Vitamin K2 promotes mesenchymal stem cell differentiation by inhibiting miR‑133a expression

Zhang,Yuelei; Weng,Shiyang; Yin,Junhui; Ding,Hao; Zhang,Changqing; Gao,Youshui

doi:10.3892/mmr.2017.6308

Vitamin K2 promotes mesenchymal stem cell differentiation by inhibiting miR‑133a expression

Authors:
- Yuelei Zhang
- Shiyang Weng
- Junhui Yin
- Hao Ding
- Changqing Zhang
- Youshui Gao
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Affiliations: Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
Published online on: March 9, 2017 https://doi.org/10.3892/mmr.2017.6308
Pages: 2473-2480
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Vitamin K2 has been demonstrated to promote the osteogenic differentiation of mesenchymal stem cells; however, the mechanisms underlying this effect remain unclear. As microRNA (miR)‑133a has been identified as a negative regulator of osteogenic differentiation, the present study hypothesized that vitamin K2 promoted osteogenesis by inhibiting miR‑133a. Using human bone marrow stromal cells (hBMSCs) overexpressing miR‑133a, or a control, the expression levels of osteogenesis‑associated proteins, including runt‑related transcription factor 2, alkaline phosphatase and osteocalcin, were analyzed. miR‑133a significantly suppressed the osteogenic differentiation of hBMSCs. To determine the effect of vitamin K2 on miR‑133a expression and osteogenesis, hBMSCs were treated with vitamin K2. Vitamin K2 inhibited miR‑133a expression, which was accompanied by enhanced osteogenic differentiation. Furthermore, the expression levels of vitamin K epoxide reductase complex subunit 1, the key protein in γ‑carboxylation, were downregulated by miR‑133a overexpression and upregulated by vitamin K2 treatment, indicating a positive feedback on γ‑carboxylation. The results of the present study suggested that vitamin K2 targets miR‑133a to regulate osteogenesis.

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1	Wang L, Li X, Zhou Y, Shi H, Xu C, He H, Wang S, Xiong X, Zhang Y, Du Z, et al: Downregulation of miR-133 via MAPK/ERK signaling pathway involved in nicotine-induced cardiomyocyte apoptosis. Naunyn Schmiedebergs Arch Pharmacol. 387:197–206. 2014. View Article : Google Scholar : PubMed/NCBI
2	Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, Lian JB and Stein GS: A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci USA. 105:13906–13911. 2008. View Article : Google Scholar : PubMed/NCBI
3	van Rooij E, Liu N and Olson EN: MicroRNAs flex their muscles. Trends Genet. 24:159–166. 2008. View Article : Google Scholar : PubMed/NCBI
4	Xu M and Wang YZ: miR133a suppresses cell proliferation, migration and invasion in human lung cancer by targeting MMP-14. Oncol Rep. 30:1398–1404. 2013.PubMed/NCBI
5	Fan J, Li J and Fan Q: Naringin promotes differentiation of bone marrow stem cells into osteoblasts by upregulating the expression levels of microRNA-20a and downregulating the expression levels of PPARγ. Mol Med Rep. 12:4759–4765. 2015.PubMed/NCBI
6	Zuo B, Zhu J, Li J, Wang C, Zhao X, Cai G, Li Z, Peng J, Wang P, Shen C, et al: microRNA-103a functions as a mechanosensitive microRNA to inhibit bone formation through targeting Runx2. J Bone Miner Res. 30:330–345. 2015. View Article : Google Scholar : PubMed/NCBI
7	Li H, Yang F, Wang Z, Fu Q and Liang A: MicroRNA-21 promotes osteogenic differentiation by targeting small mothers against decapentaplegic 7. Mol Med Rep. 12:1561–1567. 2015.PubMed/NCBI
8	Li CJ, Cheng P, Liang MK, Chen YS, Lu Q, Wang JY, Xia ZY, Zhou HD, Cao X, Xie H, et al: MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. J Clin Invest. 125:1509–1522. 2015. View Article : Google Scholar : PubMed/NCBI
9	Liu N and Olson EN: MicroRNA regulatory networks in cardiovascular development. Dev Cell. 18:510–525. 2010. View Article : Google Scholar : PubMed/NCBI
10	Zhou Q, Zhao ZN, Cheng JT, Zhang B, Xu J, Huang F, Zhao RN and Chen YJ: Ibandronate promotes osteogenic differentiation of periodontal ligament stem cells by regulating the expression of microRNAs. Biochem Biophys Res Commun. 404:127–132. 2011. View Article : Google Scholar : PubMed/NCBI
11	Zhang Y, Xie RL, Croce CM, Stein JL, Lian JB, van Wijnen AJ and Stein GS: A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2. Proc Natl Acad Sci USA. 108:9863–9868. 2011. View Article : Google Scholar : PubMed/NCBI
12	Zhang Y, Xie RL, Gordon J, LeBlanc K, Stein JL, Lian JB, van Wijnen AJ and Stein GS: Control of mesenchymal lineage progression by microRNAs targeting skeletal gene regulators Trps1 and Runx2. J Biol Chem. 287:21926–21935. 2012. View Article : Google Scholar : PubMed/NCBI
13	Wang Y, Li L, Moore BT, Peng XH, Fang X, Lappe JM, Recker RR and Xiao P: MiR-133a in human circulating monocytes: A potential biomarker associated with postmenopausal osteoporosis. PLoS One. 7:e346412012. View Article : Google Scholar : PubMed/NCBI
14	Wu X, Zhang Y, Guo X, Xu H, Xu Z, Duan D and Wang K: Identification of differentially expressed microRNAs involved in non-traumatic osteonecrosis through microRNA expression profiling. Gene. 565:22–29. 2015. View Article : Google Scholar : PubMed/NCBI
15	Perez-Andreu V, Teruel R, Corral J, Roldán V, García-Barberá N, Salloum-Asfar S, Gómez-Lechón MJ, Bourgeois S, Deloukas P, Wadelius M, et al: miR-133a regulates vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), a key protein in the vitamin K cycle. Mol Med. 18:1466–1472. 2013.PubMed/NCBI
16	Hamidi MS, Gajic-Veljanoski O and Cheung AM: Vitamin K and bone health. J Clin Densitom. 16:409–413. 2013. View Article : Google Scholar : PubMed/NCBI
17	Neve A, Corrado A and Cantatore FP: Osteocalcin: Skeletal and extra-skeletal effects. J Cell Physiol. 228:1149–1153. 2013. View Article : Google Scholar : PubMed/NCBI
18	Koshihara Y, Hoshi K, Okawara R, Ishibashi H and Yamamoto S: Vitamin K stimulates osteoblastogenesis and inhibits osteoclastogenesis in human bone marrow cell culture. J Endocrinol. 176:339–348. 2003. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Takeuchi Y, Suzawa M, Fukumoto S and Fujita T: Vitamin K(2) inhibits adipogenesis, osteoclastogenesis, and ODF/RANK ligand expression in murine bone marrow cell cultures. Bone. 27:769–776. 2000. View Article : Google Scholar : PubMed/NCBI
21	Koshihara Y and Hoshi K: Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro. J Bone Miner Res. 12:431–438. 1997. View Article : Google Scholar : PubMed/NCBI
22	Liao XB, Zhang ZY, Yuan K, Liu Y, Feng X, Cui RR, Hu YR, Yuan ZS, Gu L, Li SJ, et al: MiR-133a modulates osteogenic differentiation of vascular smooth muscle cells. Endocrinology. 154:3344–3352. 2013. View Article : Google Scholar : PubMed/NCBI
23	Ichikawa T, Horie-Inoue K, Ikeda K, Blumberg B and Inoue S: Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells. J Biol Chem. 281:16927–16934. 2006. View Article : Google Scholar : PubMed/NCBI
24	Shah A and Ahmad A: Role of microRNA in mesenchymal stem cells differentiation into osteoblasts. Razavi Int J Med. 1:5–10. 2013. View Article : Google Scholar
25	Hu N, Feng C, Jiang Y, Miao Q and Liu H: Regulative Effect of Mir-205 on osteogenic differentiation of bone mesenchymal stem cells (BMSCs): Possible role of SATB2/Runx2 and ERK/MAPK pathway. Int J Mol Sci. 16:10491–10506. 2015. View Article : Google Scholar : PubMed/NCBI
26	Koromila T, Baniwal SK, Song YS, Martin A, Xiong J and Frenkel B: Glucocorticoids antagonize RUNX2 during osteoblast differentiation in cultures of ST2 pluripotent mesenchymal cells. J Cell Biochem. 115:27–33. 2014. View Article : Google Scholar : PubMed/NCBI
27	Ma XL, Liu ZP, Ma JX, Han C and Zang JC: Dynamic expression of Runx2, Osterix and AJ18 in the femoral head of steroid-induced osteonecrosis in rats. Orthop Surg. 2:278–284. 2010. View Article : Google Scholar : PubMed/NCBI
28	Shearer MJ and Newman P: Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J Lipid Res. 55:345–362. 2014. View Article : Google Scholar : PubMed/NCBI
29	Atkins GJ, Welldon KJ, Wijenayaka AR, Bonewald LF and Findlay DM: Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by {gamma}-carboxylation-dependent and-independent mechanisms. Am J Physiol Cell Physiol. 297:C1358–C1367. 2009. View Article : Google Scholar : PubMed/NCBI