Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype.
Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype.
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DOI：
10.1016/j.bone.2016.01.006
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发表时间：
2016-03
期刊：
影响因子：
4.1
通讯作者：
Kondratov RV
中科院分区：
文献类型：
--
作者：
Samsa WE;Vasanji A;Midura RJ;Kondratov RV
生物钟是一种内源性计时系统，控制着许多生物体的生理和行为。转录因子脑和肌肉 ARNT 样蛋白 1 (BMAL1) 是生物钟的组成部分，是生物钟功能所必需的。 Bmal1−/− 小鼠表现出加速衰老和许多伴随年龄相关的病理。在这里，我们报告说，缺乏 BMAL1 的小鼠具有低骨量表型，这种表型在出生时并不存在，并且在其一生中逐渐恶化。这些小鼠的加速衰老与干骺端到骨骺之间骨桥的形成有关，导致长骨变短。使用微型计算机断层扫描，我们发现 Bmal1−/− 小鼠的皮质骨和小梁骨体积以及其他微观结构参数减少，骨矿物质密度降低。组织学显示 BMAL1 缺陷会导致体内活性成骨细胞和骨细胞数量减少。从 Bmal1−/− 小鼠中分离骨髓来源的间充质干细胞表明体外分化成成骨细胞的能力降低，这可能解释了观察到的成骨细胞和骨细胞的减少，并可能导致观察到的骨质减少。我们的数据支持生物钟在骨稳态调节中的作用，并表明 BMAL1 缺乏会导致低骨量表型。
The circadian clock is an endogenous time keeping system that controls the physiology and behavior of many organisms. The transcription factor Brain and Muscle ARNT-like Protein 1 (BMAL1) is a component of the circadian clock and necessary for clock function. Bmal1−/− mice display accelerated aging and many accompanying age associated pathologies. Here, we report that mice deficient for BMAL1 have a low bone mass phenotype that is absent at birth and progressively worsens over their lifespan. Accelerated aging of these mice is associated with the formation of bony bridges occurring across the metaphysis to the epiphysis, resulting in shorter long bones. Using micro-computed tomography we show that Bmal1−/− mice have reductions in cortical and trabecular bone volume and other micro-structural parameters and a lower bone mineral density. Histology shows a deficiency of BMAL1 results in a reduced number of active osteoblasts and osteocytes in vivo. Isolation of bone marrow derived mesenchymal stem cells from Bmal1−/− mice demonstrate a reduced ability to differentiate into osteoblasts in vitro, which likely explains the observed reductions in osteoblasts and osteocytes, and may contribute to the observed osteopenia. Our data support the role of the circadian clock in the regulation of bone homeostasis and shows that BMAL1 deficiency results in a low bone mass phenotype.