Deletion of ferroportin in murine myeloid cells increases iron accumulation and stimulates osteoclastogenesis in vitro and in vivo
Deletion of ferroportin in murine myeloid cells increases iron accumulation and stimulates osteoclastogenesis in vitro and in vivo
复制标题
小鼠骨髓细胞中铁转运蛋白的缺失增加铁积累并刺激体外和体内破骨细胞生成
DOI：
10.1074/jbc.ra117.000834
复制
发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Haibo Zhao
中科院分区：
文献类型：
--
作者：
Lei Wang;Bin Fang;Toshifumi Fujiwara;Kimberly Krager;Akshita Gorantla;Chaoyuan Li;Jian Q. Feng;Michael L. Jennings;Jian Zhou;Nukhet Aykin-Burns;Haibo Zhao
骨质疏松症、骨量减少和病理性骨折是遗传性血色素沉着症、地中海贫血和镰状细胞病等铁超载条件下常见的并发症。此外，铁负荷过高的动物模型显示，骨吸收增加，骨形成减少。尽管全身性铁超载影响多个器官和组织，导致骨骼模型和重塑的显著变化，但过量铁对骨细胞的细胞自主作用尚不清楚。为了阐明细胞铁稳态在破骨细胞中的作用，我们建立了两个小鼠品系，其中溶质载体家族40成员1(Slc40a1)是哺乳动物细胞中唯一的铁输出蛋白(FPN)编码基因，在髓系破骨细胞前体或成熟细胞中特异性缺失。FPN缺失轻微增加了前体破骨细胞和成熟破骨细胞中铁的水平，增加了前体细胞中铁的丢失，但不增加成熟细胞中的铁，增加了破骨细胞的生成，减少了体内的骨量。值得注意的是，这些表型在雌性小鼠中比在雄性小鼠中更明显。体外研究表明，细胞内铁的升高促进了巨噬细胞的增殖，并扩增了活化T细胞核因子1(NFATc1)和PPARG辅活化子1β(PGC-1β)的表达，这两种转录因子对破骨细胞的分化至关重要。然而，过量的铁并没有影响破骨细胞的存活。虽然铁的增加刺激了破骨细胞前体细胞的整体线粒体代谢，但对线粒体质量和活性氧的产生几乎没有影响。这些结果表明，FPN调节的细胞内铁水平对小鼠的线粒体代谢、破骨细胞形成和骨骼动态平衡至关重要。
Osteoporosis, osteopenia, and pathological bone fractures are frequent complications of iron-overload conditions such as hereditary hemochromatosis, thalassemia, and sickle cell disease. Moreover, animal models of iron overload have revealed increased bone resorption and decreased bone formation. Although systemic iron overload affects multiple organs and tissues, leading to significant changes on bone modeling and remodeling, the cell autonomous effects of excessive iron on bone cells remain unknown. Here, to elucidate the role of cellular iron homeostasis in osteoclasts, we generated two mouse strains in which solute carrier family 40 member 1 (Slc40a1), a gene encoding ferroportin (FPN), the sole iron exporter in mammalian cells, was specifically deleted in myeloid osteoclast precursors or mature cells. The FPN deletion mildly increased iron levels in both precursor and mature osteoclasts, and its loss in precursors, but not in mature cells, increased osteoclastogenesis and decreased bone mass in vivo. Of note, these phenotypes were more pronounced in female than in male mice. In vitro studies revealed that the elevated intracellular iron promoted macrophage proliferation and amplified expression of nuclear factor of activated T cells 1 (Nfatc1) and PPARG coactivator 1β (Pgc-1β), two transcription factors critical for osteoclast differentiation. However, the iron excess did not affect osteoclast survival. While increased iron stimulated global mitochondrial metabolism in osteoclast precursors, it had little influence on mitochondrial mass and reactive oxygen species production. These results indicate that FPN-regulated intracellular iron levels are critical for mitochondrial metabolism, osteoclastogenesis, and skeletal homeostasis in mice.
登录
查看更多内容
DOI：
10.1074/jbc.m113.478545
发表时间：
2013-08-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Kanzaki H;Shinohara F;Kajiya M;Kodama T
通讯作者：
Kodama T
影响因子：
6.2
作者：
Haibo Zhao;H. Väänänen
通讯作者：
Haibo Zhao;H. Väänänen
影响因子：
8
作者：
Fujiwara, Toshifumi;Ye, Shiqiao;Zhao, Haibo
通讯作者：
Zhao, Haibo
影响因子：
6.2
作者：
Kim, Haemin;Lee, Yong Deok;Kim, Hong-Hee
通讯作者：
Kim, Hong-Hee
影响因子：
3.6
作者：
Beaumont, Carole;Delaby, Constance
通讯作者：
Delaby, Constance