Mechanical stimulation of polycystin-1 induces human osteoblastic gene expression via potentiation of the calcineurin/NFAT signaling axis.
Mechanical stimulation of polycystin-1 induces human osteoblastic gene expression via potentiation of the calcineurin/NFAT signaling axis.
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DOI：
10.1007/s00018-012-1164-5
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发表时间：
2013-01
影响因子：
8
通讯作者：
Papavassiliou, Athanasios G.
中科院分区：
文献类型：
--
作者：
Dalagiorgou, Georgia;Piperi, Christina;Georgopoulou, Urania;Adamopoulos, Christos;Basdra, Efthimia K.;Papavassiliou, Athanasios G.
机械力触发骨细胞的生物反应，最终控制成骨细胞发生和骨重塑。虽然已经假设了几种机械传感器，但由于最初的机械传感事件尚未确定，因此精确的机械转导途径仍然模糊不清。肾细胞的研究表明，多胱氨酸-1 （PC1）通过其细胞外n端部分，可能作为一种“天线样”蛋白，在环境信号及其转化为生化反应之间提供联系，通过钙调神经磷酸酶/ NFAT途径调节各种细胞过程。在这里，我们探讨了PC1参与机械负荷（拉伸）诱导的信号级联反应，控制成骨细胞发生/骨形成。FACS和TransAM转录因子ELISA分析采用机械拉伸（0-6 h）的原代人成骨样表达PC1的细胞提取物，结果显示，未磷酸化/ dna结合的NFATc1在0.5-1 h时增加，在6 h时恢复正常。根据NFATc1的激活机制，经环孢素A （CsA）预处理的培养细胞拉伸，钙调磷酸酶/NFAT途径的特异性抑制剂)消除了细胞质pNFATc1（磷酸化/无活性）物种丰度的减少。此外，用针对PC1机械感应n端部分的抗体预处理的成骨细胞拉伸也消除了观察到的无活性pNFATc1物种细胞质水平的下降。重要的是，在相似的条件下（用抑制抗pc1抗体预先孵育拉伸细胞），与未处理的细胞相比，关键成骨细胞nfatc1靶基因runx2的表达降低。因此，PC1作为主要的机械传感分子，通过钙调神经磷酸酶/NFAT信号级联调节成骨细胞基因转录，从而调节骨细胞分化。
Mechanical forces trigger biological responses in bone cells that ultimately control osteoblastogenesis and bone remodelling. Although several mechanosensors have been postulated, the precise mechanotransduction pathway remains obscure as the initial mechanosensing event has not yet been identified. Studies in kidney cells have shown that polycystin-1 (PC1), via its extracellular N-terminal part, may function as an “antenna-like” protein providing a linkage between environmental cues and their conversion into biochemical responses that regulate various cellular processes via the calcineurin/ NFAT pathway. Here we explored the involvement of PC1 in mechanical load (stretching)-induced signalling cascades that control osteoblastogenesis/bone formation. FACS and TransAM Transcription Factor ELISA analyses employing extracts from primary human osteoblast-like, PC1 expressing cells subjected to mechanical stretching (0-6 h) revealed that unphosphorylated/DNA-binding competent NFATc1 increased at 0.5-1 h and returned to normal at 6 h. In accordance with the activation mechanism of NFATc1, stretching of cultured cells pre-treated with cyclosporin A (CsA, a specific inhibitor of the calcineurin/NFAT pathway) abrogated the observed decrease in the abundance of the cytoplasmic pNFATc1 (phosphorylated/inactive) species. Furthermore, stretching of osteoblastic cells pre-treated with an antibody against the mechanosensing N-terminal part of PC1 also abrogated the observed decrease in the cytoplasmic levels of the inactive pNFATc1 species. Importantly, under similar conditions (pre-incubation of stretched cells with the inhibitory anti-PC1 antibody), the expression of the key osteoblastic, NFATc1-target gene runx2 decreased compared to untreated cells. Therefore PC1 acts as chief mechanosensing molecule that modulates osteoblastic gene transcription and hence bone-cell differentiation through the calcineurin/NFAT signalling cascade.
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影响因子：
4.8
作者：
Puri, S;Magenheimer, BS;Calvet, JP
通讯作者：
Calvet, JP
影响因子：
--
作者：
NARUSE, K;SOKABE, M
通讯作者：
SOKABE, M
影响因子：
4.1
作者：
Hou, Bo;Kolpakova-Hart, Elona;Olsen, Bjorn R.
通讯作者：
Olsen, Bjorn R.
影响因子：
2.6
作者：
Basdra, EK;Komposch, G
通讯作者：
Komposch, G
影响因子：
5.4
作者：
Penolazzi, Letizia;Lisignoli, Gina;Piva, Roberta
通讯作者：
Piva, Roberta