Abstract

Declining bone mass is associated with aging and osteoporosis, a disease characterized by progressive weakening of the skeleton and increased fracture incidence. Growth and lifelong homeostasis of bone rely on interactions between different cell types including vascular cells and mesenchymal stromal cells (MSCs). As these interactions involve Notch signaling, we have explored whether treatment with secreted Notch ligand proteins can enhance osteogenesis in adult mice. We show that a bone-targeting, high affinity version of the ligand Delta-like 4, termed Dll4(E12), induces bone formation in male mice without causing adverse effects in other organs, which are known to rely on intact Notch signaling. Due to lower bone surface and thereby reduced retention of Dll4(E12), the same approach failed to promote osteogenesis in female and ovariectomized mice but strongly enhanced trabecular bone formation in combination with parathyroid hormone. Single cell analysis of stromal cells indicates that Dll4(E12) primarily acts on MSCs and has comparably minor effects on osteoblasts, endothelial cells or chondrocytes. We propose that activation of Notch signaling by bone-targeted fusion proteins might be therapeutically useful and can avoid detrimental effects in Notch-dependent processes in other organs.

Data availability

scRNA-seq data have been deposited in the GEO functional genomics data repository under the accession number GSE152285. Data can be accessed via https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152285 with the token mzcbwwqgptidxmh.

The following data sets were generated

Article and author information

Author details

  1. Cong Xu

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Van Vuong Dinh

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Kai Kruse

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Hyun-Woo Jeong

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Emma C Watson

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0986-5524
  6. Susanne Adams

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Frank Berkenfeld

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Martin Stehling

    Flow Cytometry Unit, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Seyed Javad Rasouli

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Rui Fan

    Embryonic Self-Organization Research Group, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Rui Chen

    Embryonic Self-Organization Research Group, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Ivan Bedzhov

    Embryonic Self-Organization Research Group, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Qi Chen

    CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8485-6540
  14. Katsuhiro Kato

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Mara Elena Pitulescu

    Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    For correspondence
    mara.pitulescu@mpi-muenster.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
  16. Ralf H Adams

    Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    For correspondence
    ralf.adams@mpi-muenster.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3031-7677

Funding

Max Planck Society

  • Ralf H Adams

European Research Council (AdG 339409 AngioBone)

  • Ralf H Adams

European Research Council (AdG 786672 PROVEC)

  • Ralf H Adams

Leducq Foundation

  • Ralf H Adams

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animals were housed at the Max Planck Institute for Molecular Biomedicine and protocols were approved by animal ethics committees with permissions (Az 81-02.04.2019.A114 and Az 81-02.04.2020.A416) granted by the Landesamt für Natur, Umwelt und Verbraucherschutz (LANUV) of North Rhine-Westphalia. Every effort was made to minimize suffering.

Reviewing Editor

  1. Cheryl Ackert-Bicknell, University of Colorado, United States

Version history

  1. Received: June 18, 2020
  2. Accepted: February 3, 2022
  3. Accepted Manuscript published: February 4, 2022 (version 1)
  4. Version of Record published: February 25, 2022 (version 2)

Copyright

© 2022, Xu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Cong Xu
  2. Van Vuong Dinh
  3. Kai Kruse
  4. Hyun-Woo Jeong
  5. Emma C Watson
  6. Susanne Adams
  7. Frank Berkenfeld
  8. Martin Stehling
  9. Seyed Javad Rasouli
  10. Rui Fan
  11. Rui Chen
  12. Ivan Bedzhov
  13. Qi Chen
  14. Katsuhiro Kato
  15. Mara Elena Pitulescu
  16. Ralf H Adams
(2022)
Induction of osteogenesis by bone-targeted Notch activation
eLife 11:e60183.
https://doi.org/10.7554/eLife.60183

Share this article

https://doi.org/10.7554/eLife.60183

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