miR-214 targets ATF4 to inhibit bone formation

Abstract

Emerging evidence indicates that microRNAs (miRNAs) have important roles in regulating osteogenic differentiation and bone formation. Thus far, no study has established the pathophysiological role for miRNAs identified in human osteoporotic bone specimens. Here we found that elevated miR-214 levels correlated with a lower degree of bone formation in bone specimens from aged patients with fractures. We also found that osteoblast-specific manipulation of miR-214 levels by miR-214 antagomir treatment in miR-214 transgenic, ovariectomized, or hindlimb-unloaded mice revealed an inhibitory role of miR-214 in regulating bone formation. Further, in vitro osteoblast activity and matrix mineralization were promoted by antagomir-214 and decreased by agomir-214, and miR-214 directly targeted ATF4 to inhibit osteoblast activity. These data suggest that miR-214 has a crucial role in suppressing bone formation and that miR-214 inhibition in osteoblasts may be a potential anabolic strategy for ameliorating osteoporosis.

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Figure 1: miR-214 levels negatively correlate with reduced bone formation in both human and mouse bone specimens.
Figure 2: miR-214 inhibits osteoblast activity and matrix mineralization in vitro.
Figure 3: miR-214 targets ATF4 to functionally inhibit osteoblast activity in vitro.
Figure 4: Characterization of bone phenotypes in osteoblast-specific miR-214 transgenic mice and functional rescue by antagomir-214.
Figure 5: Bone-targeted antagomir-214 promotes osteoblastic bone formation, improves trabecular architecture and increases bone mass in aged ovariectomy-induced osteoporotic mice.
Figure 6: Therapeutic inhibition of miR-214 with the bone-targeting delivery system counteracts the decrease in bone formation in hindlimb-unloaded mice.

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Acknowledgements

We thank the academic staff (L. Qin and L. Hung) from the Chinese University of Hong Kong and the research staff from G.Z.'s lab (http://www.gezhanglab.com/index.php) at Hong Kong Baptist University for providing critical comments and technical support. We thank X. Yang (Institute of Biotechnology) for providing the Bglap2 promoter vector. We also thank L. Zhang, K. Guan and H. Ouyang for constructive suggestions and careful revisions to this manuscript. This work was supported by the National Basic Research Program of China 973 program (2011CB711003 and 2011CB707704), State Key Lab of Space Medicine Fundamentals and Application Grants (SMFA10A02 and SMFA12B01), National Natural Science Foundation Projects (31170811, 31000386 and 81272045), the Hong Kong General Research Fund (HKBU 479111 and HKBU478312) and the Research Grants Council/Natural Science Foundation Council Joint Research Scheme (N_HKBU435/12).

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X.W. and B.G. performed the majority of the experiments, analyzed data and prepared the manuscript. J.P., A.W., X.P., X.X. and A.H. collected human bone samples. Z.Y. and H.W. helped with in vivo treatment. Q.L., K.L., J.S., Q.S., S.L., Yuheng Li and P.Z. assisted with in vitro experiments. G.K., H.C. and M.Z. maintained the mice. Z.H. helped with microdissection analysis. D.L. and T.T. helped with data analysis. Yinghui Li, Z.B., Y.B., A.L. and F.H. provided suggestions for the project and critically reviewed the manuscript. Yingxian Li and G.Z. supervised the project and wrote most of the manuscript.

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Correspondence to Ge Zhang or Yingxian Li.

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The authors declare no competing financial interests.

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Wang, X., Guo, B., Li, Q. et al. miR-214 targets ATF4 to inhibit bone formation. Nat Med 19, 93–100 (2013). https://doi.org/10.1038/nm.3026

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