Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis.
Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis.
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DOI：
10.1038/srep09148
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发表时间：
2015-03-16
影响因子：
4.6
通讯作者：
Shimizu T
中科院分区：
文献类型：
--
作者：
Kobayashi K;Nojiri H;Saita Y;Morikawa D;Ozawa Y;Watanabe K;Koike M;Asou Y;Shirasawa T;Yokote K;Kaneko K;Shimizu T
骨细胞是主要的骨细胞，在维持骨组织的质量和愈合骨组织损伤方面起着至关重要的作用。活骨细胞和骨小管网络的数量以年龄依赖性方式下降。然而，线粒体氧化还原失衡对骨细胞和骨代谢的病理影响尚未完全阐明。我们产生的小鼠缺乏线粒体超氧化物歧化酶2（SOD 2）的骨细胞。就像一个老化的骨头，在骨细胞中的Sod 2消耗积极增强体内细胞超氧化物的产生。骨形态学分析表明，SOD 2缺乏股骨表现出显着的骨丢失在一个年龄依赖性的方式。有趣的是，Sod 2的丢失诱导骨细胞小管网络明显紊乱，并减少了活骨细胞的数量。此外，Sod 2缺乏显著抑制骨形成并增加骨吸收，同时上调硬化素和NF-κB配体受体激活剂（RANKL）。体外实验还显示，百草枯（一种线粒体中的超氧化物诱导剂）处理可部分通过ERK磷酸化促进RANKL表达。这些结果表明，通过Sod 2消融在骨细胞中诱导的线粒体超氧化物导致年龄相关性骨丢失，这是由于骨小管网络受损和骨代谢通过sclerostin和RANKL表达失调引起的。
Osteocytes are major bone cells that play a crucial role in maintaining the quality of and healing damage to bone tissue. The number of living osteocytes and canalicular networks declines in an age-dependent manner. However, the pathological effects of mitochondrial redox imbalances on osteocytes and bone metabolism have not been fully elucidated. We generated mice lacking mitochondrial superoxide dismutase 2 (Sod2) in osteocytes. Like an aged bone, Sod2 depletion in the osteocytes positively enhanced the production of cellular superoxide in vivo. A bone morphological analysis demonstrated that the Sod2-deficient femurs showed remarkable bone loss in an age-dependent manner. Interestingly, Sod2 loss induced markedly disorganized osteocytic canalicular networks and decreased the number of live osteocytes. Furthermore, Sod2 deficiency significantly suppressed bone formation and increased bone resorption concomitant with the upregulation of sclerostin and receptor activator of NF-κB ligand (RANKL). In vitro experiments also revealed that treatment with paraquat, a superoxide inducer in mitochondria, promoted the RANKL expression via, in part, ERK phosphorylation. These findings demonstrate that the mitochondrial superoxide induced in osteocytes by Sod2 ablation causes age-related bone loss due to the impairment of canalicular networks and bone metabolism via the deregulation of the sclerostin and RANKL expression.