{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T03:47:40Z","timestamp":1792900060102,"version":"4.5.0"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["1R01HL176788-01"],"award-info":[{"award-number":["1R01HL176788-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH2110518"],"award-info":[{"award-number":["W81XWH2110518"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH2110519"],"award-info":[{"award-number":["W81XWH2110519"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,12]]},"abstract":"<jats:p>\n                    Heterotopic ossification (HO) is a debilitating condition that commonly occurs after musculoskeletal injury and is characterized by the formation of bone in soft tissues. Despite advances in understanding its pathogenesis, effective therapies to reverse established heterotopic bone remain lacking. While lymphatic vessels are associated with the destruction of bone in rare diseases such as Gorham-Stout disease, their effect on HO has not been widely explored. Here, we use transgenic mice to determine whether targeted expression of the lymphatic growth factor VEGF-D can promote the therapeutic resorption of bone in a mouse model of HO. We show that control mice lack lymphatic vessels in heterotopic bone. In contrast,\n                    <jats:italic toggle=\"yes\">Vegfd<\/jats:italic>\n                    -overexpressing (\n                    <jats:italic toggle=\"yes\">Vegfd-OE<\/jats:italic>\n                    ) mice develop lymphatic vessels in heterotopic bone and form significantly less heterotopic bone than control mice. Additionally, we demonstrate that VEGF-D overexpression or local delivery promotes the therapeutic resorption of established heterotopic bone. Mechanistically, we show that the transition of myeloid cells to osteoclasts and osteoclast-mediated bone resorption are enhanced in\n                    <jats:italic toggle=\"yes\">Vegfd-OE<\/jats:italic>\n                    mice. These findings reveal a previously unrecognized role for lymphatic vessels in regulating heterotopic bone resorption and identify VEGF-D-mediated lymphangiogenesis as a promising therapeutic strategy for HO.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2524022123","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T16:15:31Z","timestamp":1777997731000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["VEGF-D-induced intraosseous lymphangiogenesis drives site-specific heterotopic bone resorption"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8748-9034","authenticated-orcid":false,"given":"Neda","family":"Vishlaghi","sequence":"first","affiliation":[{"name":"Department of Surgery, UT Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2382-6361","authenticated-orcid":false,"given":"Danielle","family":"Griswold-Wheeler","sequence":"additional","affiliation":[{"name":"Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7336-6579","authenticated-orcid":false,"given":"Sneha","family":"Korlakunta","sequence":"additional","affiliation":[{"name":"Department of Surgery, UT Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3224-1110","authenticated-orcid":false,"given":"Angelica","family":"Vallejo","sequence":"additional","affiliation":[{"name":"Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7773-4106","authenticated-orcid":false,"given":"Monisha","family":"Mittal","sequence":"additional","affiliation":[{"name":"Department of Surgery, UT Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiao","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Surgery, UT Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00f54p054","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Orthopedic Surgery, Stanford University","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhi Peter","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00f54p054","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Orthopedic Surgery, Stanford University","place":["San Francisco"]},{"id":[{"id":"https:\/\/ror.org\/00f54p054","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Materials Science and Engineering, Stanford University","place":["San Francisco"]},{"id":[{"id":"https:\/\/ror.org\/00f54p054","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Bioengineering, Stanford University","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Rutkowski","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Physiology, Texas A&M University College of Medicine","place":["Bryan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Levi","sequence":"additional","affiliation":[{"name":"Department of Surgery, UT Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3315-4239","authenticated-orcid":false,"given":"Michael","family":"Dellinger","sequence":"additional","affiliation":[{"name":"Department of Surgery, UT Southwestern Medical Center","place":["Dallas"]},{"name":"Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical 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Homayun-Sepehr , KRAS-driven model of Gorham-Stout disease effectively treated with trametinib. JCI Insight 6, e149831 (2021).","journal-title":"JCI Insight"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.184291"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34323"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20181353"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.12.031"},{"key":"e_1_3_4_12_2","first-page":"162","article-title":"Bone development and fracture healing is normal in mice that have a defect in the development of the lymphatic system","volume":"53","author":"McCarter A. L.","year":"2020","unstructured":"A. L. McCarter , Bone development and fracture healing is normal in mice that have a defect in the development of the lymphatic system. 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Vishlaghi Data from \u201cVEGF-D-induced intraosseous lymphangiogenesis drives site-specific heterotopic bone resorption.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE247763. Deposited 13 March 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2524022123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T16:15:51Z","timestamp":1777997751000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2524022123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,5]]},"references-count":46,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2026,5,12]]}},"alternative-id":["10.1073\/pnas.2524022123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2524022123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,5]]},"assertion":[{"value":"2025-08-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2524022123"}}