Integral role of hematopoietic cells in PTH actions in bone

造血细胞在骨 PTH 作用中的整体作用

• 批准号: 7556574
• 负责人: Laurie K. McCauley
• 金额: $ 19.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-08 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7556574
• 关键词: Antigen-Presenting Cells; Apoptosis; Area; Biological Models; Biology; Blood; Bone Diseases; Bone Marrow; Bone Regeneration; Cell Proliferation; Cell physiology; Cells; Clinical; Complex; Condition; Data; Defect; Development; Disease; Environment; Fracture; Genes; Goals; Hematopoietic; Hematopoietic stem cells; In Vitro; Inflammatory; Interleukin-6; Investigation; Knowledge; Laboratories; Link; Localized; Location; Mediator of activation protein; Megakaryocytes; Megakaryocytopoieses; Modeling; Mus; Mutant Strains Mice; Natural regeneration; Osteoblasts; Osteogenesis; Osteoporosis; Parathyroid Hormone Receptor; Parathyroid Hormones; Periodontal Diseases; Personal Satisfaction; Physiology; Production; Regulation; Relative (related person); Role; Signal Transduction; Stem Cell Development; Stem cells; Stromal Cells; Thrombopoietin; Work; bone; bone marrow hyperplasia; cellular targeting; clinical efficacy; human PTH protein; in vitro Model; in vivo; in vivo Model; novel; response; tissue regeneration

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.

描述（由申请人提供）：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。PTH现在因其恢复骨质疏松症导致的骨丢失的能力而在临床上使用，并且还在研究其在由于骨折和/或牙周病导致的局部骨缺损的再生中的用途。PTH的作用机制是复杂的，几十年来一直困扰着骨生物学家。PTH受体（PTHR 1）存在于成骨细胞上，但PTH的作用不仅仅是简单地激活这些形成骨骼的细胞。骨髓中的辅助细胞在复杂的时间和空间组织中是必需的，其可以利用PTH的合成代谢和分解代谢活性。项目实验室的初步数据强烈支持PTH刺激成骨细胞增殖的能力，但通过骨髓微环境中的造血细胞以间接方式进行。已发现PTH具有扩增造血干细胞（HSC）隔室的细胞的新作用，造血干细胞（HSC）隔室可能在骨中PTH的影响中起作用。还发现PTH上调在巨核细胞分化和功能中重要的基因。巨核细胞是骨免疫调节细胞，是骨环境中PTH作用的有效候选细胞。该项目的总体假设是，PTH刺激成骨细胞产生巨核细胞相关基因，从而促进巨核细胞支持成骨细胞骨形成。两个具体的目标将阐明PTH在巨核细胞功能改变的模型中的作用，以便将造血细胞和成骨细胞与PTH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/prg 4）和白细胞介素-6（IL-6）在巨核细胞分化和骨中PTH作用中的作用。第二个具体目标将验证巨核细胞在骨中PTH作用中的影响。将利用良好的体外和体内模型系统来实现这些目标。这些研究将更好地阐明PTH作用的细胞靶点，并将我们现有的关于骨中关键细胞调节因子的知识扩展到包括造血谱系细胞。这些研究完成后，将更好地了解三个关键领域：1）PTH在骨中的作用，2）MSF/prg 4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。这项工作的令人信服的影响是在PTH对组织再生的应用，如在由于炎症性疾病，如牙周病的骨缺损的状态。项目叙述：甲状旁腺激素（PTH）是一种有效的骨形成剂，也支持造血干细胞发育，但尚不清楚这是如何作用的，以及这两种已知的功能是否相互作用。这个项目将描绘出对PTH构建骨和干细胞的作用重要的靶细胞。这些信息对于优化PTH作为骨再生疗法和治疗骨疾病如牙周病和骨质疏松症至关重要。