1. Cell Biology
  2. Developmental Biology
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Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the periosteal niche in the murine skeleton

  1. Valerie S Salazar
  2. Luciane P Capelo
  3. Claudio Cantù
  4. Dario Zimmerli
  5. Nehal Gosalia
  6. Steven Pregizer
  7. Karen Cox
  8. Satoshi Ohte
  9. Marina Feigenson
  10. Laura Gamer
  11. Jeffry S Nyman
  12. David J Carey
  13. Aris Economides
  14. Konrad Basler
  15. Vicki Rosen  Is a corresponding author
  1. Harvard School of Dental Medicine, United States
  2. Universidade Federal de São Paulo, Brazil
  3. University of Zürich, Switzerland
  4. Regeneron Pharmaceuticals, United States
  5. Vanderbilt University Medical Centre, United States
  6. Geisinger Health System, United States
Research Article
  • Cited 13
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Cite this article as: eLife 2019;8:e42386 doi: 10.7554/eLife.42386

Abstract

Two decades after signals controlling bone length were discovered, the endogenous ligands determining bone width remain unknown. We show that postnatal establishment of normal bone width in mice, as mediated by bone-forming activity of the periosteum, requires BMP signaling at the innermost layer of the periosteal niche. This developmental signaling center becomes quiescent during adult life. Its reactivation however, is necessary for periosteal growth, enhanced bone strength, and accelerated fracture repair in response to bone-anabolic therapies used in clinical orthopedic settings. Although many BMPs are expressed in bone, periosteal BMP signaling and bone formation require only Bmp2 in the Prx1-Cre lineage. Mechanistically, BMP2 functions downstream of Lrp5/6 pathway to activate a conserved regulatory element upstream of Sp7 via recruitment of Smad1 and Grhl3. Consistent with our findings, human variants of BMP2 and GRHL3 are associated with increased risk of fractures.

Data availability

The DiscoverEHR human dataset is published and publicly available at http://www.discovehrshare.com. Using search terms 'BMP2' and 'GRHL3' and a Bonferroni significance threshold of P < 1.86e-7 for 268,192 association results, we observed three significant associations for BMP2 and six significant associations for GRHL3.Mouse limb bud ChIP-sequencing data are available through ArrayExpress website https://www.ebi.ac.uk/arrayexpress and accession #E-MTAB-7652.

The following data sets were generated

Article and author information

Author details

  1. Valerie S Salazar

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2111-9313
  2. Luciane P Capelo

    Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, São José dos Campos, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  3. Claudio Cantù

    Institute for Molecular Life Sciences, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Dario Zimmerli

    Institute for Molecular Life Sciences, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Nehal Gosalia

    Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Steven Pregizer

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Karen Cox

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Satoshi Ohte

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Marina Feigenson

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Laura Gamer

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jeffry S Nyman

    Department of Orthopaedic Surgery and Rehabilitation, Vanderbilt University Medical Centre, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. David J Carey

    Geisinger Health System, Danville, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Aris Economides

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6508-8942
  14. Konrad Basler

    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  15. Vicki Rosen

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    For correspondence
    vicki_rosen@hsdm.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4029-1055

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR055904)

  • Vicki Rosen

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

Ethics

Animal experimentation: In vivo experiments were performed in compliance with the Guide for the Care and Use of Laboratory Animals and were approved by the Harvard Medical Area Institutional Animal Care and Use Committee (protocol #04043 to Vicki Rosen).

Reviewing Editor

  1. Clifford J Rosen, Maine Medical Center Research Institute, United States

Publication history

  1. Received: September 27, 2018
  2. Accepted: February 6, 2019
  3. Accepted Manuscript published: February 8, 2019 (version 1)
  4. Version of Record published: February 22, 2019 (version 2)

Copyright

© 2019, Salazar 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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