Ionizing Radiation Stimulates Expression of Pro-Osteoclastogenic Genes in Marrow and Skeletal Tissue.
Ionizing Radiation Stimulates Expression of Pro-Osteoclastogenic Genes in Marrow and Skeletal Tissue.
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DOI：
10.1089/jir.2014.0152
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
Globus RK
中科院分区：
文献类型：
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作者：
Alwood JS;Shahnazari M;Chicana B;Schreurs AS;Kumar A;Bartolini A;Shirazi-Fard Y;Globus RK
暴露在电离辐射下会导致矿物质的快速流失，增加代谢活跃的松质骨组织中的骨吸收破骨细胞，导致结构缺陷。为了更好地理解辐射引起的快速骨质流失的机制，我们确定了全身照射对一些已知的细胞因子表达的影响，这些细胞因子既能刺激破骨细胞生成，又能导致炎症性骨病。成年（16周）雄性C57BL/6J小鼠分别暴露于2 Gy γ射线（137Cs, 0.8 Gy/min）或重离子（56Fe, 600MeV, 0.50-1.1 Gy/min）；这一剂量或相当于放疗的一小部分（典型总剂量≥10戈瑞），或在长时间的行星际任务中累积。4 - 7天后采集血清、骨髓和矿化组织。伽马辐射导致骨髓细胞内专性破骨细胞因子、核因子κ b配体受体激活剂（Rankl）的表达迅速（4小时内增加2.6倍）和持续（1天内达到峰值4.1倍）高于对照组。同样，骨髓细胞中的Rankl表达在铁暴露3天内达到峰值（9.2倍）。伽马辐射诱导的Rankl表达变化先于骨髓中其他促破骨细胞因子的表达升高，并与之重叠（例如，单核细胞趋化蛋白-1比对照组升高11.9倍，肿瘤坏死因子- α升高1.7倍）。骨髓中Rankl/Opg的比值增加了1.8倍，达到促吸收的净平衡。在骨髓中，抗氧化转录因子Nfe2l2的表达与Nfatc1、Csf1、Tnf和Rankl的表达水平密切相关。辐射暴露增加了骨吸收的血清标志物（抗酒石酸酸性磷酸酶）并导致松质骨丢失（1周后减少16%）。我们的结论是，全身照射（γ或重离子）导致骨髓和矿化组织中与骨吸收相关的特定基因的浓度在时间上升高，包括导致破骨细胞生成和骨吸收升高的特定细胞因子；这可能是暴露于电离辐射后松质微结构迅速和渐进恶化的原因。
Exposure to ionizing radiation can cause rapid mineral loss and increase bone-resorbing osteoclasts within metabolically active, cancellous bone tissue leading to structural deficits. To better understand mechanisms involved in rapid, radiation-induced bone loss, we determined the influence of total body irradiation on expression of select cytokines known both to stimulate osteoclastogenesis and contribute to inflammatory bone disease. Adult (16 week), male C57BL/6J mice were exposed to either 2 Gy gamma rays (137Cs, 0.8 Gy/min) or heavy ions (56Fe, 600MeV, 0.50–1.1 Gy/min); this dose corresponds to either a single fraction of radiotherapy (typical total dose is ≥10 Gy) or accumulates over long-duration interplanetary missions. Serum, marrow, and mineralized tissue were harvested 4 h—7 days later. Gamma irradiation caused a prompt (2.6-fold within 4 h) and persistent (peaking at 4.1-fold within 1 day) rise in the expression of the obligate osteoclastogenic cytokine, receptor activator of nuclear factor kappa-B ligand (Rankl), within marrow cells over controls. Similarly, Rankl expression peaked in marrow cells within 3 days of iron exposure (9.2-fold). Changes in Rankl expression induced by gamma irradiation preceded and overlapped with a rise in expression of other pro-osteoclastic cytokines in marrow (eg, monocyte chemotactic protein-1 increased by 11.9-fold, and tumor necrosis factor-alpha increased by 1.7-fold over controls). The ratio, Rankl/Opg, in marrow increased by 1.8-fold, a net pro-resorption balance. In the marrow, expression of the antioxidant transcription factor, Nfe2l2, strongly correlated with expression levels of Nfatc1, Csf1, Tnf, and Rankl. Radiation exposure increased a serum marker of bone resorption (tartrate-resistant acid phosphatase) and led to cancellous bone loss (16% decrement after 1 week). We conclude that total body irradiation (gamma or heavy-ion) caused temporal elevations in the concentrations of specific genes expressed within marrow and mineralized tissue related to bone resorption, including select cytokines that lead to osteoclastogenesis and elevated resorption; this is likely to account for rapid and progressive deterioration of cancellous microarchitecture following exposure to ionizing radiation.