Bones do not normally have lymphatics. However, patients 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 preexisting 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. Lastly, 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 preexisting LECs and that rapamycin can prevent the growth of bone lymphatics.
Lymphatics in bone arise from preexisting lymphatics
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