Integral role of hematopoietic cells in PTH actions in bone

描述（由申请人提供）：甲状旁腺激素（PTH）以其在骨中的分解代谢和合成代谢作用而闻名。甲状旁腺激素目前用于临床，因为它有能力恢复骨质疏松症造成的骨质流失，也在研究它在骨折和/或牙周病引起的局部骨缺损再生中的应用。甲状旁腺激素的作用机制很复杂，几十年来一直困扰着骨生物学家。PTH受体（PTHR1）存在于成骨细胞中，但PTH的作用不仅仅是激活这些形成骨的细胞。骨髓中的辅助细胞在复杂的时间和空间组织中是必需的，可以利用甲状旁腺激素的合成代谢和分解代谢活动。来自项目实验室的初步数据强烈支持甲状旁腺激素刺激成骨细胞增殖的能力，但以间接方式通过骨髓微环境中的造血细胞。PTH已被发现具有新的作用，以扩大造血干细胞（HSC）室的细胞，这可能在PTH对骨的影响中起作用。甲状旁腺激素也被发现上调巨核细胞分化和功能的重要基因。巨核细胞是一种有趣的骨免疫调节细胞，也是骨环境中甲状旁腺激素作用的有效候选细胞。本项目的总体假设是，甲状旁腺激素刺激成骨细胞产生巨核细胞相关基因，进而促进巨核细胞支持成骨细胞的形成。两个特定的目的将阐明甲状旁腺激素在巨核细胞功能改变模型中的作用，以便将造血细胞和成骨细胞在甲状旁腺激素在骨中的作用联系起来。第一个具体目标将确定巨核细胞刺激因子（MSF/prg4）和白细胞介素-6 （IL-6）在骨中巨核细胞分化和甲状旁腺激素作用中的作用。第二个具体目标将验证巨核细胞对骨中甲状旁腺激素的作用的影响。良好表征的体外和体内模型系统将用于实现这些目标。这些研究将更好地阐明甲状旁腺激素作用的细胞靶点，并将我们对骨中关键细胞调节因子的现有知识扩展到包括造血谱系的细胞。在完成这些研究后，三个关键领域将得到更好的理解；1) PTH在骨中的作用2)MSF/prg4在骨中的作用3)巨核细胞和巨核细胞刺激介质在骨中的作用这项工作的引人注目的影响是PTH在组织再生中的应用，如在炎症性疾病（如牙周病）引起的骨缺损状态中。项目描述：甲状旁腺激素（PTH）是一种有效的骨形成剂，也支持血液干细胞的发育，但尚不清楚它是如何起作用的，以及这两种已知功能是否相互作用。本项目将描述促甲状旁腺激素对骨和干细胞的作用的重要靶细胞。这一信息对于优化PTH作为骨再生和治疗牙周病和骨质疏松等骨疾病的治疗至关重要。

DESCRIPTION (provided by applicant): Parathyroid hormone (PTH) is well known for its catabolic and anabolic actions in bone. PTH is now in clinical use for its ability to restore bone lost to osteoporosis, and also under investigation for its use in the regeneration of localized osseous defects due to fractures and/or periodontal disease. The mechanisms of PTH action are complex and have eluded bone biologists for decades. The PTH receptor (PTHR1) is present on osteoblasts, but actions of PTH are more than simple activation of these cells that form bone. Accessory cells in the bone marrow are required in an intricate temporal and spatial organization that may utilize both anabolic and catabolic activities of PTH. Preliminary data from the project laboratory strongly support the ability of PTH to stimulate osteoblastic cell proliferation, but in an indirect manner through a hematopoietic cell in the bone marrow microenvironment. PTH has been found to have novel actions to expand cells of the hematopoietic stem cell (HSC) compartment which may function in the impact of PTH in bone. PTH has also been found to up regulate genes important in megakaryocyte differentiation and function. Megakaryocytes are intriguing osteoimmunomodulatory cells and valid candidates of PTH actions in the bone environment. The overall hypothesis of this project is that PTH stimulates osteoblast production of megakaryocyte-associated genes that in turn promote megakaryocytes to support osteoblastic bone formation. Two specific aims will elucidate the action of PTH in models of altered megakaryocyte function in order to link hematopoietic and osteoblastic cells in the actions of PTH in bone. The first specific aim will determine the role of megakaryocyte stimulating factor (MSF/prg4) and interleukin-6 (IL-6) in megakaryocyte differentiation and PTH action in bone. The second specific aim will verify the impact of megakaryocytes in the actions of PTH in bone. Well characterized in vitro and in vivo model systems will be utilized toward these goals. These studies will better clarify the cellular targets of PTH action and extend our existing knowledge of key cellular regulators in bone to include cells of the hematopoietic lineage. Upon the completion of these studies, three key areas will be better understood; 1) PTH action in bone, 2) the role of MSF/prg4 in bone, and 3) the role of the megakaryocyte and megakaryocyte stimulatory mediators in bone. The compelling impact of this work is in the application of PTH toward tissue regeneration as in states of osseous defects due to inflammatory diseases such as periodontal disease. Project Narrative: Parathyroid hormone (PTH) is a potent bone forming agent and also supports blood stem cell development, but is not clear how this acts and whether these two known functions are interactive. This project will delineate the target cells important for the action of PTH to build bone and stem cells. This information is critical for the optimization of PTH as a therapy for bone regeneration and the treatment of bone diseases such as periodontal disease and osteoporosis.