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Elife. 2018 Apr 5;7. pii: e34323. doi: 10.7554/eLife.34323.

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

Author information

1
Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States.
2
Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States.
3
Eli Lilly and Company, New York, United States.
4
Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M College of Medicine, Texas, United States.
5
Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
6
Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, United States.
7
Division of Surgical Oncology, Department of Surgery, UT Southwestern Medical Center, Dallas, United States.
#
Contributed equally

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.

KEYWORDS:

developmental biology; lymphangiogenesis; lymphatic anomalies; lymphatic diseases; mouse; stem cells

PMID:
29620526
PMCID:
PMC5903859
DOI:
10.7554/eLife.34323
[Indexed for MEDLINE]
Free PMC Article

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