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首页> 外文期刊>Journal of Cellular Physiology >Parathyroid hormone-related protein (107-139) increases human osteoblastic cell survival by activation of vascular endothelial growth factor receptor-2.
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Parathyroid hormone-related protein (107-139) increases human osteoblastic cell survival by activation of vascular endothelial growth factor receptor-2.

机译：甲状旁腺与荷尔蒙相关的蛋白质(107 - 139)增加人类成骨细胞的细胞生存血管内皮生长因子的激活受体2。

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摘要

Parathyroid hormone-related protein (PTHrP) (107-139), in contrast to the N-terminal fragment PTHrP (1-36), has been shown to interact with the vascular endothelial growth factor (VEGF) system to modulate human osteoblast differentiation. In this study, we evaluated whether this interaction might affect human osteoblastic cell survival. Pre-incubation with PTHrP (107-139) for 1-24 h dose-dependently (0.1-100 nM) inhibited dexamethasone- or etoposide-induced cell death in human osteoblastic MG-63 cells and human osteoblast-like cells from trabecular bone. This effect, but not that elicited by PTHrP (1-36), was abolished by the VEGF receptor (VEGFR)-2 inhibitors SU5614 and SU1498 or VEGFR-2 siRNA transfection in these cells. PTHrP (107-139), but not PTHrP (1-36), at 100 nM, rapidly (within 2 min) increased VEGFR-2 tyrosine-phosphorylation in MG-63 cells; an effect unaffected by several inhibitors of metalloproteinases, neutralizing VEGF(165) or VEGFR-2 antibodies, or the VEGF binding inhibitor CBO-PP1. The latter two antagonists also failed to affect (125)I-[Tyr(116)] PTHrP (107-115) binding to these cells. Consistent with its effect on VEGFR-2 activation, PTHrP (107-139) rapidly induced extracellular signal-regulated kinase (ERK) 1/2 and Akt activaton, and both ERK and phosphatidylinsositol-3 kinase (PI3K) inhibitors abolished its pro-survival effect in human osteoblastic cells. In addition, SU5614 and the latter two types of inhibitors abrogated Runx2 activation by this peptide in MG-63 cells. Transfection with a dominant-negative Runx2 construct abolished the pro-survival effect of PTHrP (107-139), associated with a decrease in Bcl-2/Bax protein ratio. Our findings demonstrate that PTHrP (107-139) interacts with VEGFR-2 to promote human osteoblastic cell survival by a mechanism involving Runx2 activation.
机译：甲状旁腺与荷尔蒙相关的蛋白(PTHrP)(107 - 139),而氨基片段PTHrP(1-36),已被证明与交互血管内皮生长因子(VEGF)系统调节人类成骨细胞分化。这项研究中,我们评估是否这种交互可能会影响人类成骨细胞的细胞生存。与PTHrP Pre-incubation 24 h (107 - 139)剂量依赖性抑制(0.1 -100海里)地塞米松或etoposide-induced细胞死亡人类和人类成骨细胞的mg - 63细胞osteoblast-like从骨小梁细胞。PTHrP引发的效果,但并不是说(1-36),被废除的VEGF受体(VEGFR) 2抑制剂SU5614 SU1498或VEGFR-2核在这些细胞转染。不是PTHrP(1-36),在100 nM,迅速(在2min)增加VEGFR-2 tyrosine-phosphorylation在mg - 63细胞;金属蛋白酶抑制剂,中和VEGF(165)或VEGFR-2抗体,或VEGF绑定抑制剂CBO-PP1。对手也没有影响(125) I -[酪氨酸(116)]PTHrP(107 - 115)绑定这些细胞。VEGFR-2激活,PTHrP迅速(107 - 139)诱导细胞外signal-regulated激酶(ERK) 1/2和Akt activaton, ERK和phosphatidylinsositol-3激酶抑制剂(PI3K)在人类废除了其pro-survival效果成骨细胞的细胞。后两种抑制剂废除Runx2激活肽在mg - 63细胞。转染的显性负Runx2构建废除的pro-survival效果PTHrP(107 - 139),与减少有关bcl - 2、Bax蛋白比例。PTHrP(107 - 139)与VEGFR-2交互促进人类成骨细胞的细胞生存的涉及Runx2激活的机制。

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