Yu Xiuhua, Yu Haolan, Jiang Ningning, Zhang Xiuyun, Zhang Mengmeng, Xu Hui
Department of Pediatrics, The First Hospital of Jilin University, Changchun, 130021, China.
School of pharmaceutical Sciences, Jilin University, Changchun, 130021, China, China.
Toxicol Lett. 2018 May 15;288:25-34. doi: 10.1016/j.toxlet.2018.02.014. Epub 2018 Feb 12.
Exposure to fluoride from environmental sources remains an overlooked, but serious public health risk. In this study, we looked into the role osteocytes play on the mechanism underlying fluoride induced osteopathology. We analyzed bone formation and resorption related genes generated by osteocytes that were exposed to varied doses of fluoride with and without PTH in vitro. Correspondingly, osteogenesis and osteoclastogenesis related genes were also investigated in rats exposed to fluoride for 8 weeks, and the PTH(1-34)was applied at the last 3 weeks to observe its role in regulating bone turnover upon fluoride treatment. The data in vitro indicated that fluoride treatment inhibited Sost expression of mRNA and protein and stimulated RANKL mRNA protein expression as well as the RANKL/OPG ratio in the primary osteocytes. Single PTH treatment played the similar role on expression of these genes and proteins. The PTH combined administration enhanced the action of fluoride treatment on RNAKL/OPG and SOST/Sclerostin. The up-regulation of RANKL and decreasing of Sost induced by fluoride and/or PTH treatment was validated in vivo and suggests that osteocytes are a major source of RANKL and Sost, both of which play essential roles in fluoride affecting osteogenesis and osteoclastogenesis. Expression of Wnt/β-catenin was up-regulated in both in vitro osteocytes treated with high dose of fluoride and bone tissue of rats in the presence of fluoride and PTH. In vivo, fluoride and single PTH stimulated bone turnover respectively, furthermore, PTH combined with low dose of fluoride treatment reinforced the osteogenesis and osteoclastogenesis genes expression, however, co-treatment of PTH reversed the effect of high dose of fluoride on osteogenesis and osteoclastogenensis related factors. In conclusion, this study demonstrated that osteocytes play a key role in fluoride activated bone turnover, and PTH participates in the process of fluoride modulating SOST/Sclerostin and RANKL expression.
接触来自环境源的氟化物仍然是一个被忽视但严重的公共卫生风险。在本研究中，我们探究了骨细胞在氟化物诱导骨病理机制中所起的作用。我们分析了体外暴露于不同剂量氟化物且有或无甲状旁腺激素（PTH）的骨细胞产生的与骨形成和骨吸收相关的基因。相应地，还对暴露于氟化物8周的大鼠体内与成骨和破骨细胞生成相关的基因进行了研究，并在最后3周应用PTH(1 - 34)以观察其在氟化物处理后调节骨转换中的作用。体外数据表明，氟化物处理抑制了原代骨细胞中Sost mRNA和蛋白的表达，并刺激了RANKL mRNA和蛋白的表达以及RANKL/OPG比值。单独的PTH处理对这些基因和蛋白的表达起类似作用。PTH联合给药增强了氟化物处理对RNAKL/OPG和SOST/硬骨素的作用。氟化物和/或PTH处理诱导的RANKL上调和Sost降低在体内得到验证，这表明骨细胞是RANKL和Sost的主要来源，二者在氟化物影响成骨和破骨细胞生成中均起重要作用。在高剂量氟化物处理的体外骨细胞以及存在氟化物和PTH的大鼠骨组织中，Wnt/β - 连环蛋白的表达均上调。在体内，氟化物和单独的PTH分别刺激骨转换，此外，PTH与低剂量氟化物联合处理增强了成骨和破骨细胞生成基因的表达，然而，PTH与高剂量氟化物共同处理则逆转了高剂量氟化物对成骨和破骨细胞生成相关因子的影响。总之，本研究表明骨细胞在氟化物激活的骨转换中起关键作用，且PTH参与氟化物调节SOST/硬骨素和RANKL表达的过程。
