{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T19:56:14Z","timestamp":1789934174795,"version":"4.0.1"},"reference-count":56,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,9,26]],"date-time":"2018-09-26T00:00:00Z","timestamp":1537920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81260418"],"award-info":[{"award-number":["81260418"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environmental Toxicology"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic exposure to fluoride continues to be a public health problem worldwide, affecting thousands of people. Fluoride can cause abnormal proliferation and activation of osteoblast and osteoclast, leading to skeletal fluorosis that can cause pain and harm to joints and bones and even lead to permanent disability. Nevertheless, there is no recognized mechanism to explain the bone lesions of fluorosis. In this work, we performed a population study and in vitro experiments to investigate the pathogenic mechanism of skeletal fluorosis in relation to methylation of the promoter of <jats:italic>p16<\/jats:italic>. The protein coded by the <jats:italic>p16<\/jats:italic> gene inhibits cdk (cyclin\u2010dependent kinase) 4\/cdk6\u2010mediated phosphorylation4 of retinoblastoma gene product and induces cell cycle arrest. The results showed that hypermethylation of <jats:italic>p16<\/jats:italic> and reduced gene expression was evident in peripheral blood mononuclear cells of patients with fluorosis and correlated with the level of fluoride exposure. Studies with cell cultures of osteoblasts revealed in response to sodium fluoride (NaF) treatment, there was an induction of <jats:italic>p16<\/jats:italic> hypermethylation and decreased expression, leading to increased cell proliferation, a longer S\u2010phase of the cell cycle, and development of skeletal fluorosis. Further, the methylation inhibitor, 5\u2010aza\u20102\u2010deoxycytidine, reversed the <jats:italic>p16<\/jats:italic> hypermethylation and expression in response to NaF. These results reveal a regulatory role of <jats:italic>p16<\/jats:italic> gene methylation on osteoblasts activation during the development of skeletal fluorosis.<\/jats:p>","DOI":"10.1002\/tox.22655","type":"journal-article","created":{"date-parts":[[2018,9,27]],"date-time":"2018-09-27T06:40:20Z","timestamp":1538030420000},"page":"37-47","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Aberrant methylation\u2010induced dysfunction of <i>p16<\/i> is associated with osteoblast activation caused by fluoride"],"prefix":"10.1002","volume":"34","author":[{"given":"Shouli","family":"Wu","sequence":"first","affiliation":[{"name":"School of Public Health Guizhou Medical University  Guiyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weimin","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Public Health Guizhou Medical University  Guiyang 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aihua","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Public Health Guizhou Medical University  Guiyang China"},{"name":"Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education Guizhou Medical University  Guiyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1652-0700","authenticated-orcid":false,"given":"Xueli","family":"Pan","sequence":"additional","affiliation":[{"name":"School of Public Health Guizhou Medical University  Guiyang 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