{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:05:04Z","timestamp":1790823904482,"version":"4.1.0"},"reference-count":36,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01HL144793-01"],"award-info":[{"award-number":["1R01HL144793-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1242\/dev.184291","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T16:35:14Z","timestamp":1584549314000},"source":"Crossref","is-referenced-by-count":25,"title":["Lymphatics in bone arise from preexisting lymphatics"],"prefix":"10.1242","author":[{"given":"Marco","family":"Monroy","sequence":"first","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.","family":"McCarter","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devon","family":"Hominick","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Cassidy","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3315-4239","authenticated-orcid":false,"given":"Michael T.","family":"Dellinger","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"},{"name":"Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,1,1]]},"reference":[{"key":"2021042700563294300_DEV184291C1","doi-asserted-by":"publisher","first-page":"2706","DOI":"10.1158\/0008-5472.CAN-10-0738","article-title":"Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation","volume":"71","author":"Adams","year":"2011","journal-title":"Cancer Res."},{"key":"2021042700563294300_DEV184291C2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1542\/peds.2015-3257","article-title":"Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies","volume":"137","author":"Adams","year":"2016","journal-title":"Pediatrics"},{"key":"2021042700563294300_DEV184291C3","doi-asserted-by":"publisher","first-page":"90103","DOI":"10.1172\/jci.insight.90103","article-title":"Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract","volume":"2","author":"Baluk","year":"2017","journal-title":"JCI Insight"},{"key":"2021042700563294300_DEV184291C4","doi-asserted-by":"publisher","first-page":"e0200343","DOI":"10.1371\/journal.pone.0200343","article-title":"PIK3CA mutations are specifically localized to lymphatic endothelial cells of lymphatic malformations","volume":"13","author":"Blesinger","year":"2018","journal-title":"PLoS ONE"},{"key":"2021042700563294300_DEV184291C5","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s10456-014-9453-2","article-title":"AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation","volume":"18","author":"Boscolo","year":"2015","journal-title":"Angiogenesis"},{"key":"2021042700563294300_DEV184291C6","doi-asserted-by":"publisher","first-page":"e85161","DOI":"10.1371\/journal.pone.0085161","article-title":"Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice","volume":"9","author":"Chen","year":"2014","journal-title":"PLoS ONE"},{"key":"2021042700563294300_DEV184291C7","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1161\/CIRCULATIONAHA.108.793208","article-title":"Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo","volume":"119","author":"Conrad","year":"2009","journal-title":"Circulation"},{"key":"2021042700563294300_DEV184291C8","doi-asserted-by":"publisher","first-page":"e129","DOI":"10.1097\/MPH.0000000000000514","article-title":"Gorham-Stout disease successfully treated with sirolimus and zoledronic acid therapy","volume":"38","author":"Cramer","year":"2016","journal-title":"J. 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