The role of amphiregulin in PTH's action on bone

描述（由申请人提供）：成人骨骼经历持续重塑，成骨细胞的骨形成和破骨细胞的骨吸收之间存在微妙的平衡。甲状旁腺激素（PTH）的间歇给药能够通过其受体作用于成骨细胞而极大地刺激骨形成。最近，我在Nicola Partial博士的实验室发现，双调蛋白，一种表皮生长因子（EGF）样配体，在成骨细胞中被PTH强烈上调，并且PTH信号通路在正常骨发育中起着重要作用。尽管EGF样配体及其信号通路在许多组织和癌症中已被广泛研究，但由于缺乏证据表明它们在骨中表达并参与重塑，因此在骨骼领域的报道很少。从我的初步数据，我假设EGF信号参与调节间充质细胞谱系，如成骨细胞，脂肪细胞和软骨细胞的增殖和分化，PTH使用双调蛋白作为介质来操纵骨髓基质干细胞的微环境。因此，本申请的目的是描述EGF样配体，特别是双调蛋白在骨代谢和PTH对骨的作用中的作用。为了实现它，我将使用以下方法：1.鉴定骨中的双调蛋白靶细胞并研究PTH治疗如何影响这些细胞，2.研究双调蛋白对基质干细胞增殖和分化的影响。使用动物模型检查双调蛋白信号传导在骨发育和PTH作用中的生理作用。这项工作的结果将提供一个新的和潜在的重要信号通路在骨发育和代谢及其在PTH的作用对骨的洞察。

DESCRIPTION (provided by applicant): The human adult skeleton undergoes continuous remodeling, a delicate balance between bone formation by the osteoblast and bone resorption by the osteoclast. Intermittent administration of parathyroid hormone (PTH) is able to greatly stimulate bone formation by acting through its receptor on the osteoblast. Recently, I, in Dr. Nicola Partridge's laboratory, identified that amphiregulin, an epidermal growth factor (EGF)-like ligand, is strongly upregulated by PTH in the osteoblast and that the EOF signaling pathway plays an important role in normal bone development. Although EGF-like ligands and their signaling pathways have been extensively studied in many tissues and cancers, there are few reports of them in the skeletal field due to the lack of evidence that they are expressed in bone and that they participate in remodeling. From my preliminary data, I hypothesize that EGF signaling participates in regulating the proliferation and differentiation of mesenchymal cell lineages, such as osteoblasts, adipocytes and chrondrocytes, and that PTH uses amphiregulin as the mediator to manipulate the microenvironment of bone marrow stromal stem cells. Thus, the goal of the present application is to delineate the role of EGF-like ligands, especially amphiregulin, in bone metabolism and in PTH's action on bone. To achieve it, I will use the following approaches: 1. Identifying amphiregulin target cells in bone and investigating how PTH treatment affects these cells, 2. Studying the effect of amphiregulin on the proliferation and differentiation of stromal stem cells, 3. Examining the physiological role of amphiregulin signialing in bone development and in PTH's action using animal models. The results of this work will provide insight into a novel and potentially important signaling pathway in bone development and metabolism and its role in PTH's action on bone.