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


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.


  1. Lee, J. T. Epigenetic regulation by long noncoding RNAs. Science 338, 1435–1439 (2012).

    CAS  Article  Google Scholar 

  2. Rinn, J. L. & Chang, H. Y. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145–166 (2012).

    CAS  Article  Google Scholar 

  3. Wahlestedt, C. Targeting long non-coding RNA to therapeutically upregulate gene expression. Nat. Rev. Drug Discov. 12, 433–446 (2013).

    CAS  Article  Google Scholar 

  4. Fatica, A. & Bozzoni, I. Long non-coding RNAs: new players in cell differentiation and development. Nat. Rev. Genet. 15, 7–21 (2014).

    CAS  Article  Google Scholar 

  5. Schmitt, A. M. & Chang, H. Y. Long noncoding RNAs in cancer pathways. Cancer Cell 29, 452–463 (2016).

    CAS  Article  Google Scholar 

  6. Huarte, M. The emerging role of lncRNAs in cancer. Nat. Med. 21, 1253–1261 (2015).

    CAS  Article  Google Scholar 

  7. Knoll, M., Lodish, H. F. & Sun, L. Long non-coding RNAs as regulators of the endocrine system. Nat. Rev. Endocrinol. 11, 151–160 (2015).

    CAS  Article  Google Scholar 

  8. Sun, M. & Kraus, W. L. From discovery to function: the expanding roles of long noncoding RNAs in physiology and disease. Endocr. Rev. 36, 25–64 (2015).

    CAS  Article  Google Scholar 

  9. Zhao, X. Y. & Lin, J. D. Long noncoding RNAs: a new regulatory code in metabolic control. Trends Biochem. Sci. 40, 586–596 (2015).

    CAS  Article  Google Scholar 

  10. Redis, R. S. et al. Allele-specific reprogramming of cancer metabolism by the long non-coding RNA CCAT2. Mol. Cell 61, 520–534 (2016).

    CAS  Article  Google Scholar 

  11. Atianand, M. K. & Fitzgerald, K. A. Long non-coding RNAs and control of gene expression in the immune system. Trends Mol. Med. 20, 623–631 (2014).

    CAS  Article  Google Scholar 

  12. Ng, S. Y., Bogu, G. K., Soh, B. S. & Stanton, L. W. The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Mol. Cell 51, 349–359 (2013).

    CAS  Article  Google Scholar 

  13. Ramos, A. D. et al. The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. Cell Stem Cell 16, 439–447 (2015).

    CAS  Article  Google Scholar 

  14. Uchida, S. & Dimmeler, S. Long noncoding RNAs in cardiovascular diseases. Circ. Res. 116, 737–750 (2015).

    CAS  Article  Google Scholar 

  15. Yang, L., Froberg, J. E. & Lee, J. T. Long noncoding RNAs: fresh perspectives into the RNA world. Trends Biochem. Sci. 39, 35–43 (2014).

    Article  Google Scholar 

  16. Zhuang, W. Z. et al. Upregulation of lncRNA MEG3 promotes osteogenic differentiation of mesenchymal stem cells from multiple myeloma patients by targeting BMP4 transcription. Stem Cells 33, 1985–1997 (2015).

    CAS  Article  Google Scholar 

  17. Huang, Y., Zheng, Y., Jia, L. & Li, W. Long noncoding RNA H19 promotes osteoblast differentiation via TGF-beta1/Smad3/HDAC signaling pathway by deriving miR-675. Stem Cells 33, 3481–3492 (2015).

    CAS  Article  Google Scholar 

  18. Nakashima, K. et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108, 17–29 (2002).

    CAS  Article  Google Scholar 

  19. Sun, Y. et al. Osteoblast-targeting-peptide modified nanoparticle for siRNA/microRNA delivery. ACS Nano 10, 5759–5768 (2016).

    CAS  Article  Google Scholar 

  20. Margueron, R. & Reinberg, D. The polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).

    CAS  Article  Google Scholar 

  21. Simon, J. A. & Kingston, R. E. Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put. Mol. Cell 49, 808–824 (2013).

    CAS  Article  Google Scholar 

  22. Baron, R. & Kneissel, M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat. Med. 19, 179–192 (2013).

    CAS  Article  Google Scholar 

  23. Ettinger, M. P. Aging bone and osteoporosis: strategies for preventing fractures in the elderly. Arch. Intern. Med. 163, 2237–2246 (2003).

    Article  Google Scholar 

  24. Liu, W. et al. GDF11 decreases bone mass by stimulating osteoclastogenesis and inhibiting osteoblast differentiation. Nat. Commun. 7, 12794 (2016).

    CAS  Article  Google Scholar 

  25. Liu, Z. et al. Mediator MED23 cooperates with RUNX2 to drive osteoblast differentiation and bone development. Nat. Commun. 7, 11149 (2016).

    CAS  Article  Google Scholar 

  26. Zeng, H. C. et al. MicroRNA miR-23a cluster promotes osteocyte differentiation by regulating TGF-beta signalling in osteoblasts. Nat. Commun. 8, 15000 (2017).

    CAS  Article  Google Scholar 

  27. Flynn, R. A. & Chang, H. Y. Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell 14, 752–761 (2014).

    CAS  Article  Google Scholar 

  28. Gong, C. et al. A long non-coding RNA, LncMyoD, regulates skeletal muscle differentiation by blocking IMP2-mediated mRNA translation. Dev. Cell 34, 181–191 (2015).

    CAS  Article  Google Scholar 

  29. Thum, T. Noncoding RNAs and myocardial fibrosis. Nat. Rev. Cardiol. 11, 655–663 (2014).

    CAS  Article  Google Scholar 

  30. Zhu, L. & Xu, P. C. Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. Biochem. Biophys. Res. Commun. 432, 612–617 (2013).

    CAS  Article  Google Scholar 

  31. Chang-Jun Li et al. Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging. J. Clin. Invest. 128, 5251–5266 (2018).

  32. Zhou, X. et al. Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice. Proc. Natl Acad. Sci. USA 20, 12919–12924 (2010).

    Article  Google Scholar 

  33. Nakashima, K. & de Crombrugghe, B. Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet. 19, 458–466 (2003).

    CAS  Article  Google Scholar 

  34. Long, F. Building strong bones: molecular regulation of the osteoblast lineage. Rev. Mol. Cell Biol. 13, 27–38 (2011).

    Article  Google Scholar 

  35. Koga, T. et al. NFAT and Osterix cooperatively regulate bone formation. Nat. Med. 11, 880–885 (2005).

    CAS  Article  Google Scholar 

  36. Hojo, H., Ohba, S., He, X. J., Lai, L. P. & McMahon, A. P. Sp7/Osterix is restricted to bone-forming vertebrates where It acts as a Dlx co-factor in osteoblast specification. Dev. Cell 37, 238–253 (2016).

    CAS  Article  Google Scholar 

  37. Crandall, C. Parathyroid hormone for treatment of osteoporosis. Arch. Intern. Med. 162, 2297–2309 (2002).

    CAS  Article  Google Scholar 

  38. Canalis, E. New treatment modalities in osteoporosis. Endocr. Pract. 16, 855–863 (2010).

    Article  Google Scholar 

  39. Nikitovic, D. et al. Parathyroid hormone/parathyroid hormone-related peptide regulate osteosarcoma cell functions: focus on the extracellular matrix. Oncol. Rep. 36, 1787–1792 (2016).

    CAS  Article  Google Scholar 

  40. Cheloha, R. W., Gellman, S. H., Vilardaga, J. P. & Gardella, T. J. PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat. Rev. Endocrinol. 11, 712–724 (2015).

    CAS  Article  Google Scholar 

  41. Morlan, J. D., Qu, K. & Sinicropi, D. V. Selective depletion of rRNA enables whole transcriptome profiling of archival fixed tissue. PLoS ONE 7, e42882 (2012).

    CAS  Article  Google Scholar 

  42. Necsulea, A. et al. The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature 505, 635–640 (2014).

    CAS  Article  Google Scholar 

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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).

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