破骨细胞
骨质疏松症
肝细胞
串扰
细胞生物学
细胞外
骨髓
骨吸收
下调和上调
骨矿物
骨重建
肝细胞核因子4
癌症研究
化学
内科学
生物
内分泌学
医学
免疫学
受体
生物化学
体外
核受体
基因
转录因子
物理
光学
作者
Longshuai Lin,Zengya Guo,Enjun He,Xi-Dai Long,Difei Wang,Yingting Zhang,Weihong Guo,Wei Qian,Wei He,Wanying Wu,Jingchi Li,Lulu Wo,Dengli Hong,Junke Zheng,Ming He,Qinghua Zhao
标识
DOI:10.1038/s42255-023-00803-0
摘要
The interplay between liver and bone metabolism remains largely uncharacterized. Here, we uncover a mechanism of liver-bone crosstalk regulated by hepatocyte SIRT2. We demonstrate that hepatocyte SIRT2 expression is increased in aged mice and elderly humans. Liver-specific SIRT2 deficiency inhibits osteoclastogenesis and alleviates bone loss in mouse models of osteoporosis. We identify leucine-rich α-2-glycoprotein 1 (LRG1) as a functional cargo in hepatocyte-derived small extracellular vesicles (sEVs). In SIRT2-deficient hepatocytes, LRG1 levels in sEVs are upregulated, leading to increased transfer of LRG1 to bone-marrow-derived monocytes (BMDMs), and in turn, to inhibition of osteoclast differentiation via reduced nuclear translocation of NF-κB p65. Treatment with sEVs carrying high levels of LRG1 inhibits osteoclast differentiation in human BMDMs and in mice with osteoporosis, resulting in attenuated bone loss in mice. Furthermore, the plasma level of sEVs carrying LRG1 is positively correlated with bone mineral density in humans. Thus, drugs targeting hepatocyte-osteoclast communication may constitute a promising therapeutic strategy for primary osteoporosis.
科研通智能强力驱动
Strongly Powered by AbleSci AI