VEGF-C promotes the development of lymphatics in bone and bone loss.
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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.
author list (cited authors)
Hominick, D., Silva, A., Khurana, N., Liu, Y., Dechow, P. C., Feng, J. Q., ... Dellinger, M. T.
complete list of authors
Hominick, Devon||Silva, Asitha||Khurana, Noor||Liu, Ying||Dechow, Paul C||Feng, Jian Q||Pytowski, Bronislaw||Rutkowski, Joseph M||Alitalo, Kari||Dellinger, Michael T