{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T15:23:50Z","timestamp":1780327430437,"version":"3.54.1"},"reference-count":12,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,4,17]],"date-time":"2016-04-17T00:00:00Z","timestamp":1460851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European J Oral Sciences"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:p>Mutation of the dihydroorotate dehydrogenase (<jats:italic><jats:styled-content style=\"fixed-case\">DHODH<\/jats:styled-content><\/jats:italic>) gene is responsible for Miller syndrome, which is characterized by craniofacial malformations with limb abnormalities. We previously demonstrated that <jats:styled-content style=\"fixed-case\">DHODH<\/jats:styled-content> was involved in forming a mitochondrial supercomplex and that mutated <jats:italic><jats:styled-content style=\"fixed-case\">DHODH<\/jats:styled-content><\/jats:italic> led to protein instability, loss of enzyme activity, and increased levels of reactive oxygen species in HeLa cells. To explore the etiology of Miller syndrome in more detail, we investigated the effects of <jats:styled-content style=\"fixed-case\">DHODH<\/jats:styled-content> inhibition in the cells involved in skeletal structure. Dihydroorotate dehydrogenase in <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>3T3\u2010E1 cells derived from mouse calvaria osteoblast precursor cells was knocked down by specific small interfering <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>s (si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>s), and cell proliferation, <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content> production, and expression of bone\u2010related genes were investigated in these cells. After depletion of <jats:styled-content style=\"fixed-case\">DHODH<\/jats:styled-content> using specific si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>s, inhibition of cell proliferation and cell cycle arrest occurred in <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>3T3\u2010E1 cells. In addition, <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content> production was reduced in whole cells, especially in mitochondria. Furthermore, the levels of runt\u2010related transcription factor 2 (<jats:italic>Runx2<\/jats:italic>) and osteocalcin (<jats:italic>Ocn<\/jats:italic>) <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>s were lower in <jats:styled-content style=\"fixed-case\">DHODH<\/jats:styled-content> si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010treated cells compared with controls. These data suggest that depletion of <jats:styled-content style=\"fixed-case\">DHODH<\/jats:styled-content> affects the differentiation and maturation of osteoblasts. This study shows that mitochondrial dysfunction by <jats:styled-content style=\"fixed-case\">DHODH<\/jats:styled-content> depletion in osteoblasts can be directly linked to the abnormal bone formation in Miller syndrome.<\/jats:p>","DOI":"10.1111\/eos.12270","type":"journal-article","created":{"date-parts":[[2016,4,18]],"date-time":"2016-04-18T04:56:43Z","timestamp":1460955403000},"page":"241-245","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Dihydroorotate dehydrogenase depletion hampers mitochondrial function and osteogenic differentiation in osteoblasts"],"prefix":"10.1111","volume":"124","author":[{"given":"JingXian","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Pediatric Dentistry Graduate School of Dental Science Kyushu University Fukuoka Japan"},{"name":"Department of Clinical Chemistry and Laboratory Medicine Graduate School of Medical Sciences Kyushu University Fukuoka Japan"},{"name":"Department of Orthodontics and Craniofacial Biology Radboud Institute for Molecular Life Sciences Radboud University Medical Centre Nijmegen the Netherlands"},{"name":"Department of Pediatric Dentistry Guangdong Provincial Stomatological Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1138-3943","authenticated-orcid":false,"given":"Haruyoshi","family":"Yamaza","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry Graduate School of Dental Science Kyushu University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Uchiumi","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Laboratory Medicine Graduate School of Medical Sciences Kyushu University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Hoshino","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry Graduate School of Dental Science Kyushu University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiji","family":"Masuda","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry Graduate School of Dental Science Kyushu University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Hirofuji","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry Graduate School of Dental Science Kyushu University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank A. 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