Maintenance of Bone Homeostasis by DLL1-Mediated Notch Signaling.
Maintenance of Bone Homeostasis by DLL1-Mediated Notch Signaling.
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DOI：
10.1002/jcp.25647
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发表时间：
2017-09
影响因子：
5.6
通讯作者：
Ando K
中科院分区：
文献类型：
--
作者：
Muguruma Y;Hozumi K;Warita H;Yahata T;Uno T;Ito M;Ando K
成人骨量是通过成骨细胞和破骨细胞的活动平衡来维持的。虽然Notch信号已被证明通过控制成骨细胞和破骨细胞谱系中细胞的定型、分化和功能来维持骨稳态，但Notch在骨生理学中发挥如此多样和复杂作用的确切机制仍不清楚。通过使用转基因方法，以成骨细胞特异性的方式修饰δ样1（DLL 1）或Jagged 1（JAG 1）的表达，我们研究了Notch信号在骨稳态中的配体特异性作用。这项研究首次证明，在成骨细胞中，DLL 1表达的适当调节，而不是JAG 1表达，对于维持骨重建至关重要。DLL 1诱导的Notch信号传导通过促进定向但未成熟的成骨细胞的增殖来负责骨形成细胞库的扩增。然而，DLL 1-Notch信号抑制了扩增成骨细胞的进一步分化，使其成为完全成熟的功能性成骨细胞，从而大大减少了骨形成。DLL 1的成骨细胞特异性表达不改变破骨细胞谱系细胞的内在分化能力。然而，由DLL 1转基因引起的成骨细胞的成熟停滞由于成骨细胞-破骨细胞偶联失败而损害破骨细胞的成熟和功能，导致骨代谢转换的严重抑制。总而言之，DLL 1介导的Notch信号传导对于适当的骨重建至关重要，因为它调节成骨细胞和破骨细胞的分化和功能。我们的研究阐明了Notch信号的配体特异性激活在维持骨稳态中的重要性。J.细胞。232：2569-2580，2017。© 2016作者。细胞生理学杂志由Wiley Periodicals Inc.出版。
Adult bone mass is maintained through a balance of the activities of osteoblasts and osteoclasts. Although Notch signaling has been shown to maintain bone homeostasis by controlling the commitment, differentiation, and function of cells in both the osteoblast and osteoclast lineages, the precise mechanisms by which Notch performs such diverse and complex roles in bone physiology remain unclear. By using a transgenic approach that modified the expression of delta‐like 1 (DLL1) or Jagged1 (JAG1) in an osteoblast‐specific manner, we investigated the ligand‐specific effects of Notch signaling in bone homeostasis. This study demonstrated for the first time that the proper regulation of DLL1 expression, but not JAG1 expression, in osteoblasts is essential for the maintenance of bone remodeling. DLL1‐induced Notch signaling was responsible for the expansion of the bone‐forming cell pool by promoting the proliferation of committed but immature osteoblasts. However, DLL1‐Notch signaling inhibited further differentiation of the expanded osteoblasts to become fully matured functional osteoblasts, thereby substantially decreasing bone formation. Osteoblast‐specific expression of DLL1 did not alter the intrinsic differentiation ability of cells of the osteoclast lineage. However, maturational arrest of osteoblasts caused by the DLL1 transgene impaired the maturation and function of osteoclasts due to a failed osteoblast‐osteoclast coupling, resulting in severe suppression of bone metabolic turnover. Taken together, DLL1‐mediated Notch signaling is critical for proper bone remodeling as it regulates the differentiation and function of both osteoblasts and osteoclasts. Our study elucidates the importance of ligand‐specific activation of Notch signaling in the maintenance of bone homeostasis. J. Cell. Physiol. 232: 2569–2580, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals Inc.