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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2018

Open Access 01-12-2018 | Research article

Osteogenic differentiation of fibroblast-like synovial cells in rheumatoid arthritis is induced by microRNA-218 through a ROBO/Slit pathway

Authors: Naoki Iwamoto, Shoichi Fukui, Ayuko Takatani, Toshimasa Shimizu, Masataka Umeda, Ayako Nishino, Takashi Igawa, Tomohiro Koga, Shin-ya Kawashiri, Kunihiro Ichinose, Mami Tmai, Hideki Nakamura, Tomoki Origuchi, Ko Chiba, Makoto Osaki, Astrid Jüngel, Steffen Gay, Atsushi Kawakami

Published in: Arthritis Research & Therapy | Issue 1/2018

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Abstract

Background

Fibroblast-like synovial cells (FLS) have multilineage differentiation potential including osteoblasts. We aimed to investigate the role of microRNAs during the osteogenic differentiation of rheumatoid arthritis (RA)-FLS.

Methods

RA-FLS were differentiated in osteogenic medium for 21 days. Osteogenic differentiation was evaluated by alkaline phosphatase (ALP) staining and Alizarin Red staining. MicroRNA (miRNA) array analysis was performed to investigate the differentially expressed miRNAs during osteogenic differentiation. Expression of miR-218-5p (miR-218) during the osteogenic differentiation was determined by quantitative real-time PCR. Transfections with an miR-218 precursor and inhibitor were used to confirm the targets of miR-218 and to analyze the ability of miR-218 to induce osteogenic differentiation. Secreted Dickkopf-1 (DKK1) from FLS transfected with miR-218 precursor/inhibitor or roundabout 1 (ROBO1) knockdown FLS established using ROBO1-small interfering RNA (siRNA) were measured by ELISA.

Results

The miRNA array revealed that 12 miRNAs were upregulated and 24 miRNAs were downregulated after osteogenic differentiation. We observed that the level of miR-218 rose in the early phase of osteogenic differentiation and then decreased. Pro-inflammatory cytokines modified the expression of miR-218. The induction of miR-218 in RA-FLS decreased ROBO1 expression, and promoted osteogenic differentiation. Both the overexpression of miR-218 and the knockdown of ROBO1 in RA-FLS decreased DKK1 secretion.

Conclusion

We identified miR-218 as a crucial inducer of the osteogenic differentiation of RA-FLS. MiR-218 modulates the osteogenic differentiation of RA-FLS through the ROBO1/DKK-1 axis. The induction of the osteogenic differentiation of proliferating RA-FLS through the provision of miR-218 into RA-FLS or by boosting the cellular reservoir of miR-218 might thus become a therapeutic strategy for RA.
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Literature
1.
Stanczyk J, Ospelt C, Gay RE, Gay S. Synovial cell activation. Curr Opin Rheumatol. 2006;18:262–7.CrossRefPubMed
2.
3.
Ianculescu I, Weisman MH. Infection, malignancy, switching, biosimilars, antibody formation, drug survival and withdrawal, and dose reduction: what have we learned over the last year about tumor necrosis factor inhibitors in rheumatoid arthritis? Curr Opin Rheumatol. 2016;28:303–9.CrossRefPubMed
4.
Joensuu JT, Huoponen S, Aaltonen KJ, Konttinen YT, Nordstrom D, Blom M. The cost-effectiveness of biologics for the treatment of rheumatoid arthritis: a systematic review. PLoS One. 2015;10:e0119683.CrossRefPubMedPubMedCentral
5.
6.
Tian J, Chen JW, Gao JS, Li L, Xie X. Resveratrol inhibits TNF-alpha-induced IL-1beta, MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway. Rheumatol Int. 2013;33:1829–35.CrossRefPubMed
7.
8.
Choi HS, Ryu CJ, Choi HM, Park JS, Lee JH, Kim KI, Yang HI, Yoo MC, Kim KS. Effects of the pro-inflammatory milieu on the dedifferentiation of cultured fibroblast-like synoviocytes. Mol Med Rep. 2012;5:1023–6.CrossRefPubMedPubMedCentral
9.
Yamasaki S, Nakashima T, Kawakami A, Miyashita T, Tanaka F, Ida H, Migita K, Origuchi T, Eguchi K. Cytokines regulate fibroblast-like synovial cell differentiation to adipocyte-like cells. Rheumatology (Oxford). 2004;43:448–52.CrossRef
10.
Zvaifler NJ, Tsai V, Alsalameh S, von Kempis J, Firestein GS, Lotz M. Pannocytes: distinctive cells found in rheumatoid arthritis articular cartilage erosions. Am J Pathol. 1997;150:1125–38.PubMedPubMedCentral
11.
De Bari C, Dell'Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001;44:1928–42.CrossRefPubMed
12.
Marinova-Mutafchieva L, Williams RO, Funa K, Maini RN, Zvaifler NJ. Inflammation is preceded by tumor necrosis factor-dependent infiltration of mesenchymal cells in experimental arthritis. Arthritis Rheum. 2002;46:507–13.CrossRefPubMed
13.
Li X, Makarov SS. An essential role of NF-kappaB in the “tumor-like” phenotype of arthritic synoviocytes. Proc Natl Acad Sci USA. 2006;103:17432–7.CrossRefPubMed
14.
Okada A, Yamasaki S, Koga T, Kawashiri SY, Tamai M, Origuchi T, Nakamura H, Eguchi K, Kawakami A. Adipogenesis of the mesenchymal stromal cells and bone oedema in rheumatoid arthritis. Clin Exp Rheumatol. 2012;30:332–7.PubMed
15.
Axtell MJ. Evolution of microRNAs and their targets: are all microRNAs biologically relevant? Biochim Biophys Acta. 2008;1779:725–34.CrossRefPubMed
16.
Churov AV, Oleinik EK, Knip M. MicroRNAs in rheumatoid arthritis: altered expression and diagnostic potential. Autoimmun Rev. 2015;14:1029–37.CrossRefPubMed
17.
Lee CH, Kim JH, Lee SW. The role of microRNA in pathogenesis and as markers of HCV chronic infection. Curr Drug Targets. 2017;18:756–765.
18.
Yang G, Wu D, Zhu J, Jiang O, Shi Q, Tian J, Weng Y. Upregulation of miR-195 increases the sensitivity of breast cancer cells to Adriamycin treatment through inhibition of Raf-1. Oncol Rep. 2013;30:877–89.CrossRefPubMed
19.
Kim KM, Lim SK. Role of miRNAs in bone and their potential as therapeutic targets. Curr Opin Pharmacol. 2014;16:133–41.CrossRefPubMed
20.
Jia J, Tian Q, Ling S, Liu Y, Yang S, Shao Z. miR-145 suppresses osteogenic differentiation by targeting Sp7. FEBS Lett. 2013;587:3027–31.CrossRefPubMed
21.
Grunhagen J, Bhushan R, Degenkolbe E, Jager M, Knaus P, Mundlos S, Robinson PN, Ott CE. MiR-497 approximately 195 cluster microRNAs regulate osteoblast differentiation by targeting BMP signaling. J Bone Miner Res. 2015;30:796–808.CrossRefPubMed
22.
Hassan MQ, Maeda Y, Taipaleenmaki H, Zhang W, Jafferji M, Gordon JA, Li Z, Croce CM, van Wijnen AJ, Stein JL, Stein GS, Lian JB. miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. J Biol Chem. 2012;287:42084–92.CrossRefPubMedPubMedCentral
23.
Wei J, Shi Y, Zheng L, Zhou B, Inose H, Wang J, Guo XE, Grosschedl R, Karsenty G. miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2. J Cell Biol. 2012;197:509–21.CrossRefPubMedPubMedCentral
24.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580–8.CrossRefPubMed
25.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.CrossRefPubMed
26.
Ospelt C, Kurowska-Stolarska M, Neidhart M, Michel BA, Gay RE, Laufer S, Gay S. The dual inhibitor of lipoxygenase and cyclooxygenase ML3000 decreases the expression of CXCR3 ligands. Ann Rheum Dis. 2008;67:524–9.CrossRefPubMed
27.
Suzuki T, Iwamoto N, Yamasaki S, Nishino A, Nakashima Y, Horai Y, Kawashiri SY, Ichinose K, Arima K, Tamai M, Nakamura H, Origuchi T, Miyamoto C, Osaki M, Ohyama K, Kuroda N, Kawakami A. Upregulation of thrombospondin 1 expression in synovial tissues and plasma of rheumatoid arthritis: role of transforming growth factor-beta1 toward fibroblast-like synovial cells. J Rheumatol. 2015;42:943–7.CrossRefPubMed
28.
Sun H, Dai K, Tang T, Zhang X. Regulation of osteoblast differentiation by slit2 in osteoblastic cells. Cells Tissues Organs. 2009;190:69–80.CrossRefPubMed
29.
Lerner UH, Ohlsson C. The WNT system: background and its role in bone. J Intern Med. 2015;277:630–49.CrossRefPubMed
30.
Deal C. Bone loss in rheumatoid arthritis: systemic, periarticular, and focal. Curr Rheumatol Rep. 2012;14:231–7.CrossRefPubMed
31.
Li Y, Backesjo CM, Haldosen LA, Lindgren U. IL-6 receptor expression and IL-6 effects change during osteoblast differentiation. Cytokine. 2008;43:165–73.CrossRefPubMed
32.
Malaval L, Liu F, Vernallis AB, Aubin JE. GP130/OSMR is the only LIF/IL-6 family receptor complex to promote osteoblast differentiation of calvaria progenitors. J Cell Physiol. 2005;204:585–93.CrossRefPubMed
33.
Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, Korb A, Smolen J, Hoffmann M, Scheinecker C, van der Heide D, Landewe R, Lacey D, Richards WG, Schett G. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156–63.CrossRefPubMed
34.
Walsh NC, Reinwald S, Manning CA, Condon KW, Iwata K, Burr DB, Gravallese EM. Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J Bone Miner Res. 2009;24:1572–85.CrossRefPubMed
35.
Dohn UM, Ejbjerg B, Boonen A, Hetland ML, Hansen MS, Knudsen LS, Hansen A, Madsen OR, Hasselquist M, Moller JM, Ostergaard M. No overall progression and occasional repair of erosions despite persistent inflammation in adalimumab-treated rheumatoid arthritis patients: results from a longitudinal comparative MRI, ultrasonography, CT and radiography study. Ann Rheum Dis. 2011;70:252–8.CrossRefPubMed
36.
Finzel S, Rech J, Schmidt S, Engelke K, Englbrecht M, Stach C, Schett G. Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion. Ann Rheum Dis. 2011;70:1587–93.CrossRefPubMed
37.
Tang S, Wang D, Zhang Q, Li L. miR-218 suppresses gastric cancer cell proliferation and invasion via regulation of angiopoietin-2. Exp Ther Med. 2016;12:3837–42.CrossRefPubMedPubMedCentral
38.
Gu JJ, Gao GZ, Zhang SM. MiR-218 inhibits the tumorgenesis and proliferation of glioma cells by targeting Robo1. Cancer Biomark. 2016;16:309–17.CrossRefPubMed
39.
Zhang WB, Zhong WJ, Wang L. A signal-amplification circuit between miR-218 and Wnt/beta-catenin signal promotes human adipose tissue-derived stem cells osteogenic differentiation. Bone. 2014;58:59–66.CrossRefPubMed
40.
Brose K, Bland KS, Wang KH, Arnott D, Henzel W, Goodman CS, Tessier-Lavigne M, Kidd T. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell. 1999;96:795–806.CrossRefPubMed
41.
Dickinson RE, Duncan WC. The SLIT-ROBO pathway: a regulator of cell function with implications for the reproductive system. Reproduction. 2010;139:697–704.CrossRefPubMedPubMedCentral
42.
Rama N, Dubrac A, Mathivet T, Ni Charthaigh RA, Genet G, Cristofaro B, Pibouin-Fragner L, Ma L, Eichmann A, Chedotal A. Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization. Nat Med. 2015;21:483–91.CrossRefPubMedPubMedCentral
43.
Wang Y, Li YP, Paulson C, Shao JZ, Zhang X, Wu M, Chen W. Wnt and the Wnt signaling pathway in bone development and disease. Front Biosci (Landmark Ed). 2014;19:379–407.CrossRef
44.
Seror R, Boudaoud S, Pavy S, Nocturne G, Schaeverbeke T, Saraux A, Chanson P, Gottenberg JE, Devauchelle-Pensec V, Tobon GJ, Mariette X, Miceli-Richard C. Increased Dickkopf-1 in recent-onset rheumatoid arthritis is a new biomarker of structural severity. Data from the ESPOIR cohort. Sci Rep. 2016;6:18421.CrossRefPubMedPubMedCentral
45.
Wang SY, Liu YY, Ye H, Guo JP, Li R, Liu X, Li ZG. Circulating Dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. J Rheumatol. 2011;38:821–7.CrossRefPubMed
46.
Cui H, Ge J, Xie N, Banerjee S, Zhou Y, Antony VB, Thannickal VJ, Liu G. miR-34a inhibits lung fibrosis by inducing lung fibroblast senescence. Am J Respir Cell Mol Biol. 2017;56:168–78.PubMedPubMedCentral
47.
Han X, Zhen S, Ye Z, Lu J, Wang L, Li P, Li J, Zheng X, Li H, Chen W, Li X, Zhao L. A feedback loop between miR-30a/c-5p and DNMT1 mediates cisplatin resistance in ovarian Cancer cells. Cell Physiol Biochem. 2017;41:973–86.CrossRefPubMed
48.
Kim HY, Kwon HY, Ha Thi HT, Lee HJ, Kim GI, Hahm KB, Hong S. MicroRNA-132 and microRNA-223 control positive feedback circuit by regulating FOXO3a in inflammatory bowel disease. J Gastroenterol Hepatol. 2016;31:1727–35.CrossRefPubMed
49.
Wang G, Zhao Y, Zheng Y. MiR-122/Wnt/beta-catenin regulatory circuitry sustains glioma progression. Tumour Biol. 2014;35:8565–72.CrossRefPubMed
50.
Zhou AD, Diao LT, Xu H, Xiao ZD, Li JH, Zhou H, Qu LH. Beta-catenin/LEF1 transactivates the microRNA-371-373 cluster that modulates the Wnt/beta-catenin-signaling pathway. Oncogene. 2012;31:2968–78.CrossRefPubMed
Metadata
Title
Osteogenic differentiation of fibroblast-like synovial cells in rheumatoid arthritis is induced by microRNA-218 through a ROBO/Slit pathway
Authors
Naoki Iwamoto
Shoichi Fukui
Ayuko Takatani
Toshimasa Shimizu
Masataka Umeda
Ayako Nishino
Takashi Igawa
Tomohiro Koga
Shin-ya Kawashiri
Kunihiro Ichinose
Mami Tmai
Hideki Nakamura
Tomoki Origuchi
Ko Chiba
Makoto Osaki
Astrid Jüngel
Steffen Gay
Atsushi Kawakami
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2018
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-018-1703-z

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