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

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