Colon epithelial cell-specific Bmal1 deletion impairs bone formation in mice.
Colon epithelial cell-specific Bmal1 deletion impairs bone formation in mice.
复制标题
结肠上皮细胞特异性 Bmal1 缺失会损害小鼠的骨形成。
DOI：
10.1016/j.bone.2022.116650
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发表时间：
2023
期刊：
影响因子：
4.1
通讯作者：
Sumner,DRick
中科院分区：
文献类型：
--
作者：
Ko,FrankC;Jochum,SarahB;Wilson,BrittanyM;Adra,Amal;Patel,Nikhil;Lee,Hoomin;Wilber,Sherry;Shaikh,Maliha;Forsyth,Christopher;Keshavarzian,Ali;Swanson,GarthR;Sumner,DRick
生物钟系统调节多种代谢过程，包括骨代谢。先前的研究表明，中枢和外周昼夜节律信号调节小鼠骨骼生长和体内平衡。中心昼夜节律的中断与人类骨密度的下降有关，骨组织中时钟基因的全球和成骨细胞特异性中断导致小鼠骨量降低。肠道生理对昼夜节律紊乱高度敏感。由于已知肠道也会影响骨骼重塑，我们试图验证结肠上皮细胞昼夜节律信号中断会影响骨骼的假设。因此，我们评估了8周大的Ts4-Cre和Ts4-Cre的骨结构、功能和细胞特性；Bmal1fl/fl（cBmalKO）小鼠，其中时钟基因Bmal1在结肠上皮细胞中被删除。与8周龄的Ts4-Cre小鼠相比，cBmalKO小鼠的轴状骨和尾状骨小梁体积显著降低，且呈性别依赖性，雄性小鼠而非雌性小鼠表现出这种表型。同样，cBmalKO雄性小鼠的整体骨力学性能下降。组织水平机制涉及抑制骨形成与正常吸收，证明了血清标志物和动态组织形态计量学。我们的研究表明，结肠上皮细胞特异性的Bmal1缺失导致雄性小鼠无法获得小梁骨和皮质骨。
The circadian clock system regulates multiple metabolic processes, including bone metabolism. Previous studies have demonstrated that both central and peripheral circadian signaling regulate skeletal growth and homeostasis in mice. Disruption in central circadian rhythms has been associated with a decline in bone mineral density in humans and the global and osteoblast-specific disruption of clock genes in bone tissue leads to lower bone mass in mice. Gut physiology is highly sensitive to circadian disruption. Since the gut is also known to affect bone remodeling, we sought to test the hypothesis that circadian signaling disruption in colon epithelial cells affects bone. We therefore assessed structural, functional, and cellular properties of bone in 8 week old Ts4-Cre and Ts4-Cre;Bmal1fl/fl(cBmalKO) mice, where the clock gene Bmal1 is deleted in colon epithelial cells. Axial and appendicular trabecular bone volume was significantly lower in cBmalKO compared to Ts4-Cre 8-week old mice in a sex-dependent fashion, with male but not female mice showing the phenotype. Similarly, the whole bone mechanical properties were deteriorated in cBmalKO male mice. The tissue level mechanisms involved suppressed bone formation with normal resorption, as evidenced by serum markers and dynamic histomorphometry. Our studies demonstrate that colon epithelial cell-specific deletion of Bmal1 leads to failure to acquire trabecular and cortical bone in male mice.