Notch signaling promotes osteoclast maturation and resorptive activity.
Notch signaling promotes osteoclast maturation and resorptive activity.
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DOI：
10.1002/jcb.25205
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发表时间：
2015-11
影响因子：
4
通讯作者：
Hankenson KD
中科院分区：
文献类型：
--
作者：
Ashley JW;Ahn J;Hankenson KD
Notch信号在破骨细胞分化中的作用是有争议的，有相互矛盾的实验证据表明刺激和抑制作用。实验方案和体内与体外模型的差异可以解释研究之间的差异。在这项研究中，我们研究了Notch信号在破骨细胞分化和功能中的细胞自主作用，通过使用固定化配体Jagged 1或Delta-like 1刺激或通过γ-分泌酶抑制剂DAPT或转录抑制剂SAHM 1抑制来改变破骨细胞分化期间的Notch信号。刺激定向破骨细胞前体中的Notch信号传导导致具有更多细胞核和再吸收活性的较大破骨细胞，而抑制导致具有较少细胞核和抑制再吸收活性的较小破骨细胞。相反，在诱导破骨细胞生成之前，刺激破骨细胞前体中的Notch信号传导导致更少的破骨细胞。我们的数据支持上下文特异性Notch信号传导效应的机制，其中Notch刺激抑制破骨细胞分化的承诺，但增强了承诺前体的成熟和功能。
The role of Notch signaling in osteoclast differentiation is controversial with conflicting experimental evidence indicating both stimulatory and inhibitory roles. Differences in experimental protocols and in vivo versus in vitro models may explain the discrepancies between studies. In this study, we investigated cell autonomous roles of Notch signaling in osteoclast differentiation and function by altering Notch signaling during osteoclast differentiation using stimulation with immobilized ligands Jagged1 or Delta-like1 or by suppression with γ-secretase inhibitor DAPT or transcriptional inhibitor SAHM1. Stimulation of Notch signaling in committed osteoclast precursors resulted in larger osteoclasts with a greater number of nuclei and resorptive activity whereas suppression resulted in smaller osteoclasts with fewer nuclei and suppressed resorptive activity. Conversely, stimulation of Notch signaling in osteoclast precursors prior to induction of osteoclastogenesis resulted in fewer osteoclasts. Our data support a mechanism of context-specific Notch signaling effects wherein Notch stimulation inhibits commitment to osteoclast differentiation, but enhances the maturation and function of committed precursors.