Notch signaling is involved in Fgf23 upregulation in osteocytes.
Notch signaling is involved in Fgf23 upregulation in osteocytes.
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Notch 信号传导参与骨细胞中 Fgf23 的上调。
DOI：
10.1016/j.bbrc.2019.08.038
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Yamaguchi A.
中科院分区：
文献类型：
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作者：
Tamamura Y;Sakamoto K;Katsube KI;Yamaguchi A.
Fgf23是骨细胞分泌的一种磷酸化因子，但其调控机制尚不完全清楚。在这里，我们展示了Fgf23、Notch和Hes1 （Notch信号的下游靶点）在野生型小鼠股骨皮质骨的许多骨细胞中的共定位。我们用2.3 kb的胶原α1 (I) （Col1a1）启动子片段驱动了NICD （Notch胞内结构域）转基因小鼠。Western blot和RT-PCR分析显示，与野生型小鼠相比，转基因小鼠骨骼中Notch蛋白和mRNA水平上调。在转基因小鼠中，免疫组织化学研究表明，肋骨中有许多骨细胞和成骨细胞表达Notch，而股骨中只有成骨细胞表达Notch。与野生型小鼠相比，nicd转基因小鼠的特点是肋骨的ofFgf23 mRNA水平上调，而股骨的ofFgf23 mRNA水平上调。这些小鼠表现出与骨软化表型相关的侏儒症。与野生型小鼠相比，nicd转基因小鼠中alpl、Col1a1和bglap的表达下降。在jagged1固定孔上培养的UMR-106 细胞显著增加fgf23的表达，并上调hes1和hey1。这些结果表明Notch信号是骨细胞中Fgf23表达的积极调节因子。
Fgf23 acts as a phosphaturic factor secreted from osteocytes in bone, but the mechanism regulating Fgf23 is not fully understood. Here, we showed the colocalization of Fgf23, Notch, and Hes1, a downstream target of Notch signaling, in numerous osteocytes in cortical bone of femur in wild-type mice. We generated NICD (Notch intracellular domain)-transgenic mice driven by a 2.3 kb collagenα1 (I) (Col1a1) promoter fragment. Western blot and RT-PCR analyses revealed upregulation of Notch protein and mRNA levels in the bones of transgenic mice compared with those in wild-type mice. In the transgenic mice, immunohistochemical studies demonstrated that numerous osteocytes and osteoblasts express Notch in the rib, whereas only osteoblasts exhibit Notch in the femur.NICD-transgenic mice were characterized by upregulation ofFgf23 mRNA levels in the rib but not in the femur compared with that in wild type mice. These mice exhibited dwarfism associated with an osteomalacia phenotype. The expression ofAlpl, Col1a1, andBglapdecreased in NICD-transgenic mice compared with wild-type mice. UMR-106 cells cultured on Jagged1-immobilized wells significantly increasedFgf23expressions associating with upregulation ofHes1andHey1. These results imply that Notch signaling is a positive regulator for Fgf23 expression in osteocytes.