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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Review

MicroRNAs in fibrosis: opportunities and challenges

Author: Steven O’Reilly

Published in: Arthritis Research & Therapy | Issue 1/2016

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Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs that mediate mRNA cleavage, translational repression or mRNA destabilisation and are around 22–25 nucleotides in length via partial complementary binding to the 3′ untranslated region in target transcripts. They are master regulators of gene expression. Fibrosis is an important cause of morbidity and mortality in the world, and there are currently no accepted treatments for fibrosis. Many novel miRNAs are now associated with fibrosis, both organ-specific and systemic, as in the prototypical fibrotic disease systemic sclerosis. Recently, the targets of these altered miRNAs have been validated and defined new biochemical pathways. Dysregulated miRNAs are amenable to therapeutic modulation. This review will examine the role of miRNAs in fibrosis and the opportunities and challenges of targeting them.
Literature
1.
2.
3.
van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A. 2008;105:13027–32.PubMedPubMedCentralCrossRef
4.
Roderburg C, Urban G-W, Bettermann K, Vucur M, Zimmermann H, Schmidt S, et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology. 2011;53:209–18.PubMedCrossRef
5.
Wang B, Komers R, Carew R, Winbanks CE, Xu B, Herman-Edelstein M, et al. Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis. J Am Soc Nephrol. 2012;23:252–65.PubMedPubMedCentralCrossRef
6.
Maurer B, Stanczyk J, Jüngel A, Akhmetshina A, Trenkmann M, Brock M, et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 2010;62:1733–43.PubMedCrossRef
7.
Pottier N, Cauffiez C, Perrais M, Barbry P, Mari B. FibromiRs: translating molecular discoveries into new anti-fibrotic drugs. Trends Pharmacol Sci. 2014;35:119–26.PubMedCrossRef
8.
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;32:514–22.PubMedCrossRef
9.
Ciechomska M, O’Reilly S, Suwara M, Bogunia-Kubik K, van Laar JM. MiR-29a reduces TIMP-1 production by dermal fibroblasts via targeting TGF-β activated kinase 1 binding protein 1, implications for systemic sclerosis. PLoS One. 2014;9:e115596.PubMedPubMedCentralCrossRef
10.
Bhattacharyya S, Kelley K, Melichian DS, Tamaki Z, Fang F, Su Y, et al. Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am J Pathol. 2013;182:192–205.PubMedPubMedCentralCrossRef
11.
Kim SI, Kwak JH, Na H-J, Kim JK, Ding Y, Choi ME. Transforming growth factor-β (TGF-β1) activates TAK1 via TAB1-mediated autophosphorylation, independent of TGF-β receptor kinase activity in mesangial cells. J Biol Chem. 2009;284:22285–96.PubMedPubMedCentralCrossRef
12.
Kwiecinski M, Elfimova N, Noetel A, Tox U, Steffen H-M, Hacker U, et al. Expression of platelet-derived growth factor-C and insulin-like growth factor I in hepatic stellate cells is inhibited by miR-29. Lab Invest. 2012;92:978–87.PubMedCrossRef
13.
Yamakage A, Kikuchi K, Smith EA, LeRoy EC, Trojanowska M. Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts. J Exp Med. 1992;175:1227–34.PubMedCrossRef
14.
Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A. 2007;104:15805–10.PubMedPubMedCentralCrossRef
15.
Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, et al. miR-29 is a major regulator of genes associated with pulmonary fibrosis. Am J Respir Cell Mol Biol. 2011;45:287–94.PubMedPubMedCentralCrossRef
16.
Ramdas V, McBride M, Denby L, Baker AH. Canonical transforming growth factor-β signaling regulates disintegrin metalloprotease expression in experimental renal fibrosis via miR-29. Am J Pathol. 2013;183:1885–96.PubMedPubMedCentralCrossRef
17.
Xiao J, Meng X-M, Huang XR, Chung AC, Feng Y-L, Hui DS, et al. miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice. Mol Ther. 2012;20:1251–60.PubMedPubMedCentralCrossRef
18.
19.
Zhu J-N, Chen R, Fu Y-H, Lin Q-X, Huang S, Guo L-L, et al. Smad3 inactivation and MiR-29b upregulation mediate the effect of carvedilol on attenuating the acute myocardium infarction-induced myocardial fibrosis in rat. PLoS One. 2013;8:e75557.PubMedPubMedCentralCrossRef
20.
Millar NL, Gilchrist DS, Akbar M, Reilly JH, Kerr SC, Campbell AL, et al. MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease. Nat Commun. 2015;6:6774.PubMedPubMedCentralCrossRef
21.
Knabel MK, Ramachandran K, Karhadkar S, Hwang H-W, Creamer TJ, Chivukula RR, et al. Systemic delivery of scAAV8-encoded MiR-29a ameliorates hepatic fibrosis in carbon tetrachloride-treated mice. PLoS One. 2015;10:e0124411.PubMedPubMedCentralCrossRef
22.
Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008;456:980–4.PubMedCrossRef
23.
Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med. 2010;207:1589–97.PubMedPubMedCentralCrossRef
24.
25.
Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell. 2010;39:493–506.PubMedPubMedCentralCrossRef
26.
O’Reilly S, Ciechomska M, Cant R, van Laar JM. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via gremlin protein. J Biol Chem. 2014;289:9952–60.PubMedPubMedCentralCrossRef
27.
Vinciguerra M, Sgroi A, Veyrat-Durebex C, Rubbia-Brandt L, Buhler LH, Foti M. Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes. Hepatology. 2009;49:1176–84.PubMedCrossRef
28.
Roderburg C, Luedde M, Vargas Cardenas D, Vucur M, Mollnow T, Zimmermann HW, et al. miR-133a mediates TGF-β-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis. J Hepatol. 2013;58:736–42.PubMedCrossRef
29.
Hazra S, Xiong S, Wang J, Rippe RA, Krishna V, Chatterjee K, et al. Peroxisome proliferator-activated receptor γ induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem. 2004;279:11392–401.PubMedCrossRef
30.
31.
Krupa A, Jenkins R, Luo DD, Lewis A, Phillips A, Fraser D. Loss of microRNA-192 promotes fibrogenesis in diabetic nephropathy. J Am Soc Nephrol. 2010;21:438–47.PubMedPubMedCentralCrossRef
32.
Vandewalle C, Van Roy F, Berx G. The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci. 2009;66:773–87.PubMedCrossRef
33.
Yang S, Cui H, Xie N, Icyuz M, Banerjee S, Antony VB, et al. miR-145 regulates myofibroblast differentiation and lung fibrosis. FASEB J. 2013;27:2382–91.PubMedPubMedCentralCrossRef
34.
Yu F, Guo Y, Chen B, Dong P, Zheng J. MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7. Lab Invest. 2015;95:781–9.PubMedCrossRef
35.
Lu Y, Thomson JM, Wong HY, Hammond SM, Hogan BL. Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells. Dev Biol. 2007;310:442–53.PubMedPubMedCentralCrossRef
36.
Dakhlallah D, Batte K, Wang Y, Cantemir-Stone CZ, Yan P, Nuovo G, et al. Epigenetic regulation of miR-17 ~ 92 contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2013;187:397–405.PubMedPubMedCentralCrossRef
37.
Kodama T, Takehara T, Hikita H, Shimizu S, Shigekawa M, Tsunematsu H, et al. Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice. J Clin Invest. 2011;121:3343–56.PubMedPubMedCentralCrossRef
38.
O’Reilly S, Hügle T, van Laar JM. T cells in systemic sclerosis: a reappraisal. Rheumatology. 2012;51:1540–9.PubMedCrossRef
39.
Nakashima T, Jinnin M, Yamane K, Honda N, Kajihara I, Makino T, et al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J Immunol. 2012;188:3573–83.PubMedCrossRef
40.
Truchetet M-E, Allanore Y, Montanari E, Chizzolini C, Brembilla NC. Prostaglandin I2 analogues enhance already exuberant Th17 cell responses in systemic sclerosis. Ann Rheum Dis. 2012;71:2044–50.PubMedCrossRef
41.
Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology. 2010;138:705–14. e704.PubMedPubMedCentralCrossRef
42.
Bala S, Marcos M, Kodys K, Csak T, Catalano D, Mandrekar P, et al. Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor α (TNFα) production via increased mRNA half-life in alcoholic liver disease. J Biol Chem. 2011;286:1436–44.PubMedPubMedCentralCrossRef
43.
O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007;104:1604–9.PubMedPubMedCentralCrossRef
44.
Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, et al. TLR4 enhances TGF-[beta] signaling and hepatic fibrosis. Nat Med. 2007;13:1324–32.PubMedCrossRef
45.
Miller AM, Gilchrist DS, Nijjar J, Araldi E, Ramirez CM, Lavery CA, et al. MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice. PLoS One. 2013;8:e72324.PubMedPubMedCentralCrossRef
46.
Dai W, Zhao J, Tang N, Zeng X, Wu K, Ye C, et al. MicroRNA-155 attenuates activation of hepatic stellate cell by simultaneously preventing EMT process and ERK1 signalling pathway. Liver Int. 2015;35:1234–43.PubMedCrossRef
47.
Lino Cardenas CL, Henaoui IS, Courcot E, Roderburg C, Cauffiez C, Aubert S, et al. miR-199a-5p is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1. PLoS Genet. 2013;9:e1003291.PubMedPubMedCentralCrossRef
48.
Galdo FD, Sotgia F, de Almeida CJ, Jasmin J-F, Musick M, Lisanti MP, et al. Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis. Arthritis Rheum. 2008;58:2854–65.PubMedPubMedCentralCrossRef
49.
Manetti M, Allanore Y, Saad M, Fatini C, Cohignac V, Guiducci S, et al. Evidence for caveolin-1 as a new susceptibility gene regulating tissue fibrosis in systemic sclerosis. Ann Rheum Dis. 2012;71:1034–41.PubMedCrossRef
50.
Wang XM, Zhang Y, Kim HP, Zhou Z, Feghali-Bostwick CA, Liu F, et al. Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med. 2006;203:2895–906.PubMedPubMedCentralCrossRef
51.
da Costa Martins PA, Salic K, Gladka MM, Armand A-S, Leptidis S, el Azzouzi H, et al. MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling. Nat Cell Biol. 2010;12:1220–7.PubMedCrossRef
52.
van Rooij E, Olson EN. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat Rev Drug Discov. 2012;11:860–72.PubMedCrossRef
53.
Petersen M, Wengel J. LNA: a versatile tool for therapeutics and genomics. Trends Biotechnol. 2003;21:74–81.PubMedCrossRef
54.
Elmen J, Lindow M, Schutz S, Lawrence M, Petri A, Obad S, et al. LNA-mediated microRNA silencing in non-human primates. Nature. 2008;452:896–9.PubMedCrossRef
55.
Czauderna F, Fechtner M, Dames S, Aygün H, Klippel A, Pronk GJ, et al. Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. Nucleic Acids Res. 2003;31:2705–16.PubMedPubMedCentralCrossRef
56.
Janssen HLA, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368:1685–94.PubMedCrossRef
57.
Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 2010;327:198–201.PubMedPubMedCentralCrossRef
58.
Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science. 2005;309:1577–81.PubMedCrossRef
59.
Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006;3:87–98.PubMedCrossRef
60.
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;43:371–8.PubMedPubMedCentralCrossRef
61.
Trang P, Wiggins JF, Daige CL, Cho C, Omotola M, Brown D, et al. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol Ther. 2011;19:1116–22.PubMedPubMedCentralCrossRef
62.
Denby L, Ramdas V, Lu R, Conway BR, Grant JS, Dickinson B, et al. MicroRNA-214 antagonism protects against renal fibrosis. J Am Soc Nephrol. 2014;25:65–80.PubMedPubMedCentralCrossRef
63.
Chau BN, Xin C, Hartner J, Ren S, Castano AP, Linn G, et al. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med. 2012;4:121ra118.CrossRef
64.
65.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.PubMedCrossRef
66.
Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, et al. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology. 2008;48:1810–20.PubMedPubMedCentralCrossRef
67.
Pirola CJ, Fernández Gianotti T, Castaño GO, Mallardi P, San Martino J, Mora Gonzalez Lopez Ledesma M, et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut. 2015;64:800–12.PubMedPubMedCentralCrossRef
68.
Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One. 2011;6:e23937.PubMedPubMedCentralCrossRef
69.
Bala S, Petrasek J, Mundkur S, Catalano D, Levin I, Ward J, et al. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology. 2012;56:1946–57.PubMedPubMedCentralCrossRef
70.
Chen L, Charrier A, Zhou Y, Chen R, Yu B, Agarwal K, et al. Epigenetic regulation of connective tissue growth factor by MicroRNA-214 delivery in exosomes from mouse or human hepatic stellate cells. Hepatology. 2014;59:1118–29.PubMedPubMedCentralCrossRef
71.
Charrier A, Chen R, Chen L, Kemper S, Hattori T, Takigawa M, et al. Exosomes mediate intercellular transfer of pro-fibrogenic connective tissue growth factor (CCN2) between hepatic stellate cells, the principal fibrotic cells in the liver. Surgery. 2014;156:548–55.PubMedPubMedCentralCrossRef
72.
Roncarati R, Viviani Anselmi C, Losi MA, Papa L, Cavarretta E, Da Costa Martins P, et al. Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2014;63:920–7.PubMedCrossRef
73.
Makino K, Jinnin M, Kajihara I, Honda N, Sakai K, Masuguchi S, et al. Circulating miR-142-3p levels in patients with systemic sclerosis. Clin Exp Dermatol. 2012;37:34–9.PubMedCrossRef
74.
Honda N, Jinnin M, Kajihara I, Makino T, Makino K, Masuguchi S, et al. TGF-β–mediated downregulation of microRNA-196a contributes to the constitutive upregulated type I collagen expression in scleroderma dermal fibroblasts. J Immunol. 2012;188:3323–31.PubMedCrossRef
75.
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;72:134–41.PubMedCrossRef
Metadata
Title
MicroRNAs in fibrosis: opportunities and challenges
Author
Steven O’Reilly
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-0929-x

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