Integral role of hematopoietic cells in PTH actions in bone

描述(申请人提供)：甲状旁腺激素(PTH)是众所周知的分解代谢和合成代谢作用的骨骼。甲状旁腺激素因其修复骨质疏松所致的骨丢失的能力而被临床使用，并因其在骨折和/或牙周病引起的局部骨缺损的再生中的应用而被研究。甲状旁腺素的作用机制是复杂的，几十年来骨生物学家一直对其一无所知。甲状旁腺素受体(PTHR1)存在于成骨细胞上，但甲状旁腺素的作用不仅仅是这些形成骨的细胞的简单激活。骨髓中的辅助细胞需要复杂的时间和空间组织，可以利用甲状旁腺激素的合成代谢和分解代谢活性。来自项目实验室的初步数据强烈支持甲状旁腺素刺激成骨细胞增殖的能力，但间接地通过骨髓微环境中的造血细胞实现。甲状旁腺激素被发现具有扩增造血干细胞(HSC)隔室细胞的新作用，这可能在甲状旁腺素对骨骼的影响中发挥作用。甲状旁腺素还被发现上调巨核细胞分化和功能中重要的基因。巨核细胞是耐人寻味的骨免疫调节细胞，是骨环境中甲状旁腺素作用的有效候选细胞。该项目的总体假设是，甲状旁腺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骨形成。两个特定的目的将阐明甲状旁腺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与甲状旁腺素在骨中的作用联系起来。第一个特定目标将确定巨核细胞刺激因子(MSF/Prg4)和白细胞介素6(IL-6)在巨核细胞分化和骨中甲状旁腺激素(PTH)作用中的作用。第二个具体目的是验证巨核细胞在甲状旁腺激素在骨骼中的作用。良好的体外和体内模型系统将被用于实现这些目标。这些研究将更好地阐明甲状旁腺素作用的细胞靶点，并扩展我们对骨骼中关键细胞调节因子的现有知识，以包括造血系的细胞。随着这些研究的完成，三个关键领域将得到更好的理解：1)甲状旁腺素在骨中的作用，2)MSF/Prg4在骨中的作用，以及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在于甲状旁腺素在组织再生方面的应用，就像在因炎症疾病(如牙周病)而导致的骨缺损状态中一样。项目简介：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展，但不清楚这是如何发挥作用的，以及这两种已知功能是否相互作用。该项目将勾勒出对甲状旁腺素构建骨和干细胞的作用非常重要的靶细胞。这些信息对于优化甲状旁腺素作为骨再生疗法和治疗骨病，如牙周病和骨质疏松症至关重要。

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.