Cellular senescence mediates the detrimental effect of prenatal dexamethasone exposure on postnatal long bone growth in mouse offspring
Cellular senescence mediates the detrimental effect of prenatal dexamethasone exposure on postnatal long bone growth in mouse offspring
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DOI：
10.1186/s13287-020-01790-9
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发表时间：
2020-07-06
影响因子：
7.5
通讯作者：
Zhang, Xianrong
中科院分区：
文献类型：
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作者：
Su, Jianwen;Chai, Yu;Zhang, Xianrong
研究背景产前接触地塞米松(PDE)可导致低出生体重和胎儿骨骼发育迟缓，并与成年子代峰值骨量降低有关。在这里，我们评估了PDE是否以及如何影响小鼠后代的出生后长骨生长。方法妊娠12~14天的小鼠每天早晨皮下注射地塞米松1.2 mg/kg/d。取2周龄、4周龄、6周龄和12周龄雌性后代的股骨和胫骨进行组织学、免疫荧光、流式细胞仪分析或微计算机断层扫描(MU CT)测量。结果PDE可导致子代雌性小鼠长骨骨改建受损，骨量减少。在出生后骨生长过程中，PDE后子代小鼠长骨干骺端CD45(-)、CD29(+)、CD105(+)、SCA-1(+)、骨髓间充质干细胞(BMSCs)和CD45(-)巢蛋白(+)细胞明显减少，H型血管消失，细胞衰老增加。达沙替尼(5 mg/kg/d)和栎素(50 mg/kg/d)在GD12-14期间清除过多的衰老细胞，可挽救PDE对雌性子代出生后长骨生长的上述毒性效应。结论细胞衰老介导了PDE对仔鼠长骨生长的毒性作用，抑制细胞衰老可用于治疗PDE所致的骨生长迟缓。
Background Prenatal dexamethasone exposure (PDE) induces low birth weight and retardation of fetal bone development which are associated with lower peak bone mass in adult offspring. Here we evaluated whether and how PDE affects postnatal long bone growth in mouse offspring. Methods Pregnant mice were injected subcutaneously with dexamethasone (1.2 mg/kg/day) every morning from gestational days (GD) 12-14. Femurs and tibias of 2-, 4-, 6-, and 12-week-old female offspring were harvested for histological, immunofluorescence, flow cytometric analysis, or microcomputed tomography (mu CT) measurement. Results PDE leads to impaired bone remodeling as well as decreased bone mass in the long bone of female mouse offspring. During postnatal bone growth, significant decrease of CD45(-)CD29(+)CD105(+)Sca-1(+)bone marrow mesenchymal stem cells (BMSCs) and CD45(-)Nestin(+)cells, loss of type H vessels, and increment of cellular senescence were found in metaphysis of long bone in mouse offspring after PDE. We further show that eliminating the excessive senescent cells with dasatinib (5 mg/kg/day) and quercetin (50 mg/kg/day) during GD 12-14 rescues the above toxic effect of PDE on the postnatal long bone growth in female mouse offspring. Conclusion Cellular senescence mediates the toxic effect of PDE on postnatal long bone growth in mouse offspring, and inhibition of cellular senescence may be proposed for treating the retardation of bone growth caused by PDE.