Aberrant methylation‐induced dysfunction of p16 is associated with osteoblast activation caused by fluoride

• DOI: 10.1002/tox.22655
• Publication Date: 2018-09-27T06:40:20Z
• Authors: Shouli Wu; Weimin Yan; Bing Qiu; Yongfang Liao; Junying Gu; Shaofeng Wei; Aihua Zhang; Xueli Pan
• Keywords: Adult; Male; 0301 basic medicine; Osteoblasts; Gene Expression; DNA Methylation; 3. Good health; Fluorides; Young Adult; 03 medical and health sciences; Child, Preschool; Leukocytes, Mononuclear; Humans; Sodium Fluoride; Female; Bone Diseases; Promoter Regions, Genetic; Cell Division; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p16; Cell Proliferation

AbstractChronic 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 p16. The protein coded by the p16 gene inhibits cdk (cyclin‐dependent kinase) 4/cdk6‐mediated phosphorylation4 of retinoblastoma gene product and induces cell cycle arrest. The results showed that hypermethylation of p16 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 p16 hypermethylation and decreased expression, leading to increased cell proliferation, a longer S‐phase of the cell cycle, and development of skeletal fluorosis. Further, the methylation inhibitor, 5‐aza‐2‐deoxycytidine, reversed the p16 hypermethylation and expression in response to NaF. These results reveal a regulatory role of p16 gene methylation on osteoblasts activation during the development of skeletal fluorosis.