Abstract
Receptor activator for nuclear factor κB ligand (RANKL)-independent osteoclastogenic pathway was reported recently. MicroRNA (miR)-124 has been known to suppress RANKL-dependent osteoclastogenesis by inhibiting NFATc1 expression. However, whether miR-124 regulates a RANKL-independent pathway has not been elucidated. In this study, we examined whether a RANKL-independent pathway is regulated by miR-124 in addition to the RANKL-dependent one. Using osteoclastogenic culture and pit-formation assay, we found that a miR-124 mimic inhibited osteoclastogenesis in mouse bone marrow-derived macrophages stimulated by TNF-α, IL-6, and M-CSF in the presence of osteoprotegerin. We also showed that the expression levels of osteoclast-specific genes and NFATc1 protein were suppressed in the miR-124 mimic-transfected cells by performing quantitative-polymerase chain reaction and western blotting. Our results indicate that miR-124 is important in inhibiting both RANKL-dependent and -independent osteoclast differentiation by suppressing NFATc1-mediated pathway.
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References
McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365(23):2205–2219. https://doi.org/10.1056/NEJMra1004965
Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. Lancet 388(10055):2023–2038. https://doi.org/10.1016/s0140-6736(16)30173-8
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423(6937):337–342. https://doi.org/10.1038/nature01658
Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95(7):3597–3602
Hattersley G, Owens J, Flanagan AM, Chambers TJ (1991) Macrophage colony stimulating factor (M-CSF) is essential for osteoclast formation in vitro. Biochem Biophys Res Commun 177(1):526–531
Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3(6):889–901
Hemingway F, Taylor R, Knowles HJ, Athanasou NA (2011) RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF I and IGF II. Bone 48(4):938–944. https://doi.org/10.1016/j.bone.2010.12.023
Yokota K, Sato K, Miyazaki T, Kitaura H, Kayama H, Miyoshi F, Araki Y, Akiyama Y, Takeda K, Mimura T (2014) Combination of tumor necrosis factor alpha and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity both in vitro and in vivo. Arthritis Rheumatol 66(1):121–129. https://doi.org/10.1002/art.38218
O’Brien W, Fissel BM, Maeda Y, Yan J, Ge X, Gravallese EM, Aliprantis AO, Charles JF (2016) RANK-independent osteoclast formation and bone erosion in inflammatory arthritis. Arthritis Rheumatol 68(12):2889–2900. https://doi.org/10.1002/art.39837
Nakamachi Y, Kawano S, Takenokuchi M, Nishimura K, Sakai Y, Chin T, Saura R, Kurosaka M, Kumagai S (2009) MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum 60(5):1294–1304. https://doi.org/10.1002/art.24475
Nakamachi Y, Ohnuma K, Uto K, Noguchi Y, Saegusa J, Kawano S (2016) MicroRNA-124 inhibits the progression of adjuvant-induced arthritis in rats. Ann Rheum Dis 75(3):601–608. https://doi.org/10.1136/annrheumdis-2014-206417
Lee Y, Kim HJ, Park CK, Kim YG, Lee HJ, Kim JY, Kim HH (2013) MicroRNA-124 regulates osteoclast differentiation. Bone 56(2):383–389. https://doi.org/10.1016/j.bone.2013.07.007
Gabay C, Emery P, van Vollenhoven R, Dikranian A, Alten R, Pavelka K, Klearman M, Musselman D, Agarwal S, Green J, Kavanaugh A (2013) Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 381(9877):1541–1550. https://doi.org/10.1016/s0140-6736(13)60250-0
van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, Cardiel MH, Cohen S, Nash P, Song YW, Tegzova D, Wyman BT, Gruben D, Benda B, Wallenstein G, Krishnaswami S, Zwillich SH, Bradley JD, Connell CA, Investigators OS (2013) Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum 65(3):559–570. https://doi.org/10.1002/art.37816
Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 343(22):1594–1602. https://doi.org/10.1056/nejm200011303432202
Tang P, Xiong Q, Ge W, Zhang L (2014) The role of microRNAs in osteoclasts and osteoporosis. RNA Biol 11(11):1355–1363. https://doi.org/10.1080/15476286.2014.996462
Shibuya H, Nakasa T, Adachi N, Nagata Y, Ishikawa M, Deie M, Suzuki O, Ochi M (2013) Overexpression of microRNA-223 in rheumatoid arthritis synovium controls osteoclast differentiation. Mod Rheumatol 23(4):674–685. https://doi.org/10.1007/s10165-012-0710-1
Nakasa T, Shibuya H, Nagata Y, Niimoto T, Ochi M (2011) The inhibitory effect of microRNA-146a expression on bone destruction in collagen-induced arthritis. Arthritis Rheum 63(6):1582–1590. https://doi.org/10.1002/art.30321
Murata K, Yoshitomi H, Tanida S, Ishikawa M, Nishitani K, Ito H, Nakamura T (2010) Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 12(3):R86. https://doi.org/10.1186/ar3013
Park JS, Jeong JH, Byun JK, Lim MA, Kim EK, Kim SM, Choi SY, Park SH, Min JK, Cho ML (2017) Regulator of calcineurin 3 ameliorates autoimmune arthritis by suppressing Th17 cell differentiation. Am J Pathol 187(9):2034–2045. https://doi.org/10.1016/j.ajpath.2017.05.008
Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges MR (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 368(18):1685–1694. https://doi.org/10.1056/NEJMoa1209026
Montgomery RL, Yu G, Latimer PA, Stack C, Robinson K, Dalby CM, Kaminski N, van Rooij E (2014) MicroRNA mimicry blocks pulmonary fibrosis. EMBO Mol Med 6(10):1347–1356. https://doi.org/10.15252/emmm.201303604
Liu J, Dang L, Li D, Liang C, He X, Wu H, Qian A, Yang Z, Au DW, Chiang MW, Zhang BT, Han Q, Yue KK, Zhang H, Lv C, Pan X, Xu J, Bian Z, Shang P, Tan W, Liang Z, Guo B, Lu A, Zhang G (2015) A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts. Biomaterials 52:148–160. https://doi.org/10.1016/j.biomaterials.2015.02.007
Ell B, Mercatali L, Ibrahim T, Campbell N, Schwarzenbach H, Pantel K, Amadori D, Kang Y (2013) Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell 24(4):542–556. https://doi.org/10.1016/j.ccr.2013.09.008
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Conceptualization: SK. Data curation and making figures and graphs: KO. Formal analysis: SK, JS. Investigation: YN, YN, KU. Methodology: SK, JS, SK. Integration of the study: KO, SK, JS, SK. Supervision: SK. Writing ± original draft: KO. Writing ± review and editing: SK, JS, SK.
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The authors declare no conflicts of interest. This study was approved by the Institutional Animal Care and Use Committee of Kobe University.
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We reported the data included in this manuscript in the 65th Annual Meeting of Japanese Society of Laboratory Medicine.
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Ohnuma, K., Kasagi, S., Uto, K. et al. MicroRNA-124 inhibits TNF-α- and IL-6-induced osteoclastogenesis. Rheumatol Int 39, 689–695 (2019). https://doi.org/10.1007/s00296-018-4218-7
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DOI: https://doi.org/10.1007/s00296-018-4218-7