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KMID : 0620920220540030298
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Experimental & Molecular Medicine
2022 Volume.54 No. 3 p.298 ~ p.308
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The miR-98-3p/JAG1/Notch1 axis mediates the multigenerational inheritance of osteopenia caused by maternal dexamethasone exposure in female rat offspring
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Han Hui
Xiao Hao
Wu Zhixin
Liu Liang
Chen Ming
Gu Hanwen
Wang Hui
Chen Liaobin
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Abstract
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As a synthetic glucocorticoid, dexamethasone is widely used to treat potential premature delivery and related diseases. Our previous studies have shown that prenatal dexamethasone exposure (PDE) can cause bone dysplasia and susceptibility to osteoporosis in female rat offspring. However, whether the effect of PDE on bone development can be extended to the third generation (F3 generation) and its multigenerational mechanism of inheritance have not been reported. In this study, we found that PDE delayed fetal bone development and reduced adult bone mass in female rat offspring of the F1 generation, and this effect of low bone mass caused by PDE even continued to the F2 and F3 generations. Furthermore, we found that PDE increases the expression of miR-98-3p but decreases JAG1/Notch1 signaling in the bone tissue of female fetal rats. Moreover, the expression changes of miR-98-3p/JAG1/Notch1 caused by PDE continued from the F1 to F3 adult offspring. Furthermore, the expression levels of miR-98-3p in oocytes of the F1 and F2 generations were increased. We also confirmed that dexamethasone upregulates the expression of miR-98-3p in vitro and shows targeted inhibition of JAG1/Notch1 signaling, leading to poor osteogenic differentiation of bone marrow mesenchymal stem cells. In conclusion, maternal dexamethasone exposure caused low bone mass in female rat offspring with a multigenerational inheritance effect, the mechanism of which is related to the inhibition of JAG1/Notch1 signaling caused by the continuous upregulation of miR-98-3p expression in bone tissues transmitted by F2 and F3 oocytes.
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KEYWORD
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Bone development, Reproductive disorders
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