Beclin1 Modulates Bone Homeostasis by Regulating Osteoclast and Chondrocyte Differentiation.
Beclin1 Modulates Bone Homeostasis by Regulating Osteoclast and Chondrocyte Differentiation.
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DOI：
10.1002/jbmr.3756
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发表时间：
2019-09
影响因子：
6.2
通讯作者：
Kim, Reuben H.
中科院分区：
文献类型：
--
作者：
Arai, Atsushi;Kim, Sol;Goldshteyn, Vadim;Kim, Terresa;Park, No-Hee;Wang, Cun-Yu;Kim, Reuben H.
自噬是一种重要的细胞再循环过程，自噬体包裹大分子或细胞器，并在与溶酶体融合后降解，最近被证明在骨生物学中起着重要作用。然而，自噬在骨和骨相关细胞中的参与仍不清楚。在这里，我们表明，Beclin1，自噬相关（ATG）蛋白参与自噬启动，在破骨细胞中起着关键作用。体外破骨细胞分化过程中自噬被激活。Beclin1表达增强，是破骨细胞分化所必需的。从机制上讲，我们发现TRAF6介导的Beclin 1在K117的泛素化，而不是ULK 1介导的磷酸化，是RANKL刺激的破骨细胞分化所必需的。在体内，CstK表达细胞中缺乏Becn 1的小鼠由于破骨细胞功能受损而表现出皮质骨厚度增加。有趣的是，这些小鼠也表现出减少的小梁骨量，这与软骨形成和软骨细胞分化的缺陷有关。总的来说，我们的研究强调了自噬在破骨细胞和软骨细胞中的功能重要性，并将自噬确定为管理骨相关疾病的潜在治疗靶点。
Autophagy, an important cellular recycling process whereby macromolecules or organelles are encapsulated by autophagosome and degraded upon merging with lysosome, is recently shown to play an essential role in bone biology. However, the involvement of autophagy in bone and bone-related cells remains unclear. Here, we show that Beclin1, an autophagy-related (ATG) protein involved in autophagy initiation, plays a pivotal role in osteoclasts. Autophagy was activated during osteoclast differentiation in vitro. Beclin1 was enhanced and required for osteoclast differentiation. Mechanistically, we found that TRAF6-mediated ubiquitination of Beclin1 at K117, but not ULK1-mediated phosphorylation, is required for RANKL-stimulated osteoclast differentiation. In vivo, mice lacking Becn1 in CstK-expressing cells exhibited in increased cortical bone thickness due to impaired osteoclasts’ function. Interestingly, these mice also exhibited diminished trabecular bone mass, which was associated with defect in cartilage formation and chondrocyte differentiation. Collectively, our study highlights the functional importance of autophagy in osteoclasts and chondrocytes, and identifies autophagy as a potential therapeutic target for managing bone-related diseases.
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影响因子：
4.4
作者：
Lee, Hye-Mi;Shin, Dong-Min;Jo, Eun-Kyeong
通讯作者：
Jo, Eun-Kyeong
影响因子：
6.2
作者：
Gowen, M;Lazner, F;Kola, I
通讯作者：
Kola, I
影响因子：
4.8
作者：
Feng, Yunfeng;Zhao, Haibo;Longmore, Gregory D.
通讯作者：
Longmore, Gregory D.
影响因子：
10.5
作者：
Dougall, WC;Glaccum, M;Schuh, J
通讯作者：
Schuh, J
影响因子：
56.9
作者：
BLAIR, HC;TEITELBAUM, SL;GLUCK, S
通讯作者：
GLUCK, S