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

Elife. 2018 Apr 5;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.

Keywords: developmental biology; lymphangiogenesis; lymphatic anomalies; lymphatic diseases; mouse; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Resorption / metabolism
  • Bone Resorption / pathology*
  • Bone and Bones / metabolism
  • Bone and Bones / pathology*
  • Cells, Cultured
  • Endothelium, Lymphatic / metabolism
  • Endothelium, Lymphatic / pathology*
  • Humans
  • Lymphatic Vessels / metabolism
  • Lymphatic Vessels / pathology*
  • Mice
  • Mice, Transgenic
  • Osteoclasts / metabolism
  • Osteoclasts / pathology*
  • Phenotype
  • Signal Transduction
  • Vascular Endothelial Growth Factor C / physiology*
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism

Substances

  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3

Grant support

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