Screening of differentially methylated genes in skeletal fluorosis of rats with different types and involvement of aberrant methylation of Cthrc1.
Screening of differentially methylated genes in skeletal fluorosis of rats with different types and involvement of aberrant methylation of Cthrc1.
复制标题
DOI：
10.1016/j.envpol.2023.121931
复制
发表时间：
2023-05
影响因子：
8.9
通讯作者：
Hongwei Ding;Congyu Yin;Menglan Yang;Ruiqi Zhou;Xilan Wang;Xueli Pan
中科院分区：
文献类型：
--
作者：
Hongwei Ding;Congyu Yin;Menglan Yang;Ruiqi Zhou;Xilan Wang;Xueli Pan
氟化物是环境中广泛存在的污染物。由于过量接触氟化物，患氟骨症的风险很高。氟骨症在相同的氟化物暴露下有不同的表型（包括骨硬化、骨质疏松和骨软化），并取决于饮食营养。然而，现有的氟骨症发病机制假说并不能很好地解释氟骨症的不同病理表现及其与营养因子的逻辑关系。近年来的研究表明，DNA甲基化参与氟骨症的发生和发展。DNA甲基化在整个生命过程中是动态的，可能受到营养和环境因素的影响。我们推测，氟暴露导致不同营养状态下骨骼稳态相关基因甲基化异常，从而导致不同的氟骨症表型。mRNA-Seq和靶亚硫酸盐测序（TBS）结果显示，不同类型氟骨症大鼠的基因甲基化差异。在体内和体外探讨了差异甲基化基因ecthrc1在不同类型氟骨症形成中的作用。在正常营养条件下，氟暴露通过TET2去甲基化酶导致成骨细胞低甲基化和高表达cthrc1in，通过激活Wnt3a/β-catenin信号通路促进成骨细胞分化，参与了骨硬化性氟骨症的发生。同时，CTHRC1蛋白的高表达也抑制了破骨细胞的分化。在不良饮食条件下，氟暴露通过DNMT1甲基转移酶导致成骨细胞cthrc1in高甲基化和低表达，RANKL/OPG比值升高，促进破骨细胞分化，参与骨质疏松性/骨疏松性氟骨症的发生。我们的研究扩大了对DNA甲基化在调节不同类型氟骨症形成中的作用的认识，并为氟骨症患者提供了新的预防和治疗策略。
Fluoride is a widespread pollutant in the environment. There is a high risk of developing skeletal fluorosis from excessive fluoride exposure. Skeletal fluorosis has different phenotypes (including osteosclerotic, osteoporotic and osteomalacic) under the same fluoride exposure and depends on dietary nutrition. However, the existing mechanistic hypothesis of skeletal fluorosis cannot well explain the condition's different pathological manifestations and their logical relation with nutritional factors. Recent studies have shown that DNA methylation is involved in the occurrence and development of skeletal fluorosis. DNA methylation is dynamic throughout life and may be affected by nutrition and environmental factors. We speculated that fluoride exposure leads to the abnormal methylation of genes related to bone homeostasis under different nutritional statuses, resulting in different skeletal fluorosis phenotypes. The mRNA-Seq and target bisulfite sequencing (TBS) result showed differentially methylated genes in rats with different skeletal fluorosis types. The role of the differentially methylated geneCthrc1in the formation of different skeletal fluorosis types was exploredin vivoandin vitro. Under normal nutritional conditions, fluoride exposure led to hypomethylation and high expression ofCthrc1in osteoblasts through TET2 demethylase, which promoted osteoblast differentiation by activating Wnt3a/β-catenin signalling pathway, and participated in the occurrence of osteosclerotic skeletal fluorosis. Meanwhile, the high CTHRC1 protein expression also inhibited osteoclast differentiation. Under poor dietary conditions, fluoride exposure led to hypermethylation and low expression ofCthrc1in osteoblasts through DNMT1 methyltransferase, and increased the RANKL/OPG ratio, which promoted the osteoclast differentiation and participated in the occurrence of osteoporotic/osteomalacic skeletal fluorosis. Our study expands the understanding of the role of DNA methylation in regulating the formation of different skeletal fluorosis types and provides insights into new prevention and treatment strategies for patients with skeletal fluorosis.