Ghrelin protects against depleted uranium-induced bone damage by increasing osteoprotegerin/RANKL ratio
Ghrelin protects against depleted uranium-induced bone damage by increasing osteoprotegerin/RANKL ratio
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Ghrelin 通过增加骨保护素/RANKL 比率来防止贫铀引起的骨损伤
DOI：
10.1016/j.taap.2018.02.015
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发表时间：
2018-03-15
影响因子：
3.8
通讯作者：
Li, Rong
中科院分区：
文献类型：
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作者：
Hao, Yuhui;Gao, Rui;Li, Rong
贫铀广泛应用于军事和民用领域，骨骼是贫铀慢性毒性的主要靶器官。本研究的目的是评价ghrelin对DU植入大鼠的影响并探讨其作用机制。结果表明，Ghrelin可增加骨组织Ghrelin受体的表达，从而减轻0.3gDU胫骨包埋3个月后骨组织的凋亡。微电脑断层检查显示，DU植入后，皮质骨密度无显著差异，但松质骨数量减少，密度和连接性降低。Ghrelin治疗能明显减轻DU引起的改变，并能抑制血清抗酒石酸酸性磷酸酶的升高和碱性磷酸酶、骨钙素的降低。此外，ghrelin还可显著降低DU暴露后组织中核因子κ B配体受体激活因子（RANKL）和磷酸化p38-MAPK的表达，增加骨保护素（OPG）水平。细胞实验研究表明，p38-MAPK特异性激动剂可逆转ghrelin的功能，显著抑制OPG水平，增加RANKL水平。相反，使用p38-MAPK特异性抑制剂或p38-MAPK siRNA可以增强ghrelin的功能。提示Ghrelin可抑制DU诱导的p38 MAPK活化，增加DU所致的OPG/RANKL比值，从而减轻长期DU暴露所致的骨损伤。
Depleted uranium (DU) is widely used in military and civil activities, and bone is the main target organ of chronic DU toxicity. The aim of this study was to evaluate the effects of ghrelin on rats implanted with DU and explore the underlying mechanisms. The results showed that ghrelin could increase the expression of ghrelin receptor in bone tissue, thus alleviate the apoptosis of bone tissue after 3 months of 0.3 g DU embedded in the tibia. Micro-computed tomography examination showed that after DU implantation, the density of cortical bone showed no significant difference, but the trabecular bone decreased in amount, density and connectivity. Ghrelin treatment can significantly reduce the changes caused by DU. Moreover, ghrelin can inhibit the increase of serum tartrate resistant acid phosphatase and the decrease of alkaline phosphatase and osteocalcin. Furthermore, ghrelin can also significantly reduce the receptor activator of nuclear factor kappa B ligand (RANKL) and phosphorylated p38-MAPK expression, and increase the level of osteoprotegerin (OPG) in tissues after exposure to DU. Based on cell experimental research, p38-MAPK specific agonist can reverse the function of ghrelin, significantly inhibit the level of OPG and increase the level of RANKL. On the contrary, the use of p38-MAPK specific inhibitor or p38-MAPK siRNA can enhance the function of ghrelin. These results suggest that ghrelin may inhibit p38 MAPK activation induced by DU, and increase the OPG/RANKL ratio caused by DU exposure, hence alleviating the bone damage caused by long-term DU exposure.