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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2015

Open Access 01-12-2015 | Research article

Signature of microRNA expression during osteogenic differentiation of bone marrow MSCs reveals a putative role of miR-335-5p in osteoarthritis

Authors: Pilar Tornero-Esteban, Luis Rodríguez-Rodríguez, Lydia Abásolo, María Tomé, Pedro López-Romero, Eva Herranz, Manuel A. González, Fernando Marco, Enrique Moro, Benjamín Fernández-Gutiérrez, José Ramón Lamas

Published in: BMC Musculoskeletal Disorders | Issue 1/2015

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Abstract

Background

The aim of this study was to evaluate, the existence of a signature of differentially expressed microRNAs (miRNAs) during osteogenic differentiation of bone marrow MSCs from OA and healthy donors and to describe their possible implication in joint regeneration through modulation of molecular mechanisms involved in homeostatic control in OA pathophysiology.

Methods

Following phenotypic assessment of BM-MSCs obtained from OA diagnosed patients (n = 10) and non-OA (n = 10), total small RNA was isolated after osteogenic induction for 1, 10 and 21 days, miRNA profiles were generated using a commercial expression array of 754 well-characterized miRNAs. MiRNAs, with consistent differential expression were selected for further validation by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis.

Results

A total of 246 miRNAs were differentially expressed (fold change ≥ ± 2, P ≤0.05) between OA and non-OA BM-MSC samples; these miRNAs showed variable interactions depending on the cell and differentiation status. Two miRNAs, hsa-miR-210 and hsa-miR-335-5p out of 21 used for validation showed a significant downregulated expression during induced osteogenesis. In particular hsa-miR-335-5p, a critical regulator in bone homeostasis, was further studied. hsa-miR-335-5p downregulation in OA-MSCs, as well as their host coding gene, MEST, were also assessed.

Conclusions

To our knowledge, this study represents the most comprehensive assessment to date of miRNA expression profiling in BM-MSCs from OA patients and their role during osteogenic differentiation. We describe the existence of a correlation between miR-335-5p expression and OA indicating the putative role of this miRNA in OA features. These findings, may contribute to our understanding of the molecular mechanisms involved in MSCs mediated homeostatic control in OA pathophysiology that could be applicable in future therapeutic approaches.
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Literature
1.
Bitton R. The economic burden of osteoarthritis. Am J Manag Care. 2009;15(8 Suppl):S230–5.PubMed
2.
Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci. 2010;1192:230–7.PubMedCrossRef
3.
Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage. 2010;18(1):24–33.PubMedCrossRef
4.
Reynard LN, Loughlin J. Insights from human genetic studies into the pathways involved in osteoarthritis. Nat Rev Rheumatol. 2013;9(10):573–83.PubMedCrossRef
5.
6.
Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19(2):179–92.PubMedCrossRef
7.
Miki T, Yasuda SY, Kahn M. Wnt/beta-catenin signaling in embryonic stem cell self-renewal and somatic cell reprogramming. Stem Cell Rev. 2011;7(4):836–46.PubMedCrossRef
8.
Zimmerman ZF, Moon RT, Chien AJ. Targeting Wnt pathways in disease. Cold Spring Harb Perspect Biol. 2012;4(11).
9.
Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004;5(9):691–701.PubMedCrossRef
10.
Dong S, Yang B, Guo H, Kang F. MicroRNAs regulate osteogenesis and chondrogenesis. Biochem Biophys Res Commun. 2012;418(4):587–91.PubMedCrossRef
11.
Bakhshandeh B, Soleimani M, Paylakhi SH, Ghaemi N. A microRNA signature associated with chondrogenic lineage commitment. J Genet. 2012;91(2):171–82.PubMedCrossRef
12.
Martinez-Sanchez A, Dudek KA, Murphy CL. Regulation of human chondrocyte function through direct inhibition of cartilage master regulator SOX9 by microRNA-145 (miRNA-145). J Biol Chem. 2012;287(2):916–24.PubMedCrossRef
13.
Corr M. Wnt-beta-catenin signaling in the pathogenesis of osteoarthritis. Nat Clin Pract Rheumatol. 2008;4(10):550–6.PubMedCrossRef
14.
Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, Southam L, et al. Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci U S A. 2004;101(26):9757–62.PubMedPubMedCentralCrossRef
15.
Liu Y, Huang T, Zhao X, Cheng L. MicroRNAs modulate the Wnt signaling pathway through targeting its inhibitors. Biochem Biophys Res Commun. 2011;408(2):259–64.PubMedCrossRef
16.
Su J, Zhang A, Shi Z, Ma F, Pu P, Wang T, et al. MicroRNA-200a suppresses the Wnt/beta-catenin signaling pathway by interacting with beta-catenin. Int J Oncol. 2012;40(4):1162–70.PubMed
17.
Zhang J, Tu Q, Bonewald LF, He X, Stein G, Lian J, et al. Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. J Bone Miner Res. 2011;26(8):1953–63.PubMedCrossRef
18.
19.
Zhou AD, Diao LT, Xu H, Xiao ZD, Li JH, Zhou H, et al. beta-Catenin/LEF1 transactivates the microRNA-371-373 cluster that modulates the Wnt/beta-catenin-signaling pathway. Oncogene. 2011.
20.
Tome M, Lopez-Romero P, Albo C, Sepulveda JC, Fernandez-Gutierrez B, Dopazo A, et al. miR-335 orchestrates cell proliferation, migration and differentiation in human mesenchymal stem cells. Cell Death Differ. 2011;18(6):985–95.PubMedCrossRef
21.
Jensen ED, Gopalakrishnan R, Westendorf JJ. Regulation of gene expression in osteoblasts. Biofactors. 2010;36(1):25–32.PubMedPubMedCentral
22.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.PubMedCrossRef
23.
Wylie D, Shelton J, Choudhary A, Adai AT. A novel mean-centering method for normalizing microRNA expression from high-throughput RT-qPCR data. BMC Res Notes. 2011;4:555.PubMedPubMedCentralCrossRef
24.
Smyth GK. limma: Linear Models for Microarray Data. In: Gentleman R, Carey V, Huber W, Irizarry R, Dudoit S, editors. Bioinformatics and computational biology solutions using R and Bioconductor. New York: Springer; 2005. p. 397–420.CrossRef
25.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc. 1995;B57(1):289–300.
26.
Kawaguchi H. Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models. Mol Cells. 2008;25(1):1–6.PubMed
27.
Murphy JM, Dixon K, Beck S, Fabian D, Feldman A, Barry F. Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum. 2002;46(3):704–13.PubMedCrossRef
28.
Im GI, Jung NH, Tae SK. Chondrogenic differentiation of mesenchymal stem cells isolated from patients in late adulthood: the optimal conditions of growth factors. Tissue Eng. 2006;12(3):527–36.PubMedCrossRef
29.
Lu C, Wan Y, Cao J, Zhu X, Yu J, Zhou R, et al. Wnt-mediated reciprocal regulation between cartilage and bone development during endochondral ossification. Bone. 2013;53(2):566–74.PubMedCrossRef
30.
Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PV, Komm BS, et al. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem. 2005;280(39):33132–40.PubMedCrossRef
31.
Liu G, Vijayakumar S, Grumolato L, Arroyave R, Qiao H, Akiri G, et al. Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells. J Cell Biol. 2009;185(1):67–75.PubMedPubMedCentralCrossRef
32.
de Boer J, Siddappa R, Gaspar C, van Apeldoorn A, Fodde R, van Blitterswijk C. Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells. Bone. 2004;34(5):818–26.PubMedCrossRef
33.
Li J, Khavandgar Z, Lin SH, Murshed M. Lithium chloride attenuates BMP-2 signaling and inhibits osteogenic differentiation through a novel WNT/GSK3- independent mechanism. Bone. 2011;48(2):321–31.PubMedCrossRef
34.
Liu W, Liu Y, Guo T, Hu C, Luo H, Zhang L, et al. TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments. Cell Death Dis. 2013;4:e539.PubMedPubMedCentralCrossRef
35.
Garcia-Ibarbia C, Delgado-Calle J, Casafont I, Velasco J, Arozamena J, Perez-Nunez MI, et al. Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders. Gene. 2013;532(2):165–72.PubMedCrossRef
36.
Hong E, Reddi AH. MicroRNAs in chondrogenesis, articular cartilage, and osteoarthritis: implications for tissue engineering. Tissue Eng Part B Rev. 2012;18(6):445–53.PubMedCrossRef
37.
Heyn H, Engelmann M, Schreek S, Ahrens P, Lehmann U, Kreipe H, et al. MicroRNA miR-335 is crucial for the BRCA1 regulatory cascade in breast cancer development. Int J Cancer. 2011;129(12):2797–806.PubMedCrossRef
38.
Iliopoulos D, Bimpaki EI, Nesterova M, Stratakis CA. MicroRNA signature of primary pigmented nodular adrenocortical disease: clinical correlations and regulation of Wnt signaling. Cancer Res. 2009;69(8):3278–82.PubMedPubMedCentralCrossRef
39.
Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008;451(7175):147–52.PubMedPubMedCentralCrossRef
40.
Egeblad M, Shen HC, Behonick DJ, Wilmes L, Eichten A, Korets LV, et al. Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development. Dev Dyn. 2007;236(6):1683–93.PubMedPubMedCentralCrossRef
41.
42.
Lamas JR, Rodriguez-Rodriguez L, Vigo AG, Alvarez-Lafuente R, Lopez-Romero P, Marco F, et al. Large-scale gene expression in bone marrow mesenchymal stem cells: a putative role for COL10A1 in osteoarthritis. Ann Rheum Dis. 2010;69(10):1880–5.PubMedCrossRef
Metadata
Title
Signature of microRNA expression during osteogenic differentiation of bone marrow MSCs reveals a putative role of miR-335-5p in osteoarthritis
Authors
Pilar Tornero-Esteban
Luis Rodríguez-Rodríguez
Lydia Abásolo
María Tomé
Pedro López-Romero
Eva Herranz
Manuel A. González
Fernando Marco
Enrique Moro
Benjamín Fernández-Gutiérrez
José Ramón Lamas
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2015
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-015-0652-9

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