Qiu Tao, Crane Janet L, Xie Liang, Xian Lingling, Xie Hui, Cao Xu
1Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA.
2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD USA.
Bone Res. 2018 Feb 26;6:5. doi: 10.1038/s41413-017-0002-7. eCollection 2018.
Parathyroid hormone (PTH) regulates bone remodeling by activating PTH type 1 receptor (PTH1R) in osteoblasts/osteocytes. Insulin-like growth factor type 1 (IGF-1) stimulates mesenchymal stem cell differentiation to osteoblasts. However, little is known about the signaling mechanisms that regulates the osteoblast-to-osteocyte transition. Here we report that PTH and IGF-I synergistically enhance osteoblast-to-osteocyte differentiation. We identified that a specific tyrosine residue, Y494, on the cytoplasmic domain of PTH1R can be phosphorylated by insulin-like growth factor type I receptor (IGF1R) in vitro. Phosphorylated PTH1R localized to the barbed ends of actin filaments and increased actin polymerization during morphological change of osteoblasts into osteocytes. Disruption of the phosphorylation site reduced actin polymerization and dendrite length. Mouse models with conditional ablation of PTH1R in osteoblasts demonstrated a reduction in the number of osteoctyes and dendrites per osteocyte, with complete overlap of PTH1R with phosphorylated-PTH1R positioning in osteocyte dendrites in wild-type mice. Thus, our findings reveal a novel signaling mechanism that enhances osteoblast-to-osteocyte transition by direct phosphorylation of PTH1R by IGF1R.
甲状旁腺激素（PTH）通过激活成骨细胞/骨细胞中的1型甲状旁腺激素受体（PTH1R）来调节骨重塑。胰岛素样生长因子1（IGF-1）刺激间充质干细胞分化为成骨细胞。然而，关于调节成骨细胞向骨细胞转变的信号机制知之甚少。在此，我们报告PTH和IGF-I协同增强成骨细胞向骨细胞的分化。我们发现，PTH1R细胞质结构域上的一个特定酪氨酸残基Y494在体外可被胰岛素样生长因子1受体（IGF1R）磷酸化。磷酸化的PTH1R定位于肌动蛋白丝的尖端，并在成骨细胞向骨细胞形态变化过程中增加肌动蛋白聚合。磷酸化位点的破坏减少了肌动蛋白聚合和树突长度。在成骨细胞中条件性敲除PTH1R的小鼠模型显示，每个骨细胞的骨细胞和树突数量减少，在野生型小鼠的骨细胞树突中，PTH1R与磷酸化PTH1R的定位完全重叠。因此，我们的研究结果揭示了一种新的信号机制，即通过IGF1R直接磷酸化PTH1R来增强成骨细胞向骨细胞的转变。
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