Xu Song, Zhang Yue, Liu Bin, Li Kai, Huang Bin, Yan Bo, Zhang Zhongmin, Liang Kangyan, Jia Chunhong, Lin Jun, Zeng Chun, Cai Daozhang, Jin Dadi, Jiang Yu, Bai Xiaochun
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
J Bone Miner Res. 2016 Jul;31(7):1320-33. doi: 10.1002/jbmr.2800. Epub 2016 Mar 4.
The cytokine receptor activator of nuclear factor-κB ligand (RANKL) induces osteoclast formation from monocyte/macrophage lineage cells. However, the mechanisms by which RANKL expression is controlled in cells that support osteoclast differentiation are still unclear. We show that deletion of TSC1 (tuberous sclerosis complex 1) in murine B cells causes constitutive activation of mechanistic target of rapamycin complex 1 (mTORC1) and stimulates RANKL but represses osteoprotegerin (OPG) expression and subsequently promotes osteoclast formation and causes osteoporosis in mice. Furthermore, the regulation of RANKL/OPG and stimulation of osteoclastogenesis by mTORC1 was confirmed in a variety of RANKL-expressing cells and in vivo. Mechanistically, mTORC1 controls RANKL/OPG expression through negative feedback inactivation of Akt, destabilization of β-catenin mRNA, and downregulation of β-catenin. Our findings demonstrate that mTORC1 activation-stimulated RANKL expression in B cells is sufficient to induce bone loss and osteoporosis. The study also established a link between mTORC1 and the RANKL/OPG axis via negative regulation of β-catenin. © 2016 American Society for Bone and Mineral Research.
核因子κB受体活化因子配体（RANKL）可诱导单核细胞/巨噬细胞系细胞形成破骨细胞。然而，在支持破骨细胞分化的细胞中，RANKL表达的调控机制仍不清楚。我们发现，小鼠B细胞中结节性硬化复合物1（TSC1）的缺失会导致雷帕霉素机制靶点复合物1（mTORC1）的组成性激活，刺激RANKL表达，但抑制骨保护素（OPG）表达，随后促进破骨细胞形成并导致小鼠骨质疏松。此外，在多种表达RANKL的细胞和体内均证实了mTORC1对RANKL/OPG的调控以及对破骨细胞生成的刺激作用。机制上，mTORC1通过Akt的负反馈失活、β-连环蛋白mRNA的不稳定以及β-连环蛋白的下调来控制RANKL/OPG的表达。我们的研究结果表明，mTORC1激活刺激B细胞中RANKL的表达足以导致骨质流失和骨质疏松。该研究还通过对β-连环蛋白的负调控建立了mTORC1与RANKL/OPG轴之间的联系。© 2016美国骨与矿物质研究学会。
