Abstract
MicroRNAs (miRNAs) are small non-protein-codingRNAs that function as negative gene expression regulators. miRNA-210 (miR-210) has recently been recognized in the pathogenesis of osteonecrosis associated with angiogenesis. Herein we aimed to explore the clinical significance of miR-210 treatment for postmenopausal osteoporosis. The expression of miR-210 was detected in bone marrow mesenchymal stem cells (BMSCs) in vitro and miR-210 significantly promoted the expression of vascular edothelial growth factor (VEGF) in BMSCs in a time-dependent manner (p<0.05). And miR-210 suppressed PPARγ expression but increased the expression of ALP and osterix, demonstrating that miR-210 inhibited adipocyte differentiation and promoted osteoblast differentiation of BMSCs in vitro. The protein expression of hypoxia-inducible factor 1 alpha (HIF-1α) and VEGF in 17β-estradiol (E2) treated osteoblasts were significantly increased in a dose- and time-dependent manner (p<0.05). And E2 inducted the VEGF expression through the PI3K/AKT signaling pathway in osteoblasts. Taken together, these data implied that miR-210 played an important role in ameliorating the estrogen deficiency caused-postmenopausal osteoporosis through promotion the VEGF expression and osteoblast differentiation.
Acknowledgments
This work was supported by National Natural Science Foundation of China (NSFC, No. 81372015) and Shanghai Municipal Health Bureau Project (No. 2013214).
References
Ambros, V. (2004). The functions of animal microRNAs. Nature 431, 350–355.10.1038/nature02871Search in Google Scholar
Bartel, D.P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297.10.1016/S0092-8674(04)00045-5Search in Google Scholar
Bonnick, S.L., Harris, S.T., Kendler, D.L., McClung, M.R., and Silverman, S.L. (2010). Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 17, 25–54; quiz 55–26.Search in Google Scholar
Burkhardt, R., Kettner, G., Böhm, W., Schmidmeier, M., Schlag, R., Frisch, B., Mallmann, B., Eisenmenger, W., and Gilg, T. (1987). Changes in trabecular bone, hematopoiesis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study. Bone 8, 157–164.10.1016/8756-3282(87)90015-9Search in Google Scholar
Camps, C., Buffa, F.M., Colella, S., Moore, J., Sotiriou, C., Sheldon, H., Harris, A.L., Gleadle, J.M., and Ragoussis, J. (2008). Hsa-miR-210 is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin. Cancer Res. 14, 1340–1348.10.1158/1078-0432.CCR-07-1755Search in Google Scholar PubMed
Corina, M., Vulpoi, C., and Branisteanu, D. (2012). Relationship between bone mineral density, weight, and estrogen levels in pre and postmenopausal women. Rev. Med. Chir. Soc. Med. Nat. Iasi. 116, 946–950.Search in Google Scholar
Crosby, M.E., Kulshreshtha, R., Ivan, M., and Glazer, P.M. (2009). MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res. 69, 1221–1229.10.1158/0008-5472.CAN-08-2516Search in Google Scholar PubMed PubMed Central
Ding, W.G., Wei, Z.X., and Liu, J.B. (2011). Reduced local blood supply to the tibial metaphysis is associated with ovariectomy-induced osteoporosis in mice. Connect. Tissue Res. 52, 25–29.10.3109/03008201003783011Search in Google Scholar PubMed
Ell, B., Mercatali, L., Ibrahim, T., Campbell, N., Schwarzenbach, H., Pantel, K., Amadori, D., and Kang, Y. (2013). Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell 24, 542–556.10.1016/j.ccr.2013.09.008Search in Google Scholar PubMed PubMed Central
Erwin, G.S., Crisostomo, P.R., Wang, Y., Wang, M., Markel, T.A., Guzman, M., Sando, L.C., Sharma, R., and Meldrum, D.R. (2009). Estradiol-treated mesenchymal stem cells improve myocardial recovery after ischemia. J. Surg. Res. 152, 319–324.10.1016/j.jss.2008.02.006Search in Google Scholar PubMed PubMed Central
Ettinger, B., Genant, H.K., and Cann, C.E. (1985). Long-term estrogen replacement therapy prevents bone loss and fractures. Ann. Intern. Med. 102, 319–324.10.7326/0003-4819-102-3-319Search in Google Scholar PubMed
Farh, K.K., Grimson, A., Jan, C., Lewis, B.P., Johnston, W.K., Lim, L.P., Burge, C.B., and Bartel, D.P. (2005). The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310, 1817–1821.10.1126/science.1121158Search in Google Scholar PubMed
Fasanaro, P., D’Alessandra, Y., Di Stefano, V., Melchionna, R., Romani, S., Pompilio, G., Capogrossi, M.C., and Martelli, F. (2008). MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J. Biol. Chem. 283, 15878–15883.10.1074/jbc.M800731200Search in Google Scholar PubMed PubMed Central
Fish, J.E., Santoro, M.M., Morton, S.U., Yu, S., Yeh, R.F., Wythe, J.D., Ivey, K.N., Bruneau, B.G., Stainier, D.Y., and Srivastava, D. (2008). miR-126 regulates angiogenic signaling and vascular integrity. Dev. Cell 15, 272–284.10.1016/j.devcel.2008.07.008Search in Google Scholar PubMed PubMed Central
Foekens, J.A., Sieuwerts, A.M., Smid, M., Look, M.P., de Weerd, V., Boersma, A.W., Klijn, J.G., Wiemer, E.A., and Martens, J.W. (2008). Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer. Proc. Natl. Acad. Sci. USA 105, 13021–13026.10.1073/pnas.0803304105Search in Google Scholar PubMed PubMed Central
Garnero, P. (2014). New developments in biological markers of bone metabolism in osteoporosis. Bone 66, 46–55.10.1016/j.bone.2014.05.016Search in Google Scholar PubMed
Hamrick, M.W., Herberg, S., Arounleut, P., He, H.Z., Shiver, A., Qi, R.Q., Zhou, L., Isales, C.M., and Mi, Q.S. (2010). The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice. Biochem. Biophys. Res. Commun. 400, 379–383.10.1016/j.bbrc.2010.08.079Search in Google Scholar PubMed PubMed Central
Hu, Y.C., Cheng, H.L., Hsieh, B.S., Huang, L.W., Huang, T.C., and Chang, K.L. (2012). Arsenic trioxide affects bone remodeling by effects on osteoblast differentiation and function. Bone 50, 1406–1415.10.1016/j.bone.2012.03.012Search in Google Scholar PubMed
Huang, X., Ding, L., Bennewith, K.L., Tong, R.T., Welford, S.M., Ang, K.K., Story, M., Le, Q.T., and Giaccia, A.J. (2009). Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol. Cell 35, 856–867.10.1016/j.molcel.2009.09.006Search in Google Scholar PubMed PubMed Central
Johnston, C.C. Jr., Hui, S.L., Witt, R.M., Appledorn, R., Baker, R.S., and Longcope, C. (1985). Early menopausal changes in bone mass and sex steroids. J. Clin. Endocrinol. Metab. 61, 905–911.10.1210/jcem-61-5-905Search in Google Scholar PubMed
Kanis, J.A. (1994). Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos. Int. 4, 368–381.10.1007/BF01622200Search in Google Scholar PubMed
Krützfeldt, J., Rajewsky, N., Braich, R., Rajeev, K.G., Tuschl, T., Manoharan, M., and Stoffel, M. (2005). Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438, 685–689.10.1038/nature04303Search in Google Scholar PubMed
Lee, R.C., Feinbaum, R.L., Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854.10.1016/0092-8674(93)90529-YSearch in Google Scholar
Ma, L., Reinhardt, F., Pan, E., Soutschek, J., Bhat, B., Marcusson, E.G., Teruya-Feldstein, J., Bell, G.W., Weinberg, R.A. (2010). Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat. Biotechnol. 284, 341–347.10.1038/nbt.1618Search in Google Scholar PubMed PubMed Central
Maeda, S.S., and Lazaretti-Castro, M. (2014). An overview on the treatment of postmenopausal osteoporosis. Arq. Bras. Endocrinol. Metabol. 58, 162–171.10.1590/0004-2730000003039Search in Google Scholar PubMed
Maire, G., Martin, J.W., Yoshimoto, M., Chilton-MacNeill, S., Zielenska, M., Squire, J.A. (2011). Analysis of miRNA-gene expression-genomic profiles reveals complex mechanisms of microRNA deregulation in osteosarcoma. Cancer Genet. 204, 138–146.10.1016/j.cancergen.2010.12.012Search in Google Scholar PubMed
Makins, R., and Ballinger, A. (2003). Gastrointestinal side effects of drugs. Expert Opin. Drug. Saf. 2, 421–429.10.1517/14740338.2.4.421Search in Google Scholar PubMed
Manolagas, S.C. (2000). Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 21, 115–137.Search in Google Scholar
Mizuno, Y., Tokuzawa, Y., Ninomiya, Y., Yagi, K., Yatsuka-Kanesaki, Y., Suda, T., Fukuda, T., Katagiri, T., Kondoh, Y., Amemiya, T., Tashiro, H., Okazaki, Y. (2009). miR-210 promotes osteoblastic differentiation through inhibition of AcvR1b. FEBS Lett. 583, 2263–2268.10.1016/j.febslet.2009.06.006Search in Google Scholar PubMed
Nakasa, T., Ishikawa, M., Shi, M., Shibuya, H., Adachi, N., Ochi, M. (2010). Acceleration of muscle regeneration by local injection of muscle-specific microRNAs in rat skeletal muscle injury model. J. Cell. Mol. Med. 14, 2495–2505.10.1111/j.1582-4934.2009.00898.xSearch in Google Scholar PubMed PubMed Central
Nilas, L. and Christiansen, C. (1987). Bone mass and its relationship to age and the menopause. J. Clin. Endocrinol. Metab. 65, 697–702.10.1210/jcem-65-4-697Search in Google Scholar PubMed
Ohta, H., Makita, K., Suda, Y., Ikeda, T., Masuzawa, T., Nozawa, S. (1992). Influence of oophorectomy on serum levels of sex steroids and bone metabolism and assessment of bone mineral density in lumbar trabecular bone by QCT-C value. J. Bone Miner. Res. 7, 659–665.10.1002/jbmr.5650070610Search in Google Scholar PubMed
Riggs, B.L., Khosla, S., Melton, L.J. (2002). Sex steroids and the construction and conservation of the adult skeleton. Endocr. Rev. 23, 279–302.10.1210/edrv.23.3.0465Search in Google Scholar PubMed
Rubin, M.R., and Bilezikian, J.P. (2003). The anabolic effects of parathyroid hormone therapy. Clin. Geriatr. Med. 19, 415–432.10.1016/S0749-0690(02)00074-5Search in Google Scholar
Simon, J.A. (2012). What’s new in hormone replacement therapy: focus on transdermal estradiol and micronized progesterone. Climacteric 15, 3–10.10.3109/13697137.2012.669332Search in Google Scholar PubMed
Street, J., Bao, M., deGuzman, L., Bunting, S., Peale, F.V. Jr., Ferrara, N., Steinmetz, H., Hoeffel, J., Cleland, J.L., Daugherty, A., et al. (2002). Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc. Natl. Acad. Sci. USA 99, 9656–9661.10.1073/pnas.152324099Search in Google Scholar PubMed PubMed Central
Syed, F. and Khosla, S. (2005). Mechanisms of sex steroid effects on bone. Biochem. Biophys. Res. Commun. 328, 688–696.10.1016/j.bbrc.2004.11.097Search in Google Scholar PubMed
Takeshita, F., Patrawala, L., Osaki, M., Takahashi, R.U., Yamamoto, Y., Kosaka, N., Kawamata, M., Kelnar, K., Bader, A.G., Brown, D., et al. (2010). Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol. Ther. 18, 181–187.10.1038/mt.2009.207Search in Google Scholar PubMed PubMed Central
Tazawa, H., Tsuchiya, N., Izumiya, M., and Nakagama, H. (2007). Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc. Natl. Acad. Sci. USA 104, 15472–15477.10.1073/pnas.0707351104Search in Google Scholar PubMed PubMed Central
Tornero-Esteban, P., Hoyas, J.A., Villafuertes, E., Garcia-Bullón, I., Moro, E., Fernández-Gutiérrez, B., and Marco, F. (2014). Study of the role of miRNA in mesenchymal stem cells isolated from osteoarthritis patients. Rev. Esp. Cir. Ortop. Traumatol. 58, 138–143.10.1016/j.recote.2014.03.004Search in Google Scholar
Turner, R.T., Riggs, B.L., and Spelsberg, T.C. (1994). Skeletal effects of estrogen. Endocr. Rev. 15, 275–300.Search in Google Scholar
Tyagi, A.M., Srivastava, K., Mansoori, M.N., Trivedi, R., Chattopadhyay, N., and Singh, D. (2012). Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS One 7, e44552.10.1371/journal.pone.0044552Search in Google Scholar PubMed PubMed Central
Wahid, F., Shehzad, A., Khan, T., and Kim, Y.Y. (2010) MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim. Biophys. Acta 1803, 1231–1243.Search in Google Scholar
Wang, Y., Wan, C., Deng, L., Liu, X., Cao, X., Gilbert, S.R., Bouxsein, M.L., Faugere, M.C., Guldberg, R.E., Gerstenfeld, L.C., et al. (2007). The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J. Clin. Invest. 117, 1616–1626.10.1172/JCI31581Search in Google Scholar PubMed PubMed Central
Wang, S., Aurora, A.B., Johnson, B.A., Qi, X., McAnally, J., Hill, J.A., Richardson, J.A., Bassel-Duby, R., and Olson, E.N. (2008). The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev. Cell 15, 261–271.10.1016/j.devcel.2008.07.002Search in Google Scholar PubMed PubMed Central
Weitzmann, M.N. and Pacifici, R. (2005). The role of T lymphocytes in bone metabolism. Immunol. Rev. 208, 154–168.10.1111/j.0105-2896.2005.00324.xSearch in Google Scholar PubMed
Wronski, T.J., Dann, L.M., Scott, K.S., and Cintrón, M. (1989). Long-term effects of ovariectomy and aging on the rat skeleton. Calcif. Tissue Int. 45, 360–366.10.1007/BF02556007Search in Google Scholar PubMed
Yang, B., Lin, H., Xiao, J., Lu, Y., Luo, X., Li, B., Zhang, Y., Xu, C., Bai, Y., Wang, H., et al. (2007). The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat. Med. 13, 486–491.10.1038/nm1569Search in Google Scholar PubMed
Yamasaki, K., Nakasa, T., Miyaki, S., Yamasaki, T., Yasunaga, Y., and Ochi, M. (2012). Angiogenic microRNA-210 is present in cells surrounding osteonecrosis. J. Orthop. Res. 30, 1263–1270.10.1002/jor.22079Search in Google Scholar PubMed
Zhang, Z., Sun, H., Dai, H., Walsh, R.M., Imakura, M., Schelter, J., Burchard, J., Dai, X., Chang, A.N., Diaz, R.L., et al. (2009). MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT. Cell Cycle 8, 2756–2768.10.4161/cc.8.17.9387Search in Google Scholar PubMed
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