FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation.
FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation.
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DOI：
10.1038/ncomms4773
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发表时间：
2014-04-30
影响因子：
16.6
通讯作者：
Almeida, Maria
中科院分区：
文献类型：
--
作者：
Bartell, Shoshana M.;Kim, Ha-Neui;Ambrogini, Elena;Han, Li;Iyer, Srividhya;Ucer, S. Serra;Rabinovitch, Peter;Jilka, Robert L.;Weinstein, Robert S.;Zhao, Haibo;O'Brien, Charles A.;Manolagas, Stavros C.;Almeida, Maria
除了在氧化应激环境下的细胞损伤作用外，活性氧（ROS）还通过触发细胞增殖和存活，在生理细胞内信号传导中发挥重要作用。FoxO转录因子通过上调抗氧化酶来抵消ROS的产生。在这里，我们发现细胞内H2O2积累是破骨细胞分化和存活的关键和有目的的适应，破骨细胞负责矿化骨基质的吸收。通过小鼠FoxO转录因子功能的条件丧失或获得，或破骨细胞中线粒体靶向过氧化氢酶，我们证明了这是通过下调h2o2灭活酶过氧化氢酶来实现的，至少部分是这样。过氧化氢酶下调是由于破骨细胞生成不可或缺的信号RANKL通过akt介导的机制抑制FoxO1、3和4的转录活性。值得注意的是，线粒体靶向过氧化氢酶可防止雌激素丢失引起的骨丢失，这表明减少线粒体中H2O2的产生可能是骨吸收增加疾病的合理药物治疗方法。破骨细胞是在骨质疏松症等疾病中导致骨量流失的骨吸收细胞。在这里，作者表明破骨细胞的增殖和存活受FoxO家族转录因子的调节，FoxO家族转录因子控制信号分子过氧化氢的水平。
Besides their cell-damaging effects in the setting of oxidative stress, reactive oxygen species (ROS) play an important role in physiological intracellular signalling by triggering proliferation and survival. FoxO transcription factors counteract ROS generation by upregulating antioxidant enzymes. Here we show that intracellular H2O2 accumulation is a critical and purposeful adaptation for the differentiation and survival of osteoclasts, the bone cells responsible for the resorption of mineralized bone matrix. Using mice with conditional loss or gain of FoxO transcription factor function, or mitochondria-targeted catalase in osteoclasts, we demonstrate this is achieved, at least in part, by downregulating the H2O2-inactivating enzyme catalase. Catalase downregulation results from the repression of the transcriptional activity of FoxO1, 3 and 4 by RANKL, the indispensable signal for the generation of osteoclasts, via an Akt-mediated mechanism. Notably, mitochondria-targeted catalase prevented the loss of bone caused by loss of oestrogens, suggesting that decreasing H2O2 production in mitochondria may represent a rational pharmacotherapeutic approach to diseases with increased bone resorption. Osteoclasts are bone-resorbing cells responsible for the loss of bone mass in diseases such as osteoporosis. Here the authors show that osteoclast proliferation and survival is regulated by FoxO family transcription factors, which control levels of the signalling molecule hydrogen peroxide.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
29
作者：
Ambrogini E;Almeida M;Martin-Millan M;Paik JH;Depinho RA;Han L;Goellner J;Weinstein RS;Jilka RL;O'Brien CA;Manolagas SC
通讯作者：
Manolagas SC
影响因子：
3.3
作者：
Destaing, O;Saltel, F;Bard, F
通讯作者：
Bard, F
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
20.1
作者：
Dai DF;Johnson SC;Villarin JJ;Chin MT;Nieves-Cintrón M;Chen T;Marcinek DJ;Dorn GW 2nd;Kang YJ;Prolla TA;Santana LF;Rabinovitch PS
通讯作者：
Rabinovitch PS