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: 7684217
• 负责人: Laurie K. McCauley
• 金额: $ 23.1万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684217
• 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; Data; Defect; Development; Disease; Environment; Fracture; Genes; Goals; Hematopoietic; Hematopoietic stem cells; In Vitro; Inflammatory; Interleukin-6; Investigation; Knowledge; Laboratories; Link; Location; Mediator of activation protein; Megakaryocytes; Megakaryocytopoieses; Modeling; Mus; Mutant Strains Mice; Natural regeneration; Osteoblasts; Osteogenesis; Osteoporosis; Parathyroid Hormone Receptor; Parathyroid Hormone Receptors; Parathyroid Hormones; Periodontal Diseases; 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）以其在骨骼中的分解代谢和合成代谢作用而闻名。现在，PTH正在使用临床用途，因为它能够恢复骨质疏松症损失的骨骼，并且还在研究其在局部骨缺陷中因裂缝和/或牙周疾病而用于再生。 PTH作用的机制是复杂的，并且已经避免了骨生物学家数十年。 PTH受体（PTHR1）存在于成骨细胞上，但是PTH的作用不仅仅是这些形成骨骼的细胞的简单激活。在复杂的时间和空间组织中需要骨髓中的辅助细胞，该组织可能同时利用PTH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的方式进行了间接的方式。已发现PTH具有扩展造血干细胞（HSC）室细胞的新型作用，该细胞可能在PTH对骨骼的影响中起作用。还发现PTH调节在巨核细胞分化和功能中重要的基因。巨核细胞吸引了骨气免疫调节细胞和骨环境中PTH作用的有效候选。该项目的总体假设是，PTH刺激了与巨核细胞相关基因的成骨细胞产生，而巨核细胞相关基因反过来促进巨核细胞以支持成骨细胞的形成。两个具体的目的将阐明PTH在改变的巨核细胞功能模型中的作用，以将造血细胞和成骨细胞在骨骼中的作用中联系起来。第一个具体目的将决定巨核细胞刺激因子（MSF/PRG4）和白介素6（IL-6）在骨骼中分化和PTH作用中的作用。第二个特定目的将验证巨核细胞在骨骼中PTH作用中的影响。体外和体内模型系统的特征良好，将用于这些目标。这些研究将更好地阐明PTH作用的细胞靶标，并扩展我们对骨骼中关键细胞调节剂的现有知识，以包括造血谱系的细胞。这些研究完成后，将更好地理解三个关键领域。 1）PTH在骨骼中的作用，2）MSF/PRG4在骨骼中的作用，以及3）巨核细胞和巨核细胞刺激介质在骨骼中的作用。这项工作的引人注目的影响在于将PTH应用于组织再生，如炎性疾病（如牙周疾病）所致的骨缺陷状态。项目叙述：甲状旁腺激素（PTH）是一种有效的骨骼形成剂，也支持血干细胞的发育，但尚不清楚这是如何起作用以及这两个已知功能是否相互作用。该项目将描绘目标细胞对于PTH的作用至关重要，以构建骨骼和干细胞。该信息对于优化PTH作为骨再生的治疗以及骨骼疾病（例如牙周疾病和骨质疏松症）至关重要。