Mechanosensor polycystin-1 potentiates differentiation of human osteoblastic cells by upregulating Runx2 expression via induction of JAK2/STAT3 signaling axis
Mechanosensor polycystin-1 potentiates differentiation of human osteoblastic cells by upregulating Runx2 expression via induction of JAK2/STAT3 signaling axis
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DOI：
10.1007/s00018-016-2394-8
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发表时间：
2017-03-01
影响因子：
8
通讯作者：
Papavassiliou, Athanasios G.
中科院分区：
文献类型：
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作者：
Dalagiorgou, Georgia;Piperi, Christina;Papavassiliou, Athanasios G.
多囊蛋白-1(Polycystin-1，PC1)被认为是参与骨骼形成和骨重建的主要机械传感分子。通过PC1的机械转导涉及其胞浆尾部(CT)的蛋白水解性裂解，并与细胞内途径和转录因子相互作用来调节细胞功能。在这里，我们展示了PC1-CT和JAK2/STAT3信号轴在机械刺激的人成骨细胞中的相互作用，导致了成骨细胞分化的主要调节因子Runx2基因的转录诱导。原代成骨样PC1表达细胞在机械拉伸条件下表现出依赖于PC1的JAK2磷酸化(P)/活性形式的增加。拉伸后PC1-CT与pJAK2特异性相互作用，而PC1(抗IgPKD1)和JAK2抑制剂可阻断JAK2的激活。机械刺激一直触发PC1介导的STAT3的磷酸化和核转位。拉伸后，核磷酸化(P)/DNA结合活性pSTAT3水平增加，随后DNA结合活性增加。单独使用STAT3抑制剂或与抗IgPKD1联合使用均可消除这一作用。此外，PC1介导的机械刺激可诱导Runx2基因表达水平升高。芯片分析显示，在机械拉伸后，STAT3/Runx2直接调节Runx2启动子的活性，这是PC1依赖的。我们的发现表明，机械负荷通过增强PC1-JAK2/STAT3信号轴上调Runx2基因的表达，最终可能控制成骨细胞的分化，最终控制骨形成。
Polycystin-1 (PC1) has been proposed as a chief mechanosensing molecule implicated in skeletogenesis and bone remodeling. Mechanotransduction via PC1 involves proteolytic cleavage of its cytoplasmic tail (CT) and interaction with intracellular pathways and transcription factors to regulate cell function. Here we demonstrate the interaction of PC1-CT with JAK2/STAT3 signaling axis in mechanically stimulated human osteoblastic cells, leading to transcriptional induction of Runx2 gene, a master regulator of osteoblastic differentiation. Primary osteoblast-like PC1-expressing cells subjected to mechanical-stretching exhibited a PC1-dependent increase of the phosphorylated(p)/active form of JAK2. Specific interaction of PC1-CT with pJAK2 was observed after stretching while pre-treatment of cells with PC1 (anti-IgPKD1) and JAK2 inhibitors abolished JAK2 activation. Consistently, mechanostimulation triggered PC1-mediated phosphorylation and nuclear translocation of STAT3. The nuclear phosphorylated(p)/DNA-binding competent pSTAT3 levels were augmented after stretching followed by elevated DNA-binding activity. Pre-treatment with a STAT3 inhibitor either alone or in combination with anti-IgPKD1 abrogated this effect. Moreover, PC1-mediated mechanostimulation induced elevation of Runx2 mRNA levels. ChIP assays revealed direct regulation of Runx2 promoter activity by STAT3/Runx2 after mechanical-stretching that was PC1-dependent. Our findings show that mechanical load upregulates expression of Runx2 gene via potentiation of PC1-JAK2/STAT3 signaling axis, culminating to possibly control osteoblastic differentiation and ultimately bone formation.