Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation.
Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation.
复制标题
DOI：
10.1002/jbmr.1971
复制
发表时间：
2013-11
影响因子：
6.2
通讯作者：
Guan, Jun-Lin
中科院分区：
文献类型：
--
作者：
Liu, Fei;Fang, Fang;Yuan, Hebao;Yang, Dongye;Chen, Yongqiang;Williams, Linford;Goldstein, Steven A.;Krebsbach, Paul H.;Guan, Jun-Lin
自噬是一种保守的溶酶体降解过程，在人类正常生理和疾病中具有重要作用。然而，自噬在骨稳态中的功能还不清楚。在这里，我们报告说，自噬被激活成骨细胞分化。FIP 200的消融（200 kD的粘着斑激酶家族相互作用蛋白），哺乳动物自噬的重要组成部分，导致成骨细胞中的多种自噬缺陷，包括异常增加的p62表达，缺陷的LC 3-II转化，缺陷的自噬通量，在表达转基因GFP-LC 3的FIP 200缺失成骨细胞中缺乏GFP-LC 3斑点，通过电子显微镜检查类似的结构。成骨细胞特异性FIP 200缺失导致小鼠骨质减少。组织形态计量学分析显示，骨量减少是由于FIP 200缺失对成骨细胞的细胞自主性影响。FIP 200缺失导致体外原代骨髓和颅骨成骨细胞终末分化缺陷。有趣的是，在早期培养物中，增殖和分化都没有受到FIP 200缺失的不利影响。然而，FIP 200缺失导致成骨细胞在初始增殖和分化后形成缺陷性结节。此外，用自噬抑制剂处理概括了FIP 200缺失对成骨细胞分化的影响。总之，这些数据确定FIP 200作为骨发育的重要调节因子，并通过其在支持成骨细胞结节形成和分化中的积极作用揭示了自噬在成骨细胞功能中的新作用。
Autophagy is a conserved lysosomal degradation process that has important roles in both normal human physiology and disease. However, the function of autophagy in bone homeostasis is not well understood. Here, we report that autophagy is activated during osteoblast differentiation. Ablation of FIP200 (focal adhesion kinase family interacting protein of 200 kD), an essential component of mammalian autophagy, led to multiple autophagic defects in osteoblasts including aberrantly increased p62 expression, deficient LC3-II conversion, defective autophagy flux, absence of GFP-LC3 puncta in FIP200-null osteoblasts expressing transgenic GFP-LC3 and absence of autophagosome-like structures by electron microscope examination. Osteoblast-specific deletion of FIP200 led to osteopenia in mice. Histomorphometric analysis revealed that the osteopenia was due to cell-autonomous effects of FIP200 deletion on osteoblasts. FIP200 deletion led to defective osteoblast terminal differentiation in both primary bone marrow and calvarial osteoblasts in vitro. Interestingly, both proliferation and differentiation were not adversely affected by FIP200 deletion in early cultures. However, FIP200 deletion led to defective osteoblast nodule formation after initial proliferation and differentiation. Furthermore, treatment with autophagy inhibitors recapitulated the effects of FIP200 deletion on osteoblast differentiation. Taken together, these data identify FIP200 as an important regulator of bone development and reveal a novel role of autophagy in osteoblast function through its positive role in supporting osteoblast nodule formation and differentiation.
登录
查看更多内容
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
64.8
作者：
Fimia, Gian Maria;Stoykova, Anastassia;Cecconi, Francesco
通讯作者：
Cecconi, Francesco
影响因子：
3.3
作者：
Jung, Chang Hwa;Jun, Chang Bong;Kim, Do-Hyung
通讯作者：
Kim, Do-Hyung
影响因子：
0.7
作者：
Liu, F;Woitge, HW;Kream, BE
通讯作者：
Kream, BE
影响因子：
13.3
作者：
Hara, Taichi;Mizushima, Noboru
通讯作者：
Mizushima, Noboru