Defective autophagy in osteoblasts induces endoplasmic reticulum stress and causes remarkable bone loss
Defective autophagy in osteoblasts induces endoplasmic reticulum stress and causes remarkable bone loss
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成骨细胞的自噬缺陷会诱导内质网应激并导致显着的骨质流失
DOI：
10.1080/15548627.2018.1483807
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发表时间：
2018-01-01
期刊：
影响因子：
13.3
通讯作者：
Wu, Shufang
中科院分区：
文献类型：
--
作者：
Li, Huixia;Li, Danhui;Wu, Shufang
摘要自噬是一个高度调节的过程，参与细胞质成分的转换，但其在维持骨稳态中的关键作用仍然是难以捉摸的。在本研究中，我们研究了ATG 7（自噬相关7）在体内发育和重塑阶段的直接作用，使用成骨细胞特异性Atg 7条件性敲除（cKO）小鼠。Atg 7 cKO小鼠在发育期和成年期均表现出骨量减少。在5月龄时，Atg 7 cKO小鼠的骨小梁体积显著低于对照组。该表型归因于成骨细胞形成和基质矿化减少，伴有破骨细胞数量增加和破骨细胞覆盖的骨表面范围以及TNFSF 11/RANKL（肿瘤坏死因子[配体]超家族，成员11）分泌增加和TNFRSF 11B/OPG（肿瘤坏死因子受体超家族，成员11b [骨保护素]）减少。值得注意的是，Atg 7缺乏成骨细胞触发内质网（ER）的压力，而衰减的ER压力，通过管理的苯丁酸在体内废除Atg 7消融介导的成骨细胞分化，矿化能力和骨形成的影响。结论：Atg 7缺陷在体外以DDIT 3/CHOP（DNA损伤诱导转录本3）-和MAPK 8/JNK 1（丝裂原活化蛋白激酶8）-SMAD 1/5/8依赖的方式抑制成骨细胞矿化并促进细胞凋亡，而Atg 7重建可改善ER应激，恢复骨骼平衡。总之，我们的研究结果提供了直接的证据，自噬在调节骨稳态中起着至关重要的作用，并提出了一个创新的治疗策略，对骨骼疾病。
ABSTRACT Macroautophagy/autophagy is a highly regulated process involved in the turnover of cytosolic components, however its pivotal role in maintenance of bone homeostasis remains elusive. In the present study, we investigated the direct role of ATG7 (autophagy related 7) during developmental and remodeling stages in vivo using osteoblast-specific Atg7 conditional knockout (cKO) mice. Atg7 cKO mice exhibited a reduced bone mass at both developmental and adult age. The trabecular bone volume of Atg7 cKO mice was significantly lower than that of controls at 5 months of age. This phenotype was attributed to decreased osteoblast formation and matrix mineralization, accompanied with an increased osteoclast number and the extent of the bone surface covered by osteoclasts as well as an elevated secretion of TNFSF11/RANKL (tumor necrosis factor [ligand] superfamily, member 11), and a decrease in TNFRSF11B/OPG (tumor necrosis factor receptor superfamily, member 11b [osteoprotegerin]). Remarkably, Atg7 deficiency in osteoblasts triggered endoplasmic reticulum (ER) stress, whereas attenuation of ER stress by administration of phenylbutyric acid in vivo abrogated Atg7 ablation-mediated effects on osteoblast differentiation, mineralization capacity and bone formation. Consistently, Atg7 deficiency impeded osteoblast mineralization and promoted apoptosis partially in DDIT3/CHOP (DNA-damage-inducible transcript 3)- and MAPK8/JNK1 (mitogen-activated protein kinase 8)-SMAD1/5/8-dependent manner in vitro, while reconstitution of Atg7 could improve ER stress and restore skeletal balance. In conclusion, our findings provide direct evidences that autophagy plays crucial roles in regulation of bone homeostasis and suggest an innovative therapeutic strategy against skeletal diseases.