Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Metabolism volume 1, pages 485–496 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. These authors contributed equally: Yao Sun, Mingxiang Cai, Jiayong Zhong.

Authors and Affiliations

  1. Department of Oral Implantology, School of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

    Yao Sun, Mingxiang Cai, Hui Xue & Zuolin Wang

  2. Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, and School of Biological Science and Medical Engineering, Beihang University, Beijing, China

    Jiayong Zhong, Huisheng Liu, Yongbiao Zhang, Xunming Ji & Xiaogang Wang

  3. Department of Cell Biology, and Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China

    Jiayong Zhong, Li Yang, Fujun Jin, An Hong & Xiaogang Wang

  4. Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou, China

    Jiayong Zhong & Gong Zhang

  5. Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China

    Jiayong Zhong

  6. The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China

    Jia Xiao, Xiangning Liu & Xiaogang Wang

  7. Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, Beijing, China

    Dong Jiang

  8. Department of Neurosurgery & China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China

    Xunming Ji

Authors
  1. Yao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingxiang Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiayong Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fujun Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiangning Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Huisheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yongbiao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. An Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xunming Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Zuolin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Xiaogang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence to Yao Sun or Zuolin Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figures 1–18 and Supplementary Tables 1–4

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-019-0053-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing