Advertisement

miR-140-3p exhibits repressive functions on preosteoblast viability and differentiation by downregulating MCF2L in osteoporosis

  • Jin-He Mao
  • Yu-Xin Sui
  • Shuang Ao
  • Yu Wang
  • Yu Liu
  • Hui LengEmail author
Article
  • 44 Downloads

Abstract

Previous research manifested that miR-140-3p was a latent biomarker for osteoporosis. Nevertheless, the mechanism of miR-140-3p in osteoporosis is still not clear and needs ulteriorly studying. The purpose of our paper was to ulteriorly probe the underlying mechanism of miR-140-3p on osteoporosis. Firstly, based on the data acquired from GEO database, we found that miR-140-3p was highly expressed; meanwhile, MCF2L was lowly expressed in osteoporosis patients. Upregulation/downregulation of miR-140-3p by miR-140-3p mimic/inhibitor restrained/promoted MC3T3-E1 cell viability and differentiation. However, miR-140-3p over-expression/downregulation accelerated/repressed MC3T3-E1 cell apoptosis. MCF2L was forecasted as a target of miR-140-3p by miRanda, miRWalk, and TargetScan miRNA target gene prediction software. Luciferase reporter assay confirmed that MCF2L could be directly targeted by miR-140-3p. Moreover, we identified that the expression of MCF2L was negatively regulated by miR-140-3p. From rescue assays, we discovered that knockdown of MCF2L weakened the promoting influence of miR-140-3p ablation on MC3T3-E1 cell viability and differentiation, and receded the suppressing impact of miR-140-3p reduction on MC3T3-E1 cell apoptosis. Above all, this research disclosed that miR-140-3p repressed preosteoblast viability and differentiation while promoted preosteoblast apoptosis via targeting MCF2L. Our discoveries might afford a theoretical basis of developing a latent novel target for osteoporosis therapy.

Keywords

miR-140-3p MCF2L Osteoporosis Viability Differentiation Apoptosis 

Notes

Authors’ contributions

Jin-He Mao and Yu-Xin Sui performed the experiment. Shuang Ao and Yu Wang analyzed and interpreted the data. Yu Liu drafted the article. Hui Leng designed the study, and critically revised the manuscript. All authors have read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

References

  1. Aquino-Martinez R, Farr JN, Weivoda MM, Negley BA, Onken JL, Thicke BS, Fulcer MM, Fraser DG, van Wijnen AJ, Khosla S, Monroe DG (2019) miR-219a-5p regulates Rorbeta during osteoblast differentiation and in age-related bone loss. J Bone Miner Res 34:135–144.  https://doi.org/10.1002/jbmr.3586 CrossRefPubMedGoogle Scholar
  2. Avenell A, Mak JC, O'Connell D (2014) Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev:CD000227.  https://doi.org/10.1002/14651858.CD000227.pub4
  3. Bellavia D, De Luca A, Carina V, Costa V, Raimondi L, Salamanna F, Alessandro R, Fini M, Giavaresi G (2019) Deregulated miRNAs in bone health: epigenetic roles in osteoporosis. Bone 122:52–75.  https://doi.org/10.1016/j.bone.2019.02.013 CrossRefPubMedGoogle Scholar
  4. Cheng L, Mahon GM, Kostenko EV, Whitehead IP (2004) Pleckstrin homology domain-mediated activation of the rho-specific guanine nucleotide exchange factor Dbs by Rac1. J Biol Chem 279:12786–12793.  https://doi.org/10.1074/jbc.M313099200 CrossRefPubMedGoogle Scholar
  5. Cheung DG, Buzzetti M, Di Leva G (2017) miRNAs in bone metastasis. Expert Rev Endocrinol Metab 12:451–461.  https://doi.org/10.1080/17446651.2017.1383893 CrossRefPubMedGoogle Scholar
  6. Day-Williams AG, Southam L, Panoutsopoulou K, Rayner NW, Esko T, Estrada K, Helgadottir HT, Hofman A, Ingvarsson T, Jonsson H, Keis A, Kerkhof HJ, Thorleifsson G, Arden NK, Carr A, Chapman K, Deloukas P, Loughlin J, McCaskie A, Ollier WE, Ralston SH, Spector TD, Wallis GA, Wilkinson JM, Aslam N, Birell F, Carluke I, Joseph J, Rai A, Reed M, Walker K, Arc OC, Doherty SA, Jonsdottir I, Maciewicz RA, Muir KR, Metspalu A, Rivadeneira F, Stefansson K, Styrkarsdottir U, Uitterlinden AG, van Meurs JB, Zhang W, Valdes AM, Doherty M, Zeggini E (2011) A variant in MCF2L is associated with osteoarthritis. Am J Hum Genet 89:446–450.  https://doi.org/10.1016/j.ajhg.2011.08.001 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Fushimi S, Nohno T, Nagatsuka H, Katsuyama H (2018) Involvement of miR-140-3p in Wnt3a and TGFbeta3 signaling pathways during osteoblast differentiation in MC3T3-E1 cells. Genes Cells 23:517–527.  https://doi.org/10.1111/gtc.12591 CrossRefPubMedGoogle Scholar
  8. Gao Y, Xiao F, Wang C, Wang C, Cui P, Zhang X, Chen X (2018) Long noncoding RNA MALAT1 promotes osterix expression to regulate osteogenic differentiation by targeting miRNA-143 in human bone marrow-derived mesenchymal stem cells. J Cell Biochem 119:6986–6996.  https://doi.org/10.1002/jcb.26907 CrossRefPubMedGoogle Scholar
  9. Ge DW, Wang WW, Chen HT, Yang L, Cao XJ (2017) Functions of microRNAs in osteoporosis. Eur Rev Med Pharmacol Sci 21:4784–4789PubMedGoogle Scholar
  10. Jain N, Roy J, Das B, Mallick B (2019) miR-197-5p inhibits sarcomagenesis and induces cellular senescence via repression of KIAA0101. Mol Carcinog 58:1376–1388.  https://doi.org/10.1002/mc.23021 CrossRefPubMedGoogle Scholar
  11. Karlsen TA, Jakobsen RB, Mikkelsen TS, Brinchmann JE (2014) microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. Stem Cells Dev 23:290–304.  https://doi.org/10.1089/scd.2013.0209 CrossRefPubMedGoogle Scholar
  12. Kocijan R, Muschitz C, Geiger E, Skalicky S, Baierl A, Dormann R, Plachel F, Feichtinger X, Heimel P, Fahrleitner-Pammer A, Grillari J, Redl H, Resch H, Hackl M (2016) Circulating microRNA signatures in patients with idiopathic and postmenopausal osteoporosis and fragility fractures. J Clin Endocrinol Metab 101:4125–4134.  https://doi.org/10.1210/jc.2016-2365 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Leder BZ (2018) Optimizing sequential and combined anabolic and antiresorptive osteoporosis therapy. JBMR Plus 2:62–68.  https://doi.org/10.1002/jbm4.10041 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, Xu K, Sheng ZF, Zhou HD, Wu XP, Luo XH (2009) A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 119:3666–3677.  https://doi.org/10.1172/JCI39832 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Li Y, Chen H, She P, Chen T, Chen L, Yuan J, Jiang B (2018) microRNA-23a promotes cell growth and metastasis in gastric cancer via targeting SPRY2-mediated ERK signaling. Oncol Lett 15:8433–8441.  https://doi.org/10.3892/ol.2018.8374 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Li M, Luo R, Yang W, Zhou Z, Li C (2019a) miR-363-3p is activated by MYB and regulates osteoporosis pathogenesis via PTEN/PI3K/AKT signaling pathway. In Vitro Cell Dev Biol Anim 55:376–386.  https://doi.org/10.1007/s11626-019-00344-5 CrossRefPubMedGoogle Scholar
  17. Li JY, Wei X, Sun Q, Zhao XQ, Zheng CY, Bai CX, Du J, Zhang Z, Zhu LG, Jia YS (2019b) MicroRNA-449b-5p promotes the progression of osteoporosis by inhibiting osteogenic differentiation of BMSCs via targeting Satb2. Eur Rev Med Pharmacol Sci 23:6394–6403.  https://doi.org/10.26355/eurrev_201908_18519 CrossRefPubMedGoogle Scholar
  18. Lian JB, Stein GS, van Wijnen AJ, Stein JL, Hassan MQ, Gaur T, Zhang Y (2012) MicroRNA control of bone formation and homeostasis. Nat Rev Endocrinol 8:212–227.  https://doi.org/10.1038/nrendo.2011.234 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Liston A, Papadopoulou AS, Danso-Abeam D, Dooley J (2012) MicroRNA-29 in the adaptive immune system: setting the threshold. Cell Mol Life Sci 69:3533–3541.  https://doi.org/10.1007/s00018-012-1124-0 CrossRefPubMedGoogle Scholar
  20. Liu C, Mallick B, Long D, Rennie WA, Wolenc A, Carmack CS, Ding Y (2013) CLIP-based prediction of mammalian microRNA binding sites. Nucleic Acids Res 41:e138.  https://doi.org/10.1093/nar/gkt435 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Luo W, Liu L, Yang L, Dong Y, Liu T, Wei X, Liu D, Gu H, Kong J, Yuan Z, Zhao Q (2018) The vitamin D receptor regulates miR-140-5p and targets the MAPK pathway in bone development. Metabolism 85:139–150.  https://doi.org/10.1016/j.metabol.2018.03.018 CrossRefPubMedGoogle Scholar
  22. Lv H, Jiang F, Guan D, Lu C, Guo B, Chan C, Peng S, Liu B, Guo W, Zhu H, Xu X, Lu A, Zhang G (2016) Metabolomics and its application in the development of discovering biomarkers for osteoporosis research. Int J Mol Sci 17.  https://doi.org/10.3390/ijms17122018 CrossRefGoogle Scholar
  23. Lv R, Pan X, Song L, Sun Q, Guo C, Zou S, Zhou Q (2019) MicroRNA-200a-3p accelerates the progression of osteoporosis by targeting glutaminase to inhibit osteogenic differentiation of bone marrow mesenchymal stem cells. Biomed Pharmacother 116:108960.  https://doi.org/10.1016/j.biopha.2019.108960 CrossRefPubMedGoogle Scholar
  24. Maiwald S, Motazacker MM, van Capelleveen JC, Sivapalaratnam S, van der Wal AC, van der Loos C, Kastelein JJ, Ouwehand WH, Hovingh GK, Trip MD, van Buul JD, Dallinga-Thie GM (2016) A rare variant in MCF2L identified using exclusion linkage in a pedigree with premature atherosclerosis. Eur J Hum Genet 24:86–91.  https://doi.org/10.1038/ejhg.2015.70 CrossRefPubMedGoogle Scholar
  25. McCully M, Conde J, P VB, Mullin M, Dalby MJ, Berry CC (2018) Nanoparticle-antagomiR based targeting of miR-31 to induce osterix and osteocalcin expression in mesenchymal stem cells. PLoS One 13:e0192562.  https://doi.org/10.1371/journal.pone.0192562 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Miller PD (2016) Management of severe osteoporosis. Expert Opin Pharmacother 17:473–488.  https://doi.org/10.1517/14656566.2016.1124856 CrossRefPubMedGoogle Scholar
  27. Mirnezami AH, Pickard K, Zhang L, Primrose JN, Packham G (2009) MicroRNAs: key players in carcinogenesis and novel therapeutic targets. Eur J Surg Oncol 35:339–347.  https://doi.org/10.1016/j.ejso.2008.06.006 CrossRefPubMedGoogle Scholar
  28. Murray MJ, Coleman N (2019) MicroRNA dysregulation in malignant germ cell tumors: more than a biomarker? J Clin Oncol:JCO:1900578.  https://doi.org/10.1200/JCO.19.00578 CrossRefGoogle Scholar
  29. Naidu S, Garofalo M (2015) microRNAs: an emerging paradigm in lung cancer chemoresistance. Front Med (Lausanne) 2:77.  https://doi.org/10.3389/fmed.2015.00077 CrossRefGoogle Scholar
  30. Pereira RC, Salusky IB, Bowen RE, Freymiller EG, Wesseling-Perry K (2019) Vitamin D sterols increase FGF23 expression by stimulating osteoblast and osteocyte maturation in CKD bone. Bone. 127:626–634.  https://doi.org/10.1016/j.bone.2019.07.026 CrossRefPubMedGoogle Scholar
  31. Perez-Campo FM, Santurtun A, Garcia-Ibarbia C, Pascual MA, Valero C, Garces C, Sanudo C, Zarrabeitia MT, Riancho JA (2016) Osterix and RUNX2 are transcriptional regulators of sclerostin in human bone. Calcif Tissue Int 99:302–309.  https://doi.org/10.1007/s00223-016-0144-4 CrossRefPubMedGoogle Scholar
  32. Pravoverov K, Whiting K, Thapa S, Bushong T, Trang K, Lein PJ, Chandrasekaran V (2019) MicroRNAs are necessary for BMP-7-induced dendritic growth in cultured rat sympathetic neurons. Cell Mol Neurobiol.  https://doi.org/10.1007/s10571-019-00688-2 CrossRefGoogle Scholar
  33. Ramirez-Salazar EG, Carrillo-Patino S, Hidalgo-Bravo A, Rivera-Paredez B, Quiterio M, Ramirez-Palacios P, Patino N, Valdes-Flores M, Salmeron J, Velazquez-Cruz R (2018) Serum miRNAs miR-140-3p and miR-23b-3p as potential biomarkers for osteoporosis and osteoporotic fracture in postmenopausal Mexican-Mestizo women. Gene 679:19–27.  https://doi.org/10.1016/j.gene.2018.08.074 CrossRefPubMedGoogle Scholar
  34. Roy J, Mallick B (2017) Altered gene expression in late-onset Alzheimer’s disease due to SNPs within 3′UTR microRNA response elements. Genomics 109:177–185.  https://doi.org/10.1016/j.ygeno.2017.02.006 CrossRefPubMedGoogle Scholar
  35. Saito K, Shinozuka T, Nakao A, Kiho T, Kunikata T, Shiiki T, Nagai Y, Naito S (2019) Synthesis and structure-activity relationship of 4-alkoxy-thieno[2,3-b]pyridine derivatives as potent alkaline phosphatase enhancers for osteoporosis treatment. Bioorg Med Chem Lett 29:1769–1773.  https://doi.org/10.1016/j.bmcl.2019.05.014 CrossRefPubMedGoogle Scholar
  36. Salmena L, Carracedo A, Pandolfi PP (2008) Tenets of PTEN tumor suppression. Cell 133:403–414.  https://doi.org/10.1016/j.cell.2008.04.013 CrossRefPubMedGoogle Scholar
  37. Shepherd C, Skelton AJ, Rushton MD, Reynard LN, Loughlin J (2015) Expression analysis of the osteoarthritis genetic susceptibility locus mapping to an intron of the MCF2L gene and marked by the polymorphism rs11842874. BMC Med Genet 16:108.  https://doi.org/10.1186/s12881-015-0254-2 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Sotornik I (2016) Osteoporosis - epidemiology and pathogenesis. Vnitr Lek 62(Suppl 6):84–87PubMedGoogle Scholar
  39. Sun X, Guo Q, Wei W, Robertson S, Yuan Y, Luo X (2019) Current progress on MicroRNA-based gene delivery in the treatment of osteoporosis and osteoporotic fracture. Int J Endocrinol 2019:6782653–6782617.  https://doi.org/10.1155/2019/6782653 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Tao SC, Yuan T, Zhang YL, Yin WJ, Guo SC, Zhang CQ (2017) Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics 7:180–195.  https://doi.org/10.7150/thno.17133 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Taylor MV (2017) Skeletal muscle development on the 30th Anniversary of MyoD. Semin Cell Dev Biol 72:1–2.  https://doi.org/10.1016/j.semcdb.2017.11.019 CrossRefPubMedGoogle Scholar
  42. Xie Y, Chen Y, Zhang L, Ge W, Tang P (2017) The roles of bone-derived exosomes and exosomal microRNAs in regulating bone remodelling. J Cell Mol Med 21:1033–1041.  https://doi.org/10.1111/jcmm.13039 CrossRefPubMedGoogle Scholar
  43. Yuan R, Ma S, Zhu X, Li J, Liang Y, Liu T, Zhu Y, Zhang B, Tan S, Guo H, Guan S, Ao P, Zhou G (2016) Core level regulatory network of osteoblast as molecular mechanism for osteoporosis and treatment. Oncotarget 7:3692–3701.  https://doi.org/10.18632/oncotarget.6923 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Zhang Y-J, Wen C-L, Qin Y-X, Tang X-M, Shi M-M, Shen B-Y, Fang Y (2017) Establishment of a human primary pancreatic cancer mouse model to examine and investigate gemcitabine resistance. Oncol Rep.  https://doi.org/10.3892/or.2017.6026
  45. Zhang X, Zhu Y, Zhang C, Liu J, Sun T, Li D, Na Q, Xian CJ, Wang L, Teng Z (2018) miR-542-3p prevents ovariectomy-induced osteoporosis in rats via targeting SFRP1. J Cell Physiol 233:6798–6806.  https://doi.org/10.1002/jcp.26430 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Society for In Vitro Biology 2019

Authors and Affiliations

  • Jin-He Mao
    • 1
  • Yu-Xin Sui
    • 1
  • Shuang Ao
    • 1
  • Yu Wang
    • 1
  • Yu Liu
    • 1
  • Hui Leng
    • 1
    Email author
  1. 1.Department of OrthopedicsChifeng Municipal HospitalChifengPeople’s Republic of China

Personalised recommendations