The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis.
The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis.
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DOI：
10.1084/jem.20091957
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发表时间：
2010-04-12
期刊：
影响因子：
--
通讯作者：
Miyamoto T
中科院分区：
文献类型：
--
作者：
Miyauchi Y;Ninomiya K;Miyamoto H;Sakamoto A;Iwasaki R;Hoshi H;Miyamoto K;Hao W;Yoshida S;Morioka H;Chiba K;Kato S;Tokuhisa T;Saitou M;Toyama Y;Suda T;Miyamoto T
控制破骨细胞生成对于维持生理性骨稳态和预防骨骼疾病至关重要。虽然信号活化活化的T细胞的核因子1（NFATc 1），破骨细胞生成所必需的转录因子，已被深入研究，因子拮抗破骨细胞中的NFATc 1尚未被表征。在这里，我们描述了一种新的途径，通过两个转录抑制因子，B细胞淋巴瘤6（Bcl 6）和B淋巴细胞诱导的成熟蛋白-1（Blimp 1），维持骨稳态。我们发现Bcl 6直接靶向“骨细胞”分子，如NFATc 1，组织蛋白酶K和树突状细胞特异性跨膜蛋白（DC-STAMP），所有这些都是NFATc 1的靶点。Bcl 6过表达抑制体外破骨细胞生成，而Bcl 6缺陷小鼠破骨细胞分化加速和严重的骨质疏松。我们报道Bcl 6是Blimp 1的直接靶点，破骨细胞中缺乏Blimp 1的小鼠表现出由Bcl 6上调导致的破骨细胞生成受损引起的骨硬化症。事实上，与破骨细胞特异性Blimp 1缺陷小鼠相比，破骨细胞中Blimp 1和Bcl 6双重突变的小鼠表现出骨质减少，破骨细胞生成增加。这些结果揭示了Blimp 1-Bcl 6-骨细胞分子轴，它通过控制破骨细胞生成来严格调节骨稳态，并可能为新的治疗策略提供分子基础。
Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte–induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets ‘osteoclastic’ molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1–Bcl6–osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies.
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影响因子：
15.3
作者：
Asagiri, M;Sato, K;Takayanagi, H
通讯作者：
Takayanagi, H
Bcl6基因的破坏会导致生发中心形成受损。
DOI：
10.1084/jem.186.3.439
发表时间：
1997-08-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fukuda T;Yoshida T;Okada S;Hatano M;Miki T;Ishibashi K;Okabe S;Koseki H;Hirosawa S;Taniguchi M;Miyasaka N;Tokuhisa T
通讯作者：
Tokuhisa T
影响因子：
20.3
作者：
Kim, Kabsun;Kim, Jung Ha;Kim, Nacksung
通讯作者：
Kim, Nacksung
影响因子：
30.8
作者：
Ng, D;Thakker, N;Biesecker, LG
通讯作者：
Biesecker, LG
影响因子：
10.5
作者：
Dougall, WC;Glaccum, M;Schuh, J
通讯作者：
Schuh, J