Core level regulatory network of osteoblast as molecular mechanism for osteoporosis and treatment.
Core level regulatory network of osteoblast as molecular mechanism for osteoporosis and treatment.
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成骨细胞的核心水平调控网络作为骨质疏松症和治疗的分子机制
DOI：
10.18632/oncotarget.6923
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发表时间：
2016-01-26
期刊：
影响因子：
--
通讯作者：
Zhou G
中科院分区：
文献类型：
--
作者：
Yuan R;Ma S;Zhu X;Li J;Liang Y;Liu T;Zhu Y;Zhang B;Tan S;Guo H;Guan S;Ao P;Zhou G
开发和评价骨质疏松症等慢性疾病的长期预防性治疗需要从分子和系统水平上明确其机制。虽然骨质疏松症的分子信号通路研究是广泛的，但缺乏统一的机制。在这项工作中，我们提供了实验和系统生物学证据，可能存在一个紧密相连的顶层调控网络，它控制着成骨细胞的正常和增生表型。具体而言，我们构建了一个枢纽样的相互作用网络，从雌激素，糖皮质激素，视黄酸，过氧化物酶体增殖物激活受体，维生素D受体和钙信号通路之间的充分记录的交叉谈判。该网络进行了验证，通过透射电子显微镜和基因表达谱的骨组织的卵巢切除（OVX）大鼠之前和之后的葡萄糖酸锶（GluSr）治疗。基于网络结构和实验数据，动态建模预测钙和糖皮质激素信号通路作为GluSr治疗的目标。建模结果进一步揭示，在缺失雌激素信号传导的情况下，GluSr治疗状态可能是最接近健康状态的结果。
To develop and evaluate the long-term prophylactic treatment for chronic diseases such as osteoporosis requires a clear view of mechanism at the molecular and systems level. While molecular signaling pathway studies for osteoporosis are extensive, a unifying mechanism is missing. In this work, we provide experimental and systems-biology evidences that a tightly connected top-level regulatory network may exist, which governs the normal and osteoporotic phenotypes of osteoblast. Specifically, we constructed a hub-like interaction network from well-documented cross-talks among estrogens, glucocorticoids, retinoic acids, peroxisome proliferator-activated receptor, vitamin D receptor and calcium-signaling pathways. The network was verified with transmission electron microscopy and gene expression profiling for bone tissues of ovariectomized (OVX) rats before and after strontium gluconate (GluSr) treatment. Based on both the network structure and the experimental data, the dynamical modeling predicts calcium and glucocorticoids signaling pathways as targets for GluSr treatment. Modeling results further reveal that in the context of missing estrogen signaling, the GluSr treated state may be an outcome that is closest to the healthy state.