Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States.
Biomedical Sciences, Texas A&M College of Dentistry, Dallas, United States.
Elife. 2018 Apr 5;7:e34323. doi: 10.7554/eLife.34323.
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.
戈勒姆-斯图特病（GSD）患者的骨骼中有淋巴管，其骨骼逐渐消失。在这里，我们报告称，在骨骼中过度表达 VEGF-C 的小鼠表现出类似于 GSD 的表型。为了在骨骼中驱动 VEGF-C 的表达，我们生成了双转基因小鼠。与 小鼠相比， 小鼠的骨骼中出现了淋巴管。我们发现，抑制 VEGFR3，但不抑制 VEGFR2，可防止 小鼠骨骼中淋巴管的形成。放射学和组织学分析表明，与 小鼠的骨骼相比， 小鼠的骨骼更多孔，破骨细胞更多。重要的是，我们发现，骨吸收抑制剂可减轻 小鼠的骨质流失。我们还发现，通过抑制 VEGF-C 的表达可以逆转 小鼠的突变表型。综上所述，我们的结果表明，VEGF-C 在骨骼中的表达足以在小鼠中诱导 GSD 的病理性特征。
