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

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 <i>Osx-tTA;TetO-Vegfc</i> double-transgenic mice. In contrast to <i>Osx-tTA</i> mice, <i>Osx-tTA;TetO-Vegfc</i> mice developed lymphatics in their bones. We found that inhibition of VEGFR3, but not VEGFR2, prevented the formation of bone lymphatics in <i>Osx-tTA;TetO-Vegfc</i> mice. Radiological and histological analysis revealed that bones from <i>Osx-tTA;TetO-Vegfc</i> mice were more porous and had more osteoclasts than bones from <i>Osx-tTA</i> mice. Importantly, we found that bone loss in <i>Osx-tTA;TetO-Vegfc</i> mice could be attenuated by an osteoclast inhibitor. We also discovered that the mutant phenotype of <i>Osx-tTA;TetO-Vegfc</i> 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.