Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts
Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts
复制标题
DOI：
10.1016/s0014-4827(03)00386-0
复制
发表时间：
2003-11-15
影响因子：
3.7
通讯作者：
Tuan, RS
中科院分区：
文献类型：
--
作者：
Nöth, U;Tuli, R;Tuan, RS
骨形态发生蛋白（BMPs）是一种强有力的骨诱导因子，可加速成骨细胞的成熟，并伴有细胞-基质粘附增加。BMP-2处理成骨细胞增加了细胞质BMP-2信号分子Smad 1和Smad 5的磷酸化。我们以前曾报道，BMP-2治疗增加人骨小梁来源的成骨细胞样细胞（成骨细胞）的细胞骨架组织，这也伴随着黏着斑激酶p125（FAK）的激活。我们在这里报告，激活p125（FAK）发生与Smad 1的磷酸化相同的动力学，这表明BMP-2启动Smad信号和粘附介导的信号通路之间的串扰。作为这些作用的辅助作用，我们检查了有丝分裂原活化蛋白（MAP）激酶家族成员响应粘着斑接触形成的激活。尽管所有三种激酶的磷酸化形式都是明显的，但只有SAPK 2 α/p38（p38）响应于BMP-2处理而被激活。抑制p38激酶活性抑制BMP-2诱导的Smad 1磷酸化，以及其易位到细胞核，这表明整合的p38激活与Smad 1信号。最后，在成骨细胞中抑制p38也导致BMP-2诱导的骨钙素基因表达和基质矿化的完全废除。这些发现表明，BMP-2必须激活p38，以介导成骨分化和成熟。(C)2003年爱思唯尔公司All rights reserved.
The bone morphogenetic proteins (BMPs) are potent osteoinductive factors that accelerate osteoblast maturation, accompanied by increased cell-substrate adhesion. BMP-2 treatment of osteoblastic cells increases phosphorylation of the cytoplasmic BMP-2 signaling molecules, Smad1 and Smad5. We have previously reported that BMP-2 treatment increase cytoskeletal organization of human trabecular bone-derived osteoblast-like cells (osteoblasts), which is also accompanied by an activation of the focal adhesion kinase p125(FAK). We report here that activation of p125(FAK) occurs with the same kinetics as the phosphorylation of Smad1, suggesting that BMP-2 initiates cross-talk between Smad signaling and the adhesion-mediated signaling pathway. As an adjunct to these effects, we examined activation of mitogen-activated protein (MAP) kinase family members in response to focal adhesion contact formation. Although phosphorylated forms of all three kinases were apparent, only SAPK2alpha/p38 (p38) was activated in response to BMP-2 treatment. Inhibition of p38 kinase activity suppressed BMP-2 induced Smad1 phosphorylation, as well as its translocation to the nucleus, suggesting the integration of p38 activation with Smad1 signaling. Finally, inhibition of p38 in osteoblasts also led to the complete abrogation of BMP-2 induced osteocalcin gene expression and matrix mineralization. These findings suggest that BMP-2 must activate p38 in order to mediate osteogenic differentiation and maturation. (C) 2003 Elsevier Inc. All rights reserved.