1. Developmental Biology
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VEGF-C promotes the development of lymphatics in bone and bone loss

  1. Devon Hominick
  2. Asitha Silva
  3. Noor Khurana
  4. Ying Liu
  5. Paul C Dechow
  6. Jian Q Feng
  7. Bronislaw Pytowski  Is a corresponding author
  8. Joseph M Rutkowski
  9. Kari Alitalo
  10. Michael T Dellinger  Is a corresponding author
  1. UT Southwestern Medical Center, United States
  2. Texas A&M College of Dentistry, United States
  3. Eli Lilly and Company, United States
  4. Texas A&M College of Medicine, United States
  5. University of Helsinki, Finland
Research Article
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Cite this article as: eLife 2018;7:e34323 doi: 10.7554/eLife.34323

Abstract

Patients with Gorham-Stout disease (GSD) have lymphatic vessels in their bones and their bones gradually disappear. Here we report that mice that overexpress VEGF-C in bone exhibit a phenotype that resembles GSD. To drive VEGF-C expression in bone, we generated Osx-tTA;TetO-Vegfc double-transgenic mice. In contrast to Osx-tTA mice, Osx-tTA;TetO-Vegfc mice developed lymphatics in their bones. We found that inhibition of VEGFR3, but not VEGFR2, prevented the formation of bone lymphatics in Osx-tTA;TetO-Vegfc mice. Radiological and histological analysis revealed that bones from Osx-tTA;TetO-Vegfc mice were more porous and had more osteoclasts than bones from Osx-tTA mice. Importantly, we found that bone loss in Osx-tTA;TetO-Vegfc mice could be attenuated by an osteoclast inhibitor. We also discovered that the mutant phenotype of Osx-tTA;TetO-Vegfc mice could be reversed by inhibiting the expression of VEGF-C. Taken together, our results indicate that expression of VEGF-C in bone is sufficient to induce the pathologic hallmarks of GSD in mice.

Article and author information

Author details

  1. Devon Hominick

    Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  2. Asitha Silva

    Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  3. Noor Khurana

    Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  4. Ying Liu

    Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States
    Competing interests
    No competing interests declared.
  5. Paul C Dechow

    Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States
    Competing interests
    No competing interests declared.
  6. Jian Q Feng

    Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States
    Competing interests
    No competing interests declared.
  7. Bronislaw Pytowski

    Eli Lilly and Company, New York, United States
    For correspondence
    bronek.pytowski@gmail.com
    Competing interests
    Bronislaw Pytowski, During preparation of the manuscript, B. Pytowski was an employee of Eli Lilly and continues to hold stock in the company.
  8. Joseph M Rutkowski

    Department of Medical Physiology, Texas A&M College of Medicine, College Station, United States
    Competing interests
    No competing interests declared.
  9. Kari Alitalo

    Wihuri Research Institute, University of Helsinki, Helsinki, Finland
    Competing interests
    Kari Alitalo, Reviewing editor, eLife.
  10. Michael T Dellinger

    Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States
    For correspondence
    michael.dellinger@utsouthwestern.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3315-4239

Funding

The Lymphatic Malformation Institute (Research Grant)

  • Michael T Dellinger

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

Ethics

Animal experimentation: The animal experiments described in this manuscript were carried out in accordance with animal protocols (2014-0031 and 2016-101510) approved by the Institutional Animal Care and Use Committee of UT Southwestern Medical Center.

Reviewing Editor

  1. Holger Gerhardt, Max Delbrück Centre for Molecular Medicine, Germany

Publication history

  1. Received: December 13, 2017
  2. Accepted: March 22, 2018
  3. Accepted Manuscript published: April 5, 2018 (version 1)
  4. Version of Record published: April 17, 2018 (version 2)

Copyright

© 2018, Hominick 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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