{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T18:55:57Z","timestamp":1785783357115,"version":"3.56.0"},"reference-count":21,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T00:00:00Z","timestamp":1700006400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>Gorham-Stout disease (GSD) is a rare lymphatic anomaly that can be caused by somatic activating mutations in <jats:italic toggle=\"yes\">KRAS<\/jats:italic>. This discovery has led investigators to suggest that MEK inhibitors could be a novel treatment for GSD. However, the effect of MEK inhibitors on bone disease in animal models of GSD has not been investigated. We recently reported that <jats:italic toggle=\"yes\">Osx-tTA;TetO-Vegfc<\/jats:italic> mice exhibit a phenotype that resembles GSD. <jats:italic toggle=\"yes\">Osx-tTA;TetO-Vegfc<\/jats:italic> mice overexpress vascular endothelial growth factor-C (VEGF-C) in bone, which stimulates the development of lymphatic vessels in bone and the gradual loss of cortical bone. The objective of this study was to characterize the effect of trametinib, an FDA-approved MEK1\/2 inhibitor, on lymphangiogenesis and osteolysis in <jats:italic toggle=\"yes\">Osx-tTA;TetO-Vegfc<\/jats:italic> mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Immunoblotting was performed to assess the effect of trametinib on VEGF-C-induced phosphorylation of ERK1\/2, AKT, and S6 in primary human lymphatic endothelial cells. Prevention and intervention experiments were performed to determine the effect of trametinib on lymphangiogenesis and osteolysis in <jats:italic toggle=\"yes\">Osx-tTA;TetO-Vegfc<\/jats:italic> mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>We found that trametinib blocked VEGF-C-induced phosphorylation of ERK1\/2 in primary human lymphatic endothelial cells. We also found that trametinib prevented VEGF-C-induced lymphatic invasion of bone and cortical bone loss in <jats:italic toggle=\"yes\">Osx-tTA;TetO-Vegfc<\/jats:italic> mice. Additionally, trametinib slowed the progression of disease in <jats:italic toggle=\"yes\">Osx-tTA;TetO-Vegfc<\/jats:italic> mice with established disease. However, it did not reverse disease in <jats:italic toggle=\"yes\">Osx-tTA;TetO-Vegfc<\/jats:italic> mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion:<\/jats:title>\n            <jats:p>Our results show trametinib impacts bone disease in <jats:italic toggle=\"yes\">Osx-tTA;TetO-Vegfc<\/jats:italic> mice. These findings further support the testing of MEK inhibitors in patients with GSD and other RAS pathway-driven complex lymphatic anomalies with bone involvement.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/jova.0000000000000070","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T17:12:00Z","timestamp":1700068320000},"page":"e070","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Trametinib Inhibits Lymphatic Vessel Invasion of Bone in a Mouse Model of Gorham-Stout Disease"],"prefix":"10.1097","volume":"4","author":[{"given":"Anna L.","family":"McCarter","sequence":"first","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, Texas"},{"name":"Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2023,12]]},"reference":[{"key":"R1-20240825","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1007\/s00256-012-1565-4","article-title":"Gorham-Stout disease and generalized lymphatic anomaly-clinical, radiologic, and histologic differentiation.","volume":"42","author":"Lala","year":"2013","journal-title":"Skeletal Radiol"},{"key":"R2-20240825","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.bone.2014.02.011","article-title":"Viewpoints on vessels and vanishing bones in Gorham-Stout 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