Aberrant methylation‐induced dysfunction of p16 is associated with osteoblast activation caused by fluoride
Aberrant methylation‐induced dysfunction of p16 is associated with osteoblast activation caused by fluoride
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DOI：
10.1002/tox.22655
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发表时间：
2018-09
影响因子：
4.5
通讯作者：
Shouli Wu;Weimin Yan;B. Qiu;Yongfang Liao;J. Gu;Shaofeng Wei;A. Zhang;Xueli Pan
中科院分区：
文献类型：
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作者：
Shouli Wu;Weimin Yan;B. Qiu;Yongfang Liao;J. Gu;Shaofeng Wei;A. Zhang;Xueli Pan
长期接触氟化物仍然是世界范围内的一个公共卫生问题，影响着成千上万的人。氟可引起成骨细胞和破骨细胞的异常增殖和活化，导致氟骨症，氟骨症可引起关节和骨骼的疼痛和损害，甚至导致永久性残疾。然而，目前还没有公认的机制来解释氟中毒的骨病变。本研究通过人群研究和体外实验，探讨氟骨症与p16基因启动子甲基化的关系。由p16基因编码的蛋白质抑制cdk（细胞周期蛋白依赖性激酶）4/cdk 6介导的视网膜母细胞瘤基因产物的磷酸化4，并诱导细胞周期停滞。结果表明，氟中毒患者外周血单个核细胞中p16基因甲基化水平明显升高，基因表达降低，且与氟暴露水平相关。对成骨细胞培养物的研究显示，在对氟化钠（NaF）处理的反应中，存在p16高甲基化的诱导和表达的降低，导致细胞增殖增加，细胞周期的S期延长，以及氟骨症的发展。此外，甲基化抑制剂5-氮杂-2-脱氧胞苷逆转了NaF引起的p16高甲基化和表达。这些结果揭示了p16基因甲基化在氟骨症发生发展过程中对成骨细胞活化的调节作用。
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 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.