Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells.
Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells.
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DOI：
10.1182/blood-2002-06-1740
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发表时间：
2003-03
期刊：
影响因子：
20.3
通讯作者：
Takayuki Yamada;H. Yamazaki;T. Yamane;M. Yoshino;H. Okuyama;M. Tsuneto;Tomomi Kurino;S. Hayashi;S. Sakano
中科院分区：
文献类型：
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作者：
Takayuki Yamada;H. Yamazaki;T. Yamane;M. Yoshino;H. Okuyama;M. Tsuneto;Tomomi Kurino;S. Hayashi;S. Sakano
破骨细胞来源于属于单核细胞/巨噬细胞谱系的造血前体细胞。据报道，破骨细胞的发育受到几种分子的调节，例如巨噬细胞集落刺激因子（M-CSF）、核因子（NF）-κ B配体（RANKL）的受体激活剂和RANKL的诱饵受体骨保护素（OPG）。近年来研究表明，Notch信号通路调控骨髓分化，拮抗细胞命运决定，但Notch信号通路对破骨细胞系的影响尚未见报道。在这项研究中，我们研究了通过Notch受体的信号传导的影响，通过使用细胞从骨髓，脾，腹腔和克隆的巨噬细胞样细胞系分化成破骨细胞。破骨细胞生成被固定的Notch配体Delta-1抑制。用M-CSF预培养的培养皿贴壁骨髓细胞表达Mac-1和M-CSF受体c-Fms;这些细胞的破骨细胞生成被有效抑制。固定化Delta-1还下调了表面c-Fms的表达，而c-Fms基因的表达没有改变。Notch受体和Notch配体的基因不仅在造血细胞中表达，而且在支持破骨细胞发育的基质细胞中表达。组成型活性Notch 1转染的基质细胞显示RANKL和OPG基因表达增加，M-CSF基因表达强烈抑制，导致其支持破骨细胞发育的能力降低。总之，这些发现表明Notch信号传导影响破骨细胞前体和基质细胞，从而负调节破骨细胞生成。
Osteoclasts are derived from hematopoietic precursor cells belonging to the monocyte/macrophage lineage. Osteoclast development has been reported to be regulated by several molecules such as macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor (NF)-kappaB ligand (RANKL), and a decoy receptor of RANKL, osteoprotegerin (OPG). Recently, it was demonstrated that the Notch signaling pathway regulates myeloid differentiation and antagonizes cell fate determination, however, the effect of Notch signaling on the osteoclast lineage has not been reported. In this study, we examined the effect of signaling via Notch receptors on the differentiation into osteoclasts by using cells from the bone marrow, spleen, and peritoneal cavity, and a cloned macrophagelike cell line. Osteoclastogenesis was inhibited by an immobilized Notch ligand, Delta-1. The dish-adherent bone marrow cells precultured with M-CSF expressed both Mac-1 and M-CSF receptors, c-Fms; osteoclastogenesis of these cells was efficiently inhibited. The immobilized Delta-1 also down-regulated the surface c-Fms expression, while the c-Fms gene expression was not changed. Genes for Notch receptors and Notch ligands are expressed in not only hematopoietic cells but also stromal cells that support osteoclast development. Constitutively active Notch1-transfected stromal cells showed increased expression of RANKL and OPG genes, and strong inhibition of M-CSF gene expression, resulting in reduction of their ability to support osteoclast development. Taken together, these findings indicate that Notch signaling affects both osteoclast precursors and stromal cells and thereby negatively regulates osteoclastogenesis.