1111/exd.12173
Bagnato G, Roberts WN, Roman J, Gangemi S. A systematic review of overlapping microRNA patterns in systemic sclerosis and idiopathic pulmonary fibrosis. Eur Respir Rev 2017; 26: 160125. DOI: https://doi.org/10.1183/16000617.0125-2016
Izzotti A, Calin GA, Arrigo P, Steele VE, Croce CM, De Flora S. Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke. FASEB J 2009; 23: 806-12. DOI: https://doi.org/10.1096/fj.08-121384
Schembri F, Sridhar S, Perdomo C, Gustafson AM, Zhang X, Ergun A, et al. MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium. Proc Natl Acad Sci U S A 2009; 106: 2319-24. DOI: https://doi.org/10.1073/pnas.0806383106
Yokoyama Y, Mise N, Suzuki Y, Tada-Oikawa S, Izuoka K, Zhang L, et al. MicroRNAs as potential mediators for cigarette smoking induced atherosclerosis. Int J Mol Sci 2018; 19: 1097. DOI: https://doi.org/10.3390/ijms19041097
Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am 2003; 29: 239-54. DOI: https://doi.org/10.1016/S0889-857X(03)00022-X
Wuttge DM, Carlsen AL, Teku G, Steen SO, Wildt M, Vihinen M, et al. Specific autoantibody profiles and disease subgroups correlate with circulating micro-RNA in systemic sclerosis. Rheumatology 2015; 54: 2100-7. DOI: https://doi.org/10.1093/rheumatology/kev234
Balzano F, Deiana M, Dei Giudici S, Oggiano A, Pasella S, Pinna S, et al. MicroRNA expression analysis of centenarians and rheumatoid arthritis patients reveals a common expression pattern. Int J Med Sci 2017; 14: 622-8. DOI: https://doi.org/10.7150/ijms.18972
Namas R, Elarabi M, Khan S, Mubashir A, Memisoglu E, El-Kaissi M, et al. Comprehensive description of the prevalence, serological and clinical characteristics, and visceral involvement of systemic sclerosis (scleroderma) in a large cohort from the United Arab Emirates Systemic Sclerosis Registry. J Scleroderma Relat Disord 2023; 8: 137-50. DOI: https://doi.org/10.1177/23971983221145788
Bairkdar M, Rossides M, Westerlind H, Hesselstrand R, Arkema EV, Holmqvist M. Incidence and prevalence of systemic sclerosis globally: a comprehensive systematic review and meta-analysis. Rheumatology 2021; 60: 3121-33. DOI: https://doi.org/10.1093/rheumatology/keab190
Ethics Approval
This work was accepted by the local ethical committee of the Department of Internal Medicine, School of Medicine, Cairo University. All procedures carried out in this study involving human subjects were in line with the institutional and/or national research committee's ethical standards and with the Helsinki Declaration of 1964 and its subsequent amendments or equivalent ethical standards.
Copyright (c) 2025 the Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
