Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
FASEB J. 2020 Jan;34(1):1052-1064. doi: 10.1096/fj.201901929R. Epub 2019 Nov 28.
The past decade, it has become evident that circadian rhythms within metabolically active tissues are very important for physical health. However, although shift work has also been associated with an increased risk of fractures, circadian rhythmicity has not yet been extensively studied in bone. Here, we investigated which genes are rhythmically expressed in bone, and whether circadian disruption by shifts in light-dark cycle affects bone turnover and structure in mice. Our results demonstrate diurnal expression patterns of clock genes (Rev-erbα, Bmal1, Per1, Per2, Cry1, Clock), as well as genes involved in osteoclastogenesis, osteoclast proliferation and function (Rankl, Opg, Ctsk), and osteocyte function (c-Fos) in bone. Weekly alternating light-dark cycles disrupted rhythmic clock gene expression in bone and caused a reduction in plasma levels of procollagen type 1 amino-terminal propeptide (P1NP) and tartrate-resistant acidic phosphatase (TRAP), suggestive of a reduced bone turnover. These effects coincided with an altered trabecular bone structure and increased cortical mineralization after 15 weeks of light-dark cycles, which may negatively affect bone strength in the long term. Collectively, these results show that a physiological circadian rhythm is important to maintain bone health, which stresses the importance of further investigating the association between shift work and skeletal disorders.
过去十年，人们已经明显认识到代谢活跃组织中的昼夜节律对身体健康非常重要。然而，尽管轮班工作也与骨折风险增加有关，但昼夜节律在骨骼中的研究还不够广泛。在这里，我们研究了哪些基因在骨骼中呈节律性表达，以及光-暗周期的变化是否会影响昼夜节律破坏对小鼠的骨转换和结构。我们的结果表明，时钟基因（Rev-erbα、Bmal1、Per1、Per2、Cry1、Clock）以及参与破骨细胞生成、破骨细胞增殖和功能（Rankl、Opg、Ctsk）和骨细胞功能（c-Fos）的基因在骨骼中具有昼夜表达模式。每周交替的光-暗周期扰乱了骨骼中昼夜节律的时钟基因表达，并导致血浆中Ⅰ型前胶原氨基端前肽（P1NP）和抗酒石酸酸性磷酸酶（TRAP）水平降低，提示骨转换减少。这些影响与 15 周光-暗周期后小梁骨结构的改变和皮质矿化增加相一致，这可能会对骨骼长期强度产生负面影响。总的来说，这些结果表明，生理昼夜节律对维持骨骼健康很重要，这强调了进一步研究轮班工作与骨骼紊乱之间关联的重要性。
