Lymphatics in bone arise from pre-existing lymphatics

Development. 2020 Apr 20;147(21):dev184291. doi: 10.1242/dev.184291.


Bones do not normally have lymphatics. However, individuals with generalized lymphatic anomaly (GLA) or Gorham-Stout disease (GSD) develop ectopic lymphatics in bone. Despite growing interest in the development of tissue-specific lymphatics, the cellular origin of bone lymphatic endothelial cells (bLECs) is not known and the development of bone lymphatics has not been fully characterized. Here, we describe the development of bone lymphatics in mouse models of GLA and GSD. Through lineage-tracing experiments, we show that bLECs arise from pre-existing Prox1-positive LECs. We show that bone lymphatics develop in a stepwise manner where regional lymphatics grow, breach the periosteum and then invade bone. We also show that the development of bone lymphatics is impaired in mice that lack osteoclasts. Last, we show that rapamycin can suppress the growth of bone lymphatics in our models of GLA and GSD. In summary, we show that bLECs can arise from pre-existing LECs and that rapamycin can prevent the growth of bone lymphatics.

Keywords: Generalized lymphatic anomaly; Gorham-Stout disease; PIK3CA; Rapamycin; VEGF-C.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone and Bones / drug effects
  • Bone and Bones / embryology*
  • Cell Lineage / drug effects
  • Cell Proliferation / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Homeodomain Proteins / metabolism
  • Humans
  • Integrases / metabolism
  • Lymphatic Vessels / drug effects
  • Lymphatic Vessels / embryology*
  • Mice, Transgenic
  • Mutation / genetics
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Sirolimus / pharmacology
  • Sp7 Transcription Factor / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Vascular Endothelial Growth Factor A / metabolism


  • Homeodomain Proteins
  • Sp7 Transcription Factor
  • Sp7 protein, mouse
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • prospero-related homeobox 1 protein
  • Cre recombinase
  • Integrases
  • Sirolimus