Department of Molecular Medicine, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu 41944, Republic of Korea.
Department of Food and Biotechnology, Korea University, Sejong 30019, Republic of Korea.
Bone. 2019 Dec;129:115056. doi: 10.1016/j.bone.2019.115056. Epub 2019 Aug 31.
Mitochondria are not only responsible for cellular energy production but are also involved in signaling, cellular differentiation, cell death, and aging. Mitochondrial NADP-dependent isocitrate dehydrogenase (IDH2) catalyzes the decarboxylation of isocitrate to α-ketoglutarate, accompanied by NADPH production. IDH2 plays a central role in mitochondrial function in multiple cell types and various organs, including the heart, kidneys, and brain. However, the function of IDH2 in bone tissue is yet to be elucidated. Here, we report that disruption of IDH2 in mice results in high bone mass due to decreased osteoclast number and resorption activity. Although IDH2 played no cell-intrinsic role in osteoclasts, IDH2-deficient animals showed decreased serum markers of osteoclast activity and bone resorption. Bone marrow stromal cells/osteoblasts from Idh2 knockout mice were defective in promoting osteoclastogenesis due to a reduced expression of a key osteoclastogenic factor, receptor activator of nuclear factor-κB ligand (RANKL), in osteoblasts in vivo and in vitro through the attenuation of ATF4-NFATc1 signaling. Our findings suggest that IDH2 is a novel regulator of osteoblast-to-osteoclast communication and bone metabolism, acting via the ATF4-NFATc1-RANKL signaling axis in osteoblasts, and they provide a rationale for further study of IDH2 as a potential therapeutic target for the prevention of bone loss.
线粒体不仅负责细胞能量产生，还参与信号转导、细胞分化、细胞死亡和衰老。线粒体 NADP 依赖性异柠檬酸脱氢酶 (IDH2) 催化异柠檬酸脱羧生成 α-酮戊二酸，同时产生 NADPH。IDH2 在多种细胞类型和各种器官（包括心脏、肾脏和大脑）的线粒体功能中发挥核心作用。然而，IDH2 在骨组织中的功能尚未阐明。在这里，我们报告说，由于破骨细胞数量和吸收活性降低，小鼠中 IDH2 的破坏导致骨量增加。尽管 IDH2 在破骨细胞中没有发挥细胞内在作用，但 IDH2 缺陷动物的血清破骨细胞活性和骨吸收标志物降低。由于 IDH2 敲除小鼠的骨髓基质细胞/成骨细胞中关键破骨细胞生成因子核因子κB 受体激活剂配体 (RANKL) 的表达减少，通过体内和体外 ATF4-NFATc1 信号的衰减，它们在促进破骨细胞生成方面存在缺陷。我们的发现表明 IDH2 是成骨细胞向破骨细胞通讯和骨代谢的新型调节剂，通过成骨细胞中的 ATF4-NFATc1-RANKL 信号轴发挥作用，为进一步研究 IDH2 作为预防骨丢失的潜在治疗靶点提供了依据。
