VEGF-C promotes the development of lymphatics in bone and bone loss
- UT Southwestern Medical Center, United States
- Texas A&M College of Dentistry, United States
- Eli Lilly and Company, United States
- Texas A&M College of Medicine, United States
- University of Helsinki, Finland
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
Michael T Dellinger
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.
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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VEGF-C promotes the development of lymphatics in bone and bone loss
eLife 7:e34323.
https://doi.org/10.7554/eLife.34323
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