Parathyroid hormone increases β-catenin levels through Smad3 in mouse osteoblastic cells
Parathyroid hormone increases β-catenin levels through Smad3 in mouse osteoblastic cells
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DOI：
10.1210/en.2005-1627
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发表时间：
2006-05-01
期刊：
影响因子：
4.8
通讯作者：
Chihara, K
中科院分区：
文献类型：
--
作者：
Tobimatsu, T;Kaji, H;Chihara, K
甲状旁腺激素通过甲状旁腺激素/甲状旁腺激素相关的蛋白受体1偶联到蛋白激酶A(PKA)和蛋白激酶C(PKC)通路，以及典型的Wnt-β-catenin信号通路在骨形成中发挥重要作用。在本研究中，我们研究了小鼠成骨细胞MC3T3-E1中PTH和Wnt信号通路之间的相互作用。甲状旁腺素呈剂量和时间依赖性地增加β-连环蛋白的浓度。PKA激活剂Forskolin和PKC激活剂佛波醇12-肉豆蔻酸酯-13-乙酸酯，以及PTH类似物[NIE(8，18)，Tyr(34)]人PTH-(3-34)酰胺，都能增加β-连环素水平。特异性PKA抑制剂H-89和PKC抑制剂星状孢子素和钙磷蛋白C均可拮抗PTH刺激的β-连环素水平。转化生长因子-β和转化生长因子-β信号分子Smad3的转导可提高β-连环蛋白水平，而这一作用可被显性阴性的Smad3所拮抗。甲状旁腺激素可增强显性活性β-连环蛋白的转录活性，这种作用可被显性负性Smad3共转染所拮抗。PTH和LiCl2模拟Wnt-β-catenin途径的作用，挽救了地塞米松和依托泊苷诱导的成骨细胞凋亡。综上所述，这些数据表明PTH通过Smad3刺激成骨细胞的β-连环素水平，并且参与了PKA和PKC通路。规范的Wnt-β-catenin通路可能通过作用于成骨细胞中的Smad3参与PTH的抗凋亡作用。
PTH, via the PTH/PTH-related protein receptor type 1 that couples to both protein kinase A (PKA) and protein kinase C (PKC) pathways, and the canonical Wnt-beta-catenin signaling pathway play important roles in bone formation. In the present study we have examined the interaction between the PTH and Wnt signaling pathways in mouse osteoblastic MC3T3-E1 cells. PTH dose- and time-dependently increased the concentrations of beta-catenin. The PKA activator, forskolin, and the PKC activator, phorbol 12-myristate-13-acetate, as well as the PTH analog, [NIe(8,18),Tyr(34)] human PTH-(3-34) amide, all increased beta-catenin levels. Both H-89, a specific PKA inhibitor, and PKC inhibitors, staurosporine and calphostin C, antagonized PTH stimulation of beta-catenin levels. TGF-beta as well as transfection of the TGF-beta-signaling molecule, Smad3, enhanced beta-catenin levels, and this was antagonized by transfection of a dominant-negative Smad3. The transcriptional activity of transfected dominant-active beta-catenin was enhanced by PTH, an effect that was antagonized by cotransfection of a dominant-negative Smad3. PTH as well as LiCl2, which mimics the effects of the Wnt-beta-catenin pathway, rescued the dexamethasone- and etoposide-induced apoptosis of osteoblastic cells. In conclusion, the data demonstrate that PTH stimulates osteoblast beta-catenin levels via Smad3, and that both PKA and PKC pathways are involved. The canonical Wnt-beta-catenin pathway is likely to be involved in the antiapoptotic actions of PTH by acting through Smad3 in osteoblasts.