Parathyroid hormone resets the cartilage circadian clock of the organ-cultured murine femur.
Parathyroid hormone resets the cartilage circadian clock of the organ-cultured murine femur.
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DOI：
10.3109/17453674.2015.1029393
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发表时间：
2015
影响因子：
3.7
通讯作者：
Yagita K
中科院分区：
文献类型：
--
作者：
Okubo N;Fujiwara H;Minami Y;Kunimoto T;Hosokawa T;Umemura Y;Inokawa H;Asada M;Oda R;Kubo T;Yagita K
生物钟控制着内生的昼夜变化。在骨骼中，新陈代谢和生长表现出昼夜节律。由于甲状旁腺激素(PTH)水平存在昼夜变化，我们推测PTH可能将时间信息携带到骨骼和软骨中。在这项研究中，我们分析了甲状旁腺素对股骨生物钟的影响。采用PER2：：LUC(PER2：：Luc)基因敲除小鼠，取股骨进行器官培养。使用基于光电倍增管的实时生物发光监测设备或实时生物发光显微成像设备测量生物发光。给予甲状旁腺素或甲状旁腺素载体，计算相移。免疫组织化学方法检测PTH1型受体(PTH1R)的表达。实时生物发光监测显示，PTH以给药时间依赖和剂量依赖的方式重置股骨中PER2：：Luc活性的昼夜节律。显微生物发光成像显示生长板和关节软骨中PER2：：Luc的活性表明甲状旁腺素诱导了昼夜节律及其相移。PTH1R在生长板软骨中有表达。在临床实践中，甲状旁腺素(PTH(1-34))治疗骨质疏松症被广泛应用。我们发现，甲状旁腺素给药调节股骨昼夜节律的时钟振荡，特别是在软骨中。甲状旁腺激素对局部生物钟的调节可能不仅对骨质疏松，而且对骨生长和骨折修复中的软骨内骨化有更有效的治疗作用。
The circadian clock governs endogenous day-night variations. In bone, the metabolism and growth show diurnal rhythms. The circadian clock is based on a transcription-translation feedback loop composed of clock genes including Period2 (Per2), which encodes the protein period circadian protein homolog 2. Because plasma parathyroid hormone (PTH) levels show diurnal variation, we hypothesized that PTH could carry the time information to bone and cartilage. In this study, we analyzed the effect of PTH on the circadian clock of the femur. Per2::Luciferase (Per2::Luc) knock-in mice were used and their femurs were organ-cultured. The bioluminescence was measured using photomultiplier tube-based real-time bioluminescence monitoring equipment or real-time bioluminescence microscopic imaging devices. PTH or its vehicle was administered and the phase shifts were calculated. Immunohistochemistry was performed to detect PTH type 1 receptor (PTH1R) expression. Real-time bioluminescence monitoring revealed that PTH reset the circadian rhythm of the Per2::Luc activity in the femurs in an administration time-dependent and dose-dependent manner. Microscopic bioluminescence imaging revealed that Per2::Luc activity in the growth plate and the articular cartilage showed that the circadian rhythms and their phase shifts were induced by PTH. PTH1R was expressed in the growth plate cartilage. In clinical practice, teriparatide (PTH (1-34)) treatment is widely used for osteoporosis. We found that PTH administration regulated the femoral circadian clock oscillation, particularly in the cartilage. Regulation of the local circadian clock by PTH may lead to a more effective treatment for not only osteoporosis but also endochondral ossification in bone growth and fracture repair.