Increased Endoplasmic Reticulum Stress in Mouse Osteocytes with Aging Alters Cox-2 Response to Mechanical Stimuli
Increased Endoplasmic Reticulum Stress in Mouse Osteocytes with Aging Alters Cox-2 Response to Mechanical Stimuli
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DOI：
10.1007/s00223-014-9944-6
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发表时间：
2015-02-01
影响因子：
4.2
通讯作者：
Deldicque, Louise
中科院分区：
文献类型：
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作者：
Chalil, Sreeda;Jaspers, Richard T.;Deldicque, Louise
衰老降低了骨量以及骨对机械刺激的合成代谢反应，导致骨质减少。内质网（ER）应激损害肌源性细胞对合成代谢刺激的反应，并参与肌肉减少症，但ER应激是否也有助于骨质减少症尚不清楚。因此，我们测试了老年小鼠骨骼中是否存在ER应力，以及这是否会损害骨细胞对机械刺激的反应。从成年（8个月）和老年（24-26个月）小鼠的长骨获得原代骨细胞，用或不用药理学ER应激诱导剂衣霉素处理，并且通过脉动流体流（PFF）进行或不进行机械负荷。通过测定环氧合酶-2（考克斯-2）mRNA水平和一氧化氮（NO）产生来评估骨细胞对PFF的反应。ER应激标志物的mRNA水平在老年骨细胞中比在成年骨细胞中更高（活化转录因子-4为+40%，C/EBP同源蛋白为+120%，剪接的X-box结合蛋白-1为+120%，p < 0.05）。在来自老骨的细胞中，对PFF的考克斯-2反应降低了4倍（p < 0.001），而衣霉素在来自成年骨的细胞中使PFF诱导的考克斯-2表达降低了3倍（p < 0.01）。PFF在60分钟时使来自老年骨的骨细胞与成人骨的骨细胞的NO产生增加50%（p < 0.01）。总之，我们的数据表明，几个ER应激标志物的表达是更高的骨细胞相比，成年小鼠的骨。由于内质网应激改变了骨细胞对机械负荷的反应，因此内质网应激可能是导致骨量减少的一个新因素。
Aging reduces bone mass as well as the anabolic response of bone to mechanical stimuli, resulting in osteopenia. Endoplasmic reticulum (ER) stress impairs the response of myogenic cells to anabolic stimuli, and is involved in sarcopenia, but whether ER stress also contributes to osteopenia is unknown. Therefore, we tested whether ER stress exists in bones of aged mice, and whether this impairs the osteocyte response to mechanical stimulation. Primary osteocytes were obtained from long bones of adult (8 months) and old (24-26 months) mice, treated with or without the pharmacological ER stress inducer tunicamycin, and either or not subjected to mechanical loading by pulsating fluid flow (PFF). The osteocyte response to PFF was assessed by measuring cyclooxygenase-2 (Cox-2) mRNA levels and nitric oxide (NO) production. mRNA levels of ER stress markers were higher in old versus adult osteocytes (+40 % for activating transcription factor-4, +120 % for C/EBP homologous protein, and +120 % for spliced X-box binding protein-1, p < 0.05). The Cox-2 response to PFF was fourfold decreased in cells from old bones (p < 0.001), while tunicamycin decreased PFF-induced Cox-2 expression by threefold in cells from adult bones (p < 0.01). PFF increased NO production by 50 % at 60 min in osteocytes from old versus adult bones (p < 0.01). In conclusion, our data indicate that the expression of several ER stress markers was higher in osteocytes from bones of old compared to adult mice. Since ER stress altered the response of osteocytes to mechanical loading, it could be a novel factor contributing to osteopenia.