Abstract
Scleroderma (systemic sclerosis, SSc) is a complex autoimmune disease caused by progressive fibrotic replacement of normal tissue architecture, a progressive and ultimately fatal process that currently has no cure. Although dysregulation of microRNAs (miRNAs) is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in SSc is unclear. In comparison with the normal skin tissues, miRNAs were aberrantly expressed in limited cutaneous scleroderma and diffuse cutaneous scleroderma skin tissues. We also identified miRNAs whose expressions were correlated with SSc fibrosis: miR-21, miR-31, miR-146, miR-503, miR-145, and miR-29b were predicted to be involved. This study further confirmed that miR-21 was increased whereas miR-145 and miR-29b were decreased both in the skin tissues and fibroblasts. As predicted target genes, SMAD7, SAMD3, and COL1A1 were regulated by these miRNAs. After stimulation with transforming growth factor β, the expression of miR-21 was increased and that of SMAD7 mRNA was decreased. MiR-145 was upregulated whereas the mRNA level of SMAD3 was downregulated. The downregulation of miR-29b was correlated with the upregulation of COL1A1 mRNA. MiRNAs might play an important role in the pathogenesis of SSc and suggest a potential therapy.
Similar content being viewed by others
References
Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360(19):1989–2003.
LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger Jr TA, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–5.
Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557–67.
Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000;342(18):1350–8.
Leask A, Abraham DJ, Finlay DR, Holmes A, Pennington D, Shi-Wen X, et al. Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum. 2002;46(7):1857–65.
Gabrielli A, Di Loreto C, Taborro R, Candela M, Sambo P, Nitti C, et al. Immunohistochemical localization of intracellular and extracellular associated TGF beta in the skin of patients with systemic sclerosis (scleroderma) and primary Raynaud’s phenomenon. Clin Immunol Immunopathol. 1993;68(3):340–9.
Sfikakis PP, McCune BK, Tsokos M, Aroni K, Vayiopoulos G, Tsokos GC. Immunohistological demonstration of transforming growth factor-beta isoforms in the skin of patients with systemic sclerosis. Clin Immunol Immunopathol. 1993;69(2):199–204.
Xu WD, Leroy EC, Smith EA. Fibronectin release by systemic sclerosis and normal dermal fibroblasts in response to TGF-beta. J Rheumatol. 1991;18(2):241–6.
Varga J. Scleroderma and Smads: dysfunctional Smad family dynamics culminating in fibrosis. Arthritis Rheum. 2002;46(7):1703–13.
O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010;10(2):111–22.
Stefani G, Slack FJ. Small non-coding RNAs in animal development. Nat Rev Mol Cell Biol. 2008;9(3):219–30.
Bushati N, Cohen SM. microRNA functions. Annu Rev Cell Dev Biol. 2007;23:175–205.
Jiang X, Tsitsiou E, Herrick SE, Lindsay MA. MicroRNAs and the regulation of fibrosis. FEBS J. 2010;277(9):2015–21.
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. 2010;32(2):307–13.
Maurer B, Stanczyk J, Jungel A, Akhmetshina A, Trenkmann M, Brock M, et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 2010;62(6):1733–43.
Masi AT. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980;23(5):581–90.
Sargent JL, Milano A, Bhattacharyya S, Varga J, Connolly MK, Chang HY, et al. A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J Invest Dermatol. 2010;130(3):694–705.
Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.
Brown BD, Naldini L. Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nat Rev Genet. 2009;10(8):578–85.
van Rooij E, Marshall WS, Olson EN. Toward microRNA-based therapeutics for heart disease: the sense in antisense. Circ Res. 2008;103(9):919–28.
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(7189):896–9.
Elmen J, Lindow M, Silahtaroglu A, Bak M, Christensen M, Lind-Thomsen A, et al. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res. 2008;36(4):1153–62.
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(2):87–98.
Kawashita Y, Jinnin M, Makino T, Kajihara I, Makino K, Honda N, et al. Circulating miR-29a levels in patients with scleroderma spectrum disorder. J Dermatol Sci. 2011;61(1):67–9.
Acknowledgments
This work was supported by grants from National Natural Science Foundation of China (30671947, 30900588) and Graduate Research Innovation Fund of Hunan Province (no. CX2011B061).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhu, H., Li, Y., Qu, S. et al. MicroRNA Expression Abnormalities in Limited Cutaneous Scleroderma and Diffuse Cutaneous Scleroderma. J Clin Immunol 32, 514–522 (2012). https://doi.org/10.1007/s10875-011-9647-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-011-9647-y