Lowering iron level protects against bone loss in focally irradiated and contralateral femurs through distinct mechanisms.
Lowering iron level protects against bone loss in focally irradiated and contralateral femurs through distinct mechanisms.
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DOI：
10.1016/j.bone.2018.10.005
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发表时间：
2019-03
期刊：
影响因子：
4.1
通讯作者：
Jian Zhang;Lijun Zheng;Ziyang Wang;Hailong Pei;Wentao Hu;Jing Nie;P. Shang;Bingyan Li;T. Hei;Guangming Zhou
中科院分区：
文献类型：
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作者：
Jian Zhang;Lijun Zheng;Ziyang Wang;Hailong Pei;Wentao Hu;Jing Nie;P. Shang;Bingyan Li;T. Hei;Guangming Zhou
放射治疗会增加因骨量丢失而导致的迟发性脆性和骨折的风险。另一方面，铁超载通过增强骨吸收而引起骨质疏松症。全身照射可增加机体铁水平，但全身骨丢失是否与照射后铁水平的变化及铁调素的调节有关尚不清楚。为了研究它们之间的潜在联系，我们首先通过用单次2戈伊剂量的X射线靶向股骨中段来创建辐射诱导的全身性骨丢失的动物模型。我们发现，股骨中段局部照射导致骨小梁远端区域结构恶化，与非照射对照组相比，照射组和对侧股骨中破骨细胞表面和骨吸收标志物表达增加。照射后，肝的铁调素活性降低导致血清和肝中铁水平升高。通过注射铁调素或去铁胺（一种铁螯合剂）降低铁水平，消除了辐射小鼠骨小梁微结构的恶化。铁螯合物抑制辐射诱导的破骨细胞分化的能力也在体外观察。我们进一步表明，电离辐射（IR）直接刺激破骨细胞分化和骨吸收的骨髓细胞分离，而不是从对侧股骨，但从直接照射股骨。这些结果表明，局部辐射后铁水平升高至少是全身性骨丢失的主要原因之一。此外，直接照射骨中的骨丢失不仅是由于铁水平升高，而且还由于破骨细胞分化增加。相反，对侧股骨的骨丢失主要是由于单独IR引起的铁水平升高。这些新的发现提供了使用铁螯合或铁调素作为IR诱导的骨质疏松症的治疗方法的原理证据。
Radiation therapy leads to increased risk of late-onset fragility and bone fracture due to the loss of bone mass. On the other hand, iron overloading causes osteoporosis by enhancing bone resorption. It has been shown that total body irradiation increases iron level, but whether the systemic bone loss is related to the changes in iron level and hepcidin regulation following bone irradiation remains unknown. To investigate the potential link between them, we first created an animal model of radiation-induced systemic bone loss by targeting the mid-shaft femur with a single 2 Gy dose of X-rays. We found that mid-shaft femur focal irradiation led to structural deterioration in the distal region of the trabecular bone with increased osteoclasts surface and expressions of bone resorption markers in both irradiated and contralateral femurs relative to non-irradiated controls. Following irradiation, reduced hepcidin activity of the liver contributed to elevated iron levels in the serum and liver. By injecting hepcidin or deferoxamine (an iron chelator) to reduce iron level, deterioration of trabecular bone microarchitecture in irradiated mice was abrogated. The ability of iron chelation to inhibit radiation-induced osteoclast differentiation was observed in vitro as well. We further showed that ionizing radiation (IR) directly stimulated osteoclast differentiation and bone resorption in bone marrow cells isolated not from contralateral femurs but from directly irradiated femurs. These results suggest that increased iron levels after focal radiation is at least one of the main reasons for systemic bone loss. Furthermore, bone loss in directly irradiated bones is not only due to the elevated iron level, but also from increased osteoclast differentiation. In contrast, the bone loss in the contralateral femurs is mainly due to the elevated iron level induced by IR alone. These novel findings provide proof-of-principle evidence for the use of iron chelation or hepcidin as therapeutic treatments for IR-induced osteoporosis.