miR‑483‑3p regulates osteogenic differentiation of bone marrow mesenchymal stem cells by targeting STAT1

Xiao,Ye; Guo,Qi; Jiang,Tie‑Jian; Yuan,Ying; Yang,Li; Wang,Guang‑Wei; Xiao,Wen‑Feng

doi:10.3892/mmr.2019.10700

miR‑483‑3p regulates osteogenic differentiation of bone marrow mesenchymal stem cells by targeting STAT1

Authors:
- Ye Xiao
- Qi Guo
- Tie‑Jian Jiang
- Ying Yuan
- Li Yang
- Guang‑Wei Wang
- Wen‑Feng Xiao
View Affiliations

Affiliations: Department of Endocrinology, Endocrinology Research Center, Central South University, Changsha, Hunan 410008, P.R. China, Department of Medicine, Hunan University of Medicine, Huaihua, Hunan 418000, P.R. China, Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: September 24, 2019 https://doi.org/10.3892/mmr.2019.10700
Pages: 4558-4566
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is regulated by a variety of intracellular regulatory factors including osterix, runt‑related transcription factor 2 (RUNX2), bone morphogenetic proteins and transforming growth factorβ. Recent studies have shown that microRNAs (miRs) serve a crucial role in this process. In the present study, miR‑483‑3p levels were significantly increased during osteogenic differentiation of mouse and human BMSCs. Overexpression of miR‑483‑3p promoted osteogenic differentiation, whereas inhibition of miR‑483‑3p reversed these effects. miR‑483‑3p regulated osteogenic differentiation of BMSCs by targeting STAT1, and thus enhancing RUNX2 transcriptional activity and RUNX2 nuclear translocation. In vivo, overexpression of miR‑483‑3p using a BMSC‑specific aptamer delivery system stimulated bone formation in aged mice. Therefore, the present study suggested that miR‑483‑3p promoted osteogenic differentiation of BMSCs by targeting STAT1, and miR‑483‑3 prepresent a potential therapeutic target for age‑related bone loss.

View Figures

View References

1	Krane SM: Identifying genes that regulate bone remodeling as potential therapeutic targets. J Exp Med. 201:841–843. 2005. View Article : Google Scholar : PubMed/NCBI
2	Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S and Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science. 284:143–147. 1999. View Article : Google Scholar : PubMed/NCBI
3	Crane JL and Cao X: Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling. J Clin Invest. 124:466–472. 2014. View Article : Google Scholar : PubMed/NCBI
4	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
5	Khalaj M, Woolthuis CM, Hu W, Durham BH, Chu SH, Qamar S, Armstrong SA and Park CY: miR-99 regulates normal and malignant hematopoietic stem cell self-renewal. J Exp Med. Jul 21–2017.(Epub ahead of print). jem.20161595, 2017. doi: 10.1084/jem.20161595. View Article : Google Scholar : PubMed/NCBI
6	Edmonds MD, Boyd KL, Moyo T, Mitra R, Duszynski R, Arrate MP, Chen X, Zhao Z, Blackwell TS, Andl T and Eischen CM: MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer. J Clin Invest. 126:349–364. 2016. View Article : Google Scholar : PubMed/NCBI
7	Mori MA, Thomou T, Boucher J, Lee KY, Lallukka S, Kim JK, Torriani M, Yki-Järvinen H, Grinspoon SK, Cypess AM and Kahn CR: Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Invest. 124:3339–3351. 2014. View Article : Google Scholar : PubMed/NCBI
8	Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, McManus MT and Bluestone JA: Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med. 205:1983–1991. 2008. View Article : Google Scholar : PubMed/NCBI
9	Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, Xu K, Sheng ZF, Zhou HD, Wu XP and Luo XH: A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest. 119:3666–3677. 2009. View Article : Google Scholar : PubMed/NCBI
10	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
11	Gu H, Xu J, Huang Z, Wu L, Zhou K, Zhang Y, Chen J, Xia J and Yin X: Identification and differential expression of microRNAs in 1, 25-dihydroxyvitamin D3-induced osteogenic differentiation of human adipose-derived mesenchymal stem cells. Am J Transl Res. 11:4856–4871. 2017.
12	Maruyama K, Uematsu S, Kondo T, Takeuchi O, Martino MM, Kawasaki T and Akira S: Strawberry notch homologue 2 regulates osteoclast fusion by enhancing the expression of DC-STAMP. J Exp Med. 210:1947–1960. 2013. View Article : Google Scholar : PubMed/NCBI
13	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
14	Javed A, Gutierrez S, Montecino M, van Wijnen AJ, Stein JL, Stein GS and Lian JB: Multiple Cbfa/AML sites in the rat osteocalcin promoter are required for basal and vitamin D-responsive transcription and contribute to chromatin organization. Mol Cell Biol. 19:7491–7500. 1999. View Article : Google Scholar : PubMed/NCBI
15	Li J, He X, Wei W and Zhou X: MicroRNA-194 promotes osteoblast differentiation via downregulating STAT1. Biochem Biophys Res Commun. 460:482–488. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zou W, Greenblatt MB, Brady N, Lotinun S, Zhai B, de Rivera H, Singh A, Sun J, Gygi SP, Baron R, et al: The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of RUNX2. J Exp Med. 210:1793–1806. 2013. View Article : Google Scholar : PubMed/NCBI
17	Xiao WZ, Gu XC, Hu B, Liu XW, Zi Y and Li M: Role of microRNA-129-5p in osteoblast differentiation from bone marrow mesenchymal stem cells. Cell Mol Biol (Noisy-le-grand). 62:95–99. 2016.PubMed/NCBI
18	Grünhagen J, Bhushan R, Degenkolbe E, Jäger M, Knaus P, Mundlos S, Robinson PN and Ott CE: miR-497 approximately 195 cluster microRNAs regulate osteoblast differentiation by targeting BMP signaling. J Bone Miner Res. 30:796–808. 2015. View Article : Google Scholar : PubMed/NCBI
19	Bertero T, Gastaldi C, Bourget-Ponzio I, Imbert V, Loubat A, Selva E, Busca R, Mari B, Hofman P, Barbry P, et al: miR-483-3p controls proliferation in wounded epithelial cells. FASEB J. 25:3092–3105. 2011. View Article : Google Scholar : PubMed/NCBI
20	Lupini L, Pepe F, Ferracin M, Braconi C, Callegari E, Pagotto S, Spizzo R, Zagatti B, Lanuti P, Fornari F, et al: Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma. Oncotarget. 7:31361–31371. 2016. View Article : Google Scholar : PubMed/NCBI
21	Kim S, Koga T, Isobe M, Kern BE, Yokochi T, Chin YE, Karsenty G, Taniguchi T and Takayanagi H: Stat1 functions as a cytoplasmic attenuator of RUNX2 in the transcriptional program of osteoblast differentiation. Genes Dev. 17:1979–1991. 2003. View Article : Google Scholar : PubMed/NCBI
22	Bertero T, Bourget-Ponzio I, Puissant A, Loubat A, Mari B, Meneguzzi G, Auberger P, Barbry P, Ponzio G and Rezzonico R: Tumor suppressor function of miR-483-3p on squamous cell carcinomas due to its pro-apoptotic properties. Cell Cycle. 12:2183–2193. 2013. View Article : Google Scholar : PubMed/NCBI
23	Ferland-McCollough D, Fernandez-Twinn DS, Cannell IG, David H, Warner M, Vaag AA, Bork-Jensen J, Brøns C, Gant TW, Willis AE, et al: Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes. Cell Death Differ. 19:1003–1012. 2012. View Article : Google Scholar : PubMed/NCBI
24	Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, et al: Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 84:431–442. 1996. View Article : Google Scholar : PubMed/NCBI
25	Huang Z, Richmond TD, Muntean AG, Barber DL, Weiss MJ and Crispino JD: STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice. J Clin Invest. 117:3890–3899. 2007. View Article : Google Scholar : PubMed/NCBI
26	Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, et al: T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 408:600–605. 2000. View Article : Google Scholar : PubMed/NCBI
27	Tajima K, Takaishi H, Takito J, Tohmonda T, Yoda M, Ota N, Kosaki N, Matsumoto M, Ikegami H, Nakamura T, et al: Inhibition of STAT1 accelerates bone fracture healing. J Orthop Res. 28:937–941. 2010.PubMed/NCBI
28	Slemenda C, Longcope C, Peacock M, Hui S and Johnston CC: Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri-, and postmenopausal women. J Clin Invest. 97:14–21. 1996. View Article : Google Scholar : PubMed/NCBI
29	Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E and Arnaud CD: Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest. 102:1627–1633. 1998. View Article : Google Scholar : PubMed/NCBI
30	Balani DH, Ono N and Kronenberg HM: Parathyroid hormone regulates fates of murine osteoblast precursors in vivo. J Clin Invest. 127:3327–3338. 2017. View Article : Google Scholar : PubMed/NCBI
31	Wang X, Guo B, Li Q, Peng J, Yang Z, Wang A, Li D, Hou Z, Lv K, Kan G, et al: miR-214 targets ATF4 to inhibit bone formation. Nat Med. 19:93–100. 2013. View Article : Google Scholar : PubMed/NCBI