The long noncoding RNA lnc-ob1 facilitates bone formation by upregulating Osterix in osteoblasts

Abstract

Long noncoding RNAs (lncRNAs) have emerged as integral regulators of physiology and disease, but specific roles of lncRNAs in bone disease remain largely unknown. Here, we show that lnc-ob1 regulates osteoblast activity and bone formation in mice by upregulating the osteogenic transcription factor Osterix. Expression of lnc-ob1 is enriched in osteoblasts and upregulated during osteoblastogenesis. We demonstrate that osteoblast-specific knock-in of lnc-ob1 enhances bone formation and increases bone mass. Pharmacological overexpression of lnc-ob1 specifically in osteoblasts confers resistance to ovariectomy-induced osteoporosis in mice. In humans, expression of the homologue, lnc-OB1, decreases with age in osteoblasts of patients with osteoporosis. Mechanistically, lnc-ob1 upregulates the expression of Osterix in mouse and human osteoblasts, probably via inhibition of H3K27me3 methylation. Our data indicate that lnc-OB1 regulates bone formation and might be a drug target for the treatment of osteoporosis.

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Fig. 1: An osteoblast-enriched lncRNA (lnc-OB1/lnc-ob1) is downregulated after bone loss.
Fig. 2: Osteoblast-specific lnc-ob1 KI mice exhibit an increased bone mass and enhanced bone formation rates.
Fig. 3: Osteoblast-targeted delivery of lnc-ob1 reverses bone loss in OVX mice.
Fig. 4: lnc-ob1/lnc-OB1 enhances osteoblast differentiation.
Fig. 5: lnc-ob1 modulates Osx expression in mouse osteoblasts.
Fig. 6: lnc-ob1 regulates Osx expression by reducing H3K27me3 methylation.
Fig. 7: Working model.

Data availability

The high-throughput RNA-seq data have been deposited in NCBI under accession code GSE112318. The data that support the findings of this study are available from the authors on reasonable request, see author contributions for specific datasets.

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Acknowledgements

This research was supported by grants from the National key research and development program (2016YFC102705/2017YFA0505001/2018YFC0910200); National Natural Science Foundation Projects (No. 81822012, 81771043, 81770873, 81722031, 81470715, 81771043, 31671312, 3137134); 2017BR009, 2014BAI04B07 and Kx0200020173386, Guangdong Natural Science Funds (no. 2014A030313358), the Major Project in Guangdong Province of Science (no. 2014KZDXM011) and Guangdong Natural Science Funds for Distinguished Young Scholars (no. S2013050013880). We thank C. Qin for providing the DMP1 antibody as a gift. We thank Y. Zhang and S. Gao at Tongji University for providing critical comments and technical support. We thank J. Li for help with the style of the manuscript.

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X.W. and Y.S. conceived and designed the project and wrote the manuscript with input from M.C., L.Y., J.Z., H.L., Y.Z., F.J., D.J. and X.L. M.C. performed the histological experiments. J.Z. performed the RNA-seq experiments and analysed the data. L.Y., F.J. and J.X. performed the cellular experiments. H.X. contributed the fracture model in the revised version. H.L., Y.Z., X.J., A.H., Z.W. and G.Z. analysed data and provided important suggestions regarding this project.

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Correspondence to Yao Sun or Zuolin Wang.

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Sun, Y., Cai, M., Zhong, J. et al. The long noncoding RNA lnc-ob1 facilitates bone formation by upregulating Osterix in osteoblasts. Nat Metab 1, 485–496 (2019). https://doi.org/10.1038/s42255-019-0053-8

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