MicroRNA-21 in Skin Fibrosis: Potential for Diagnosis and Treatment

Abstract

Skin fibrosis is a common pathological process characterized by fibroblast proliferation and excessive deposition of extracellular matrix. However, the pathogenesis of the disease is still not clear. Previous studies have shown that microRNA-21 may play pivotal roles in the regulation of a variety of skin fibrosis, including keloid, scleroderma, and hypertrophic scar. In this review, we outline the structure, expression, and regulation of microRNA-21 and its role in fibrotic skin diseases. In future, it may be useful as a prognostic or diagnostic marker. However, there is a significant amount of work required to increase our current understanding of the role of microRNA-21 in skin fibrosis.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    Habiel DM, Hogaboam C. Heterogeneity in fibroblast proliferation and survival in idiopathic pulmonary fibrosis. Front Pharmacol. 2014;5:2.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2.

    Andrews JP, Marttala J, Macarak E, Rosenbloom J, Uitto J. Keloids: the paradigm of skin fibrosis. Pathomechanisms and treatment. Matrix Biol. 2016;51:37–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Bijlard E, Kouwenberg CA, Timman R, Hovius SE, Busschbach JJ, Mureau MA. Burden of keloid disease: a cross-sectional health-related quality of life assessment. Acta Derm Venereol. 2017;97(2):225–9.

    PubMed  Article  Google Scholar 

  4. 4.

    Walliczek U, Engel S, Weiss C, Aderhold C, Lippert C, Wenzel A, et al. Clinical outcome and quality of life after a multimodal therapy approach to ear keloids. JAMA Facial Plast Surg. 2015;17(5):333–9.

    PubMed  Article  Google Scholar 

  5. 5.

    Bock O, Schmid-Ott G, Malewski P, Mrowietz U. Quality of life of patients with keloid and hypertrophic scarring. Arch Dermatol Res. 2006;297(10):433–8.

    PubMed  Article  Google Scholar 

  6. 6.

    Zhai XM. The epidermiology investigation of scars and the keloid susceptible gene’s mRNA expression in human skin, hypertrophic scar and keloid. Graduate thesis of Peking University. 2003. pp 18–19.

  7. 7.

    Kundan P. Keloid removal cost. 2013. http://www.buzzle.com/articles/keloid-removal-cost.html. Accessed 21 June 2013.

  8. 8.

    Sun LM, Wang KH, Lee YC. Keloid incidence in Asian people and its comorbidity with other fibrosis-related diseases: a nationwide population-based study. Arch Dermatol Res. 2014;306(9):803–8.

    PubMed  Article  Google Scholar 

  9. 9.

    Ketchum LD, Cohen IK, Masters FW. Hypertrophic scars and keloids: a collective review. Plast Reconstruct Surg. 1974;53(2):140–54.

    CAS  Article  Google Scholar 

  10. 10.

    Halim AS, Emami A, Salahshourifar I, Kannan TP. Keloid scarring: understanding the genetic basis, advances, and prospects. Arch Plast Surg. 2012;39(3):184–9.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Arias-Nunez MC, Llorca J, Vazquez-Rodriguez TR, Gomez-Acebo I, Miranda-Filloy JA, Martin J, et al. Systemic sclerosis in northwestern Spain: a 19-year epidemiologic study. Medicine. 2008;87(5):272–80.

    PubMed  Article  Google Scholar 

  12. 12.

    Lopez-Bastida J, Linertova R, Oliva-Moreno J, Serrano-Aguilar P, Posada-de-la-Paz M, Kanavos P, et al. Social/economic costs and health-related quality of life in patients with scleroderma in Europe. Eur J Health Econom. 2016;17(Suppl. 1):109–17.

    Article  Google Scholar 

  13. 13.

    Andreasson K, Saxne T, Bergknut C, Hesselstrand R, Englund M. Prevalence and incidence of systemic sclerosis in southern Sweden: population-based data with case ascertainment using the 1980 ARA criteria and the proposed ACR-EULAR classification criteria. Ann Rheum Dis. 2014;73(10):1788–92.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Scolnik M, Lancioni E, Saucedo C, Marin J, Sabelli M, Bedran Z, et al. Systemic sclerosis in Argentina: evaluation of a large cohort from a single centre and comparison with other international series. Clin Exp Rheumatol. 2014;32(6 Suppl. 86):S-94–7.

    Google Scholar 

  15. 15.

    Kanecki K, Gorynski P, Tarka P, Wierzba W, Tyszko P. Incidence and prevalence of systemic sclerosis (SSc) in Poland: differences between rural and urban regions. Ann Agric Environ Med. 2017;24(2):240–4.

    PubMed  Google Scholar 

  16. 16.

    Kawalec PP, Malinowski KP. The indirect costs of systemic autoimmune diseases, systemic lupus erythematosus, systemic sclerosis and sarcoidosis: a summary of 2012 real-life data from the Social Insurance Institution in Poland. Exp Rev Pharmacoeconom Outcomes Res. 2015;15(4):667–73.

    Article  Google Scholar 

  17. 17.

    Mirastschijski U, Sander JT, Zier U, Rennekampff HO, Weyand B, Vogt PM. The cost of post-burn scarring. Ann Burns Fire Disasters. 2015;28(3):215–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Wang W, Qu M, Xu L, Wu X, Gao Z, Gu T, et al. Sorafenib exerts an anti-keloid activity by antagonizing TGF-beta/Smad and MAPK/ERK signaling pathways. J Mol Med. 2016;94(10):1181–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Hong MJ, Ko EB, Park SK, Chang MS. Inhibitory effect of Astragalus membranaceus root on matrix metalloproteinase-1 collagenase expression and procollagen destruction in ultraviolet B-irradiated human dermal fibroblasts by suppressing nuclear factor kappa-B activity. J Pharm Pharmacol. 2013;65(1):142–8.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Sahin H, Wasmuth HE. Chemokines in tissue fibrosis. Biochim Biophys Acta. 2013;1832(7):1041–8.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Jara P, Calyeca J, Romero Y, Placido L, Yu G, Kaminski N, et al. Matrix metalloproteinase (MMP)-19-deficient fibroblasts display a profibrotic phenotype. Am J Physiol Lung Cell Mol Physiol. 2015;308(6):L511–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Messadi DV, Doung HS, Zhang Q, Kelly AP, Tuan TL, Reichenberger E, et al. Activation of NFkappaB signal pathways in keloid fibroblasts. Arch Dermatol Res. 2004;296(3):125–33.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Mun JH, Kim YM, Kim BS, Kim JH, Kim MB, Ko HC. Simvastatin inhibits transforming growth factor-beta1-induced expression of type I collagen, CTGF, and alpha-SMA in keloid fibroblasts. Wound Repair Regen. 2014;22(1):125–33.

    PubMed  Article  Google Scholar 

  24. 24.

    Unahabhokha T, Sucontphunt A, Nimmannit U, Chanvorachote P, Yongsanguanchai N, Pongrakhananon V. Molecular signalings in keloid disease and current therapeutic approaches from natural based compounds. Pharm Biol. 2015;53(3):457–63.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Li L, Xu J, Yang D, Tan X, Wang H. Computational approaches for microRNA studies: a review. Mamm Genome. 2010;21(1–2):1–12.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Sanchez CA, Andahur EI, Valenzuela R, Castellon EA, Fulla JA, Ramos CG, et al. Exosomes from bulk and stem cells from human prostate cancer have a differential microRNA content that contributes cooperatively over local and pre-metastatic niche. Oncotarget. 2016;7(4):3993–4008.

    PubMed  Article  Google Scholar 

  27. 27.

    Deng Z, He Y, Yang X, Shi H, Shi A, Lu L, et al. MicroRNA-29: a crucial player in fibrotic disease. Mol Diagn Ther. 2017;21(3):285–94.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    O’Reilly S. MicroRNAs in fibrosis: opportunities and challenges. Arthritis Res Ther. 2016;13(18):11.

    Article  CAS  Google Scholar 

  29. 29.

    Babalola O, Mamalis A, Lev-Tov H, Jagdeo J. The role of microRNAs in skin fibrosis. Arch Dermatol Res. 2013;305(9):763–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Jafarinejad-Farsangi S, Farazmand A, Gharibdoost F, Karimizadeh E, Noorbakhsh F, Faridani H, et al. Inhibition of microRNA-21 induces apoptosis in dermal fibroblasts of patients with systemic sclerosis. Int J Dermatol. 2016;55(11):1259–67.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Zhou R, Wang C, Wen C, Wang D. miR-21 promotes collagen production in keloid via Smad7. Burns. 2017;43(3):555–61.

    PubMed  Article  Google Scholar 

  32. 32.

    Zhou R, Zhang Q, Zhang Y, Fu S, Wang C. Aberrant miR-21 and miR-200b expression and its pro-fibrotic potential in hypertrophic scars. Exp Cell Res. 2015;339(2):360–6.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Lorenzen JM, Schauerte C, Hubner A, Kolling M, Martino F, Scherf K, et al. Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis. Eur Heart J. 2015;36(32):2184–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Kumarswamy R, Volkmann I, Thum T. Regulation and function of miRNA-21 in health and disease. RNA Biol. 2011;8(5):706–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Kim YJ, Park SJ, Choi EY, Kim S, Kwak HJ, Yoo BC, et al. PTEN modulates miR-21 processing via RNA-regulatory protein RNH1. PLoS One. 2011;6(12):e28308.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Lin Y, Liu X, Cheng Y, Yang J, Huo Y, Zhang C. Involvement of microRNAs in hydrogen peroxide-mediated gene regulation and cellular injury response in vascular smooth muscle cells. J Biol Chem. 2009;284(12):7903–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Li Y, Yan L, Zhang W, Hu N, Chen W, Wang H, et al. MicroRNA-21 inhibits platelet-derived growth factor-induced human aortic vascular smooth muscle cell proliferation and migration through targeting activator protein-1. Am J Transl Res. 2014;6(5):507–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Chen B, Huang SG, Ju L, Li M, Nie FF, Zhang Y, et al. Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4. Braz J Med Biol Res. 2016. doi:10.1590/1414-431X20155020.

    Google Scholar 

  39. 39.

    Zhang Z, Zha Y, Hu W, Huang Z, Gao Z, Zang Y, et al. The autoregulatory feedback loop of microRNA-21/programmed cell death protein 4/activation protein-1 (MiR-21/PDCD4/AP-1) as a driving force for hepatic fibrosis development. J Biol Chem. 2013;288(52):37082–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Zhu Q, Wang Z, Hu Y, Li J, Li X, Zhou L, et al. miR-21 promotes migration and invasion by the miR-21-PDCD4-AP-1 feedback loop in human hepatocellular carcinoma. Oncol Rep. 2012;27(5):1660–8.

    CAS  PubMed  Google Scholar 

  41. 41.

    Kang H, Davis-Dusenbery BN, Nguyen PH, Lal A, Lieberman J, Van Aelst L, et al. Bone morphogenetic protein 4 promotes vascular smooth muscle contractility by activating microRNA-21 (miR-21), which down-regulates expression of family of dedicator of cytokinesis (DOCK) proteins. J Biol Chem. 2012;287(6):3976–86.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Ahmed MI, Mardaryev AN, Lewis CJ, Sharov AA, Botchkareva NV. MicroRNA-21 is an important downstream component of BMP signalling in epidermal keratinocytes. J Cell Sci. 2011;124(Pt 20):3399–404.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Smith CM, Michael MZ, Watson DI, Tan G, Astill DS, Hummel R, et al. Impact of gastro-oesophageal reflux on microRNA expression, location and function. BMC Gastroenterol. 2013;8(13):4.

    Article  CAS  Google Scholar 

  44. 44.

    Mari W, Alsabri SG, Tabal N, Younes S, Sherif A, Simman R. Novel insights on understanding of keloid scar: article review. J Am Coll Clin Wound Spec. 2015;7(1–3):1–7.

    PubMed  Google Scholar 

  45. 45.

    Sidgwick GP, Bayat A. Extracellular matrix molecules implicated in hypertrophic and keloid scarring. J Eur Acad Dermatol Venereol. 2012;26(2):141–52.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    van Leeuwen MC, Stokmans SC, Bulstra AE, Meijer OW, Heymans MW, Ket JC, et al. Surgical excision with adjuvant irradiation for treatment of keloid scars: a systematic review. Plast Reconstruct Surg Glob Open. 2015;3(7):e440.

    Article  Google Scholar 

  47. 47.

    Wang CM, Hiko H, Nakazawa N. Investigation of p53 polymorphism for genetic predisposition of keloid and hypertrophic scar. Zhonghua zheng xing wai ke za zhi. 2005;21(1):32–5.

    PubMed  Google Scholar 

  48. 48.

    He Y, Deng Z, Alghamdi M, Lu L, Fear MW, He L. From genetics to epigenetics: new insights into keloid scarring. Cell Prolif. 2017. doi:10.1111/cpr.12326 (Epub 2017 Jan 5).

    Google Scholar 

  49. 49.

    Kashiyama K, Mitsutake N, Matsuse M, Ogi T, Saenko VA, Ujifuku K, et al. miR-196a downregulation increases the expression of type I and III collagens in keloid fibroblasts. J Invest Dermatol. 2012;132(6):1597–604.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Liu Y, Yang D, Xiao Z, Zhang M. miRNA expression profiles in keloid tissue and corresponding normal skin tissue. Aesthet Plast Surg. 2012;36(1):193–201.

    Article  Google Scholar 

  51. 51.

    Wu ZY, Lu L, Liang J, Guo XR, Zhang PH, Luo SJ. Keloid microRNA expression analysis and the influence of miR-199a-5p on the proliferation of keloid fibroblasts. Genet Mol Res. 2014;13(2):2727–38.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Makino K, Jinnin M, Hirano A, Yamane K, Eto M, Kusano T, et al. The downregulation of microRNA let-7a contributes to the excessive expression of type I collagen in systemic and localized scleroderma. J Immunol. 2013;190(8):3905–15.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Guo XR, Liang J, Huang RL, Lu L, Jin YD, Luo SJ, et al. Differential expression of microRNAs in human keloids. Zhongguo Zuzhi Gongcheng Yanjiu. 2012;16:9370–5.

    CAS  Google Scholar 

  54. 54.

    Li C, Bai Y, Liu H, Zuo X, Yao H, Xu Y, et al. Comparative study of microRNA profiling in keloid fibroblast and annotation of differential expressed microRNAs. Acta Biochim Biophys Sin. 2013;45(8):692–9.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Luan Y, Liu Y, Liu C, Lin Q, He F, Dong X, et al. Serum miRNAs signature plays an important role in keloid disease. Curr Mol Med. 2016;16(5):504–14.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Li S, Liu W, Lei Y, Long J. Regulatory effects of electronic beam irradiation on mir-21/smad7-mediated collagen I synthesis in keloid-derived fibroblasts. Biol Open. 2016;5(11):1567–74.

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Wang X, Liu Y, Chen X, Zhang M, Xiao Z. Impact of MiR-21 on the expression of FasL in the presence of TGF-beta1. Aesthet Surg J. 2013;33(8):1186–98.

    PubMed  Article  Google Scholar 

  58. 58.

    Liu Y, Wang X, Yang D, Xiao Z, Chen X. MicroRNA-21 affects proliferation and apoptosis by regulating expression of PTEN in human keloid fibroblasts. Plastic Reconstruct Surg. 2014;134(4):561e–73e.

    CAS  Article  Google Scholar 

  59. 59.

    Liu Y, Li Y, Li N, Teng W, Wang M, Zhang Y, et al. TGF-beta1 promotes scar fibroblasts proliferation and transdifferentiation via up-regulating microRNA-21. Sci Rep. 2016;24(6):32231.

    Article  CAS  Google Scholar 

  60. 60.

    Yan L, Cao R, Liu Y, Wang L, Pan B, Lv X, et al. MiR-21-5p links epithelial-mesenchymal transition phenotype with stem-like cell signatures via AKT signaling in keloid keratinocytes. Sci Rep. 2016;6(6):28281.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Sperber K, Ash J, Gutwein F, Wasserrman A, Rao V, Tratenberg M. Localized scleroderma: a clinical review. Curr Rheumatol Rev. 2016 (Epub ahead of print).

  62. 62.

    Leask A. Possible strategies for anti-fibrotic drug intervention in scleroderma. J Cell Commun Signal. 2011;5(2):125–9.

    PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Distler O, Cozzio A. Systemic sclerosis and localized scleroderma: current concepts and novel targets for therapy. Semin Immunopathol. 2016;38(1):87–95.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Hoa S, Stern EP, Denton CP, Hudson M, Scleroderma Clinical Trials Consortium Scleroderma Renal Crisis Working Group Investigators of the Scleroderma Clinical Trials Consortium Scleroderma Renal Crisis Working G. Towards developing criteria for scleroderma renal crisis: a scoping review. Autoimmun Rev. 2017;16(4):407–15.

    PubMed  Article  Google Scholar 

  65. 65.

    Stern EP, Denton CP. The pathogenesis of systemic sclerosis. Rheum Dis Clin N Am. 2015;41(3):367–82.

    Article  Google Scholar 

  66. 66.

    Cong L, Xia ZK, Yang RY. Targeting the TGF-beta receptor with kinase inhibitors for scleroderma therapy. Archiv der Pharmazie. 2014;347(9):609–15.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Li H, Yang R, Fan X, Gu T, Zhao Z, Chang D, et al. MicroRNA array analysis of microRNAs related to systemic scleroderma. Rheumatol Int. 2012;32(2):307–13.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Lu J, Liu Q, Wang L, Tu W, Chu H, Ding W, et al. Increased expression of latent TGF-beta-binding protein 4 affects the fibrotic process in scleroderma by TGF-beta/SMAD signaling. Lab Invest. 2017;97(5):591–601.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Takemoto R, Jinnin M, Wang Z, Kudo H, Inoue K, Nakayama W, et al. Hair miR-29a levels are decreased in patients with scleroderma. Exp Dermatol. 2013;22(12):832–3.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Etoh M, Jinnin M, Makino K, Yamane K, Nakayama W, Aoi J, et al. microRNA-7 down-regulation mediates excessive collagen expression in localized scleroderma. Arch Dermatol Res. 2013;305(1):9–15.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    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(11):1046–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Koba S, Jinnin M, Inoue K, Nakayama W, Honda N, Makino K, et al. Expression analysis of multiple microRNAs in each patient with scleroderma. Exp Dermatol. 2013;22(7):489–91.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Steen SO, Iversen LV, Carlsen AL, Burton M, Nielsen CT, Jacobsen S, et al. The circulating cell-free microRNA profile in systemic sclerosis is distinct from both healthy controls and systemic lupus erythematosus. J Rheumatol. 2015;42(2):214–21.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    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(11):2100–7.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Christmann RB, Wooten A, Sampaio-Barros P, Borges CL, Carvalho CR, Kairalla RA, et al. miR-155 in the progression of lung fibrosis in systemic sclerosis. Arthritis Res Ther. 2016;18(1):155.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Zhu H, Li Y, Qu S, Luo H, Zhou Y, Wang Y, et al. MicroRNA expression abnormalities in limited cutaneous scleroderma and diffuse cutaneous scleroderma. J Clin Immunol. 2012;32(3):514–22.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Makino T, Jinnin M, Etoh M, Yamane K, Kajihara I, Makino K, et al. Down-regulation of microRNA-196a in the sera and involved skin of localized scleroderma patients. Eur J Dermatol. 2014;24(4):470–6.

    CAS  PubMed  Google Scholar 

  78. 78.

    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;17(7):42899.

    Article  CAS  Google Scholar 

  79. 79.

    O’Reilly S, Ciechomska M, Fullard N, Przyborski S, van Laar JM. IL-13 mediates collagen deposition via STAT6 and microRNA-135b: a role for epigenetics. Sci Rep. 2016;26(6):25066.

    Article  CAS  Google Scholar 

  80. 80.

    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 (Epub ahead of print).

  81. 81.

    Zhu H, Luo H, Li Y, Zhou Y, Jiang Y, Chai J, et al. MicroRNA-21 in scleroderma fibrosis and its function in TGF-beta-regulated fibrosis-related genes expression. J Clin Immunol. 2013;33(6):1100–9.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Friedstat JS, Hultman CS. Hypertrophic burn scar management: what does the evidence show? A systematic review of randomized controlled trials. Ann Plast Surg. 2014;72(6):S198–201.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Gugatschka M, Ainodhofer H, Gruber HJ, Graupp M, Kieslinger P, Kiesler K, et al. Age effects on extracellular matrix production of vocal fold scar fibroblasts in rats. Eur Arch Otorhinolaryngol. 2014;271(5):1107–12.

    PubMed  Article  Google Scholar 

  84. 84.

    Lian N, Li T. Growth factor pathways in hypertrophic scars: molecular pathogenesis and therapeutic implications. Biomed Pharmacother. 2016;84:42–50.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Xue M, Jackson CJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care. 2015;4(3):119–36.

    Article  Google Scholar 

  86. 86.

    Ning P, Liu DW, Mao YG, Peng Y, Lin ZW, Liu DM. Differential expression profile of microRNA between hyperplastic scar and normal skin. Zhonghua yi xue za zhi. 2012;92(10):692–4.

    CAS  PubMed  Google Scholar 

  87. 87.

    Guo L, Xu K, Yan H, Feng H, Wang T, Chai L, et al. MicroRNA expression signature and the therapeutic effect of the microRNA21 antagomir in hypertrophic scarring. Mol Med Rep. 2017;15(3):1211–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Cejka C, Cejkova J, Trosan P, Zajicova A, Sykova E, Holan V. Transfer of mesenchymal stem cells and cyclosporine A on alkali-injured rabbit cornea using nanofiber scaffolds strongly reduces corneal neovascularization and scar formation. Histol Histopathol. 2016;31(9):969–80.

    CAS  PubMed  Google Scholar 

  89. 89.

    Liu S, Jiang L, Li H, Shi H, Luo H, Zhang Y, et al. Mesenchymal stem cells prevent hypertrophic scar formation via inflammatory regulation when undergoing apoptosis. J Invest Dermatol. 2014;134(10):2648–57.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Fang S, Xu C, Zhang Y, Xue C, Yang C, Bi H, et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-beta/SMAD2 pathway during wound healing. Stem Cell Transl Med. 2016;5(10):1425–39.

    Article  Google Scholar 

  91. 91.

    Zhu HY, Li C, Bai WD, Su LL, Liu JQ, Li Y, et al. MicroRNA-21 regulates hTERT via PTEN in hypertrophic scar fibroblasts. PLoS One. 2014;9(5):e97114.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. 92.

    Mu SZ, Sun YW, Wang GD. Down-regulation of miR-21 inhibits the HSF cells proliferation and the PI3K/Akt pathways via PDCD4. Chin J Aesthet Med. 2015;24(23):39–43.

    CAS  Google Scholar 

  93. 93.

    Fan X, Chen J, Shi D, Jia J, He J, Li L, et al. The role and mechanisms of action of SIRT6 in the suppression of postoperative epidural scar formation. Int J Mol Med. 2016;37(5):1337–44.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Zhang C, Wen C, Lin J, Shen G. Protective effect of pyrroloquinoline quinine on ultraviolet A irradiation-induced human dermal fibroblast senescence in vitro proceeds via the anti-apoptotic sirtuin 1/nuclear factor-derived erythroid 2-related factor 2/heme oxygenase 1 pathway. Mol Med Rep. 2015;12(3):4382–8.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Glavac D, Ravnik-Glavac M. Essential role of microRNA in skin physiology and disease. Adv Exp Med Biol. 2015;888:307–30.

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Inoue M, Jinnin M, Wang Z, Nakamura K, Inoue K, Ichihara A, et al. microRNA level is raised in the hair shafts of patients with dematomyositis in comparison with normal subjects and patients with scleroderma. Int J Dermatol. 2016;55(7):786–90.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Wang Z, Jinnin M, Kudo H, Inoue K, Nakayama W, Honda N, et al. Detection of hair-microRNAs as the novel potent biomarker: evaluation of the usefulness for the diagnosis of scleroderma. J Dermatol Sci. 2013;72(2):134–41.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Wu W. MicroRNA: potential targets for the development of novel drugs? Drugs R&D. 2010;10(1):1–8.

    CAS  Article  Google Scholar 

  99. 99.

    Hata A, Lieberman J. Dysregulation of microRNA biogenesis and gene silencing in cancer. Sci Signal. 2015;8(368):re3.

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    Lennox KA, Owczarzy R, Thomas DM, Walder JA, Behlke MA. Improved performance of anti-miRNA oligonucleotides using a novel non-nucleotide modifier. Mol Ther Nucleic Acids. 2013;27(2):e117.

    Article  CAS  Google Scholar 

  101. 101.

    Munoz-Alarcon A, Guterstam P, Romero C, Behlke MA, Lennox KA, Wengel J, et al. Modulating anti-microRNA-21 activity and specificity using oligonucleotide derivatives and length optimization. ISRN Pharm. 2012;2012:407154.

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Lennox KA, Behlke MA. A direct comparison of anti-microRNA oligonucleotide potency. Pharm Res. 2010;27(9):1788–99.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Hanessian S, Wagger J, Merner BL, Giacometti RD, Ostergaard ME, Swayze EE, et al. A constrained tricyclic nucleic acid analogue of alpha-L-LNA: investigating the effects of dual conformational restriction on duplex thermal stability. J Organic Chem. 2013;78(18):9064–75.

    CAS  Article  Google Scholar 

  104. 104.

    Obad S, dos Santos CO, Petri A, Heidenblad M, Broom O, Ruse C, et al. Silencing of microRNA families by seed-targeting tiny LNAs. Nat Genet. 2011;43(4):371–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Garchow BG, Bartulos Encinas O, Leung YT, Tsao PY, Eisenberg RA, Caricchio R, et al. Silencing of microRNA-21 in vivo ameliorates autoimmune splenomegaly in lupus mice. EMBO Mol Med. 2011;3(10):605–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Nakamura K, Jinnin M, Harada M, Kudo H, Nakayama W, Inoue K, et al. Altered expression of CD63 and exosomes in scleroderma dermal fibroblasts. J Dermatol Sci. 2016;84(1):30–9.

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Leoni G, Tramontano A. A structural view of microRNA-target recognition. Nucleic Acids Res. 2016;44(9):e82.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    Saraiya AA, Li W, Wang CC. Transition of a microRNA from repressing to activating translation depending on the extent of base pairing with the target. PLoS One. 2013;8(2):e55672.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors thank Li He and Hui Jiang for assistance with the editing and grammar of this manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Lechun Lyu.

Ethics declarations

Funding

The authors are supported by grants from the National Natural Science Foundation of China (Grant No. 81560502), the Science and Technology Leading Talent Project of Yunnan Province (Grant No. 2017HA010), the National Natural Science Foundation of Yunnan Province (Grant No. 2016FB044, 2014FB008), the Health Science and Technology Project of Yunnan Province (Grant No. 2016NS005), the Education Department Fund of Yunnan Province (Grant No. 2014Y165, 2015Z082), and the 100 Talents Program of Kunming Medical University.

Conflict of interest

Yan Li, Juan Zhang, Yuying Lei, Lechun Lyu, Ruiling Zuo, and Ting Chen have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Zhang, J., Lei, Y. et al. MicroRNA-21 in Skin Fibrosis: Potential for Diagnosis and Treatment. Mol Diagn Ther 21, 633–642 (2017). https://doi.org/10.1007/s40291-017-0294-8

Download citation