{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T14:55:00Z","timestamp":1773672900999,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,8,26]],"date-time":"2016-08-26T00:00:00Z","timestamp":1472169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000646","name":"Japan Society for the Promotion of Science London","doi-asserted-by":"publisher","award":["15K11364"],"award-info":[{"award-number":["15K11364"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Periodontal Research"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:sec><jats:title>Background and Objective<\/jats:title><jats:p>Hypophosphatasia is a rare inherited skeletal disorder characterized by defective bone mineralization and deficiency of tissue non\u2010specific alkaline phosphatase (<jats:styled-content style=\"fixed-case\">TNSALP<\/jats:styled-content>) activity. The disease is caused by mutations in the liver\/bone\/kidney alkaline phosphatase gene (<jats:italic><jats:styled-content style=\"fixed-case\">ALPL<\/jats:styled-content><\/jats:italic>) encoding <jats:styled-content style=\"fixed-case\">TNSALP<\/jats:styled-content>. Early exfoliation of primary teeth owing to disturbed cementum formation, periodontal ligament weakness and alveolar bone resorption are major complications encountered in oral findings, and discovery of early loss of primary teeth in a dental examination often leads to early diagnosis of hypophosphatasia. Although there are no known fundamental treatments or effective dental approaches to prevent early exfoliation of primary teeth in affected patients, several possible treatments have recently been described, including gene therapy. Gene therapy has also been applied to <jats:italic><jats:styled-content style=\"fixed-case\">TNSALP<\/jats:styled-content><\/jats:italic> knockout mice (<jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>), which phenocopy the infantile form of hypophosphatasia, and improved their systemic condition. In the present study, we investigated whether gene therapy improved the dental condition of <jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and Methods<\/jats:title><jats:p>Following sublethal irradiation (4 Gy) at the age of 2 d, <jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice underwent gene therapy using bone marrow cells transduced with a lentiviral vector expressing a bone\u2010targeted form of <jats:italic><jats:styled-content style=\"fixed-case\">TNSALP<\/jats:styled-content><\/jats:italic> injected into the jugular vein (<jats:italic>n<\/jats:italic> = 3). Wild\u2010type (<jats:italic>Alpl<\/jats:italic><jats:sup>+\/+<\/jats:sup>), heterozygous mice (<jats:italic>Alpl<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>) and <jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice were analyzed at 9 d of age (<jats:italic>n<\/jats:italic> = 3 of each), while <jats:italic>Alpl<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice and treated or untreated <jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice were analyzed at 1 mo of age (<jats:italic>n<\/jats:italic> = 3 of each), and <jats:italic>Alpl<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice and <jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice with gene therapy were analyzed at 3 mo of age (<jats:italic>n<\/jats:italic> = 3 of each). A single mandibular hemi\u2010section obtained at 1 mo of age was analyzed using a small animal computed tomography machine to assess alveolar bone formation. Other mandibular hemi\u2010sections obtained at 9 d, 1 mo and 3 mo of age were subjected to hematoxylin and eosin staining and immunohistochemical analysis of osteopontin, a marker of cementum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Immunohistochemical analysis of osteopontin, a marker of acellular cementum, revealed that <jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice displayed impaired formation of cementum and alveolar bone, similar to the human dental phenotype. Cementum formation was clearly present in <jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice that underwent gene therapy, but did not recover to the same level as that in wild\u2010type (<jats:italic>Alpl<\/jats:italic><jats:sup>+\/+<\/jats:sup>) mice. Micro\u2010computed tomography examination showed that gene therapy improved alveolar bone mineral density in <jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice to a similar level to that in <jats:italic>Alpl<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results suggest that gene therapy can improve the general condition of <jats:italic>Alpl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, and induce significant alveolar bone formation and moderate improvement of cementum formation, which may contribute to inhibition of early spontaneous tooth exfoliation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jre.12412","type":"journal-article","created":{"date-parts":[[2016,8,26]],"date-time":"2016-08-26T07:03:07Z","timestamp":1472194987000},"page":"471-478","source":"Crossref","is-referenced-by-count":14,"title":["Gene therapy improves dental manifestations in hypophosphatasia model 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