STUDIES ON THE REGULATION OF OSTEOCLAST PRECURSOR CELLS

描述（由申请方提供）：这些研究的目的是了解全身调节因子甲状旁腺激素（PTH）对循环破骨细胞前体细胞迁移和归巢至骨的影响。原理：破骨细胞是吸收骨的独特细胞，是骨转换、骨量和骨质量的共同调节者（与成骨细胞一起）。然而，我们对它们的成熟所涉及的步骤只有有限的了解。具体而言，本申请将集中在破骨细胞前体迁移到骨的途径。目前，尚不清楚起源于骨髓的破骨细胞前体细胞是否1）直接从骨髓迁移到邻近的骨，在那里它们成熟并作为再吸收细胞起作用，或者它们是否2）首先从骨髓迁移到循环，经历髓外成熟步骤，然后返回骨成为再吸收细胞。目前还不清楚骨稳态的全身调节剂如PTH是否改变骨髓微环境并增加破骨细胞前体的循环和归巢骨。也有可能这两种途径都很重要，骨髓附近部位的骨内膜和骨小梁重塑受途径1调节，而不靠近骨髓部位的骨膜吸收和破骨细胞形成则依赖于途径2。通过研究在正常和病理条件下调节破骨细胞前体细胞归巢到骨的谱系进展、迁移模式和因素，我们希望更好地理解循环细胞在骨生理学中的作用，循环细胞保留了发育成破骨细胞的能力。预计这一知识将确定新的干预目标，可用于创建逆转骨丢失，改善骨质量和预防与骨质疏松症和其他代谢性骨病发展相关的发病率的疗法。具体目标1：确定骨髓和外周（血液和脾脏）中破骨细胞前体细胞的数量，并确定体内甲状旁腺激素（PTH）治疗是否会改变小鼠中破骨细胞前体细胞的相对比例或绝对数量。具体目标二：确定破骨细胞前体细胞是否迁移到髓外，然后在基础状态下或用甲状旁腺激素治疗后回到骨中。公共卫生相关性：这些研究将检查髓外循环在破骨细胞成熟中的相关性，破骨细胞是唯一能够有效吸收骨的细胞。通过研究在正常和病理条件下调节破骨细胞前体细胞归巢到骨的谱系进展、迁移模式和因素，我们希望更好地理解循环细胞在骨生理学中的作用，循环细胞保留了发育成破骨细胞的能力。预计这一知识将确定新的干预目标，可用于创建逆转骨丢失，改善骨质量和预防与骨质疏松症和其他代谢性骨病发展相关的发病率的疗法。

DESCRIPTION (provided by applicant): The goal of these studies is to understand the effects that the systemic regulatory factor, parathyroid hormone (PTH), has on the migration and homing to bone of circulating osteoclast precursor cells. Rationale: Osteoclasts are unique cells that resorb bone and are coregulators (with osteoblasts) of bone turnover, bone mass and bone quality. However, we have only limited knowledge of what steps are involved in their maturation. Specifically, this application will focus on the question of what path osteoclast precursors take to migrate to bone. Currently, it is unknown whether osteoclast precursor cells, which originate in bone marrow, 1) migrate directly from bone marrow to adjacent bone, where they mature and function as resorbing cells or if they 2) first migrate from the bone marrow to the circulation, undergo a maturation step extramedullary and then return to bone to become resorbing cells. It is also unclear whether systemic regulators of bone homeostasis like PTH alter the bone marrow microenvironment and increase the circulation and homing of osteoclast precursors to bone. It is also possible that both pathways are important and that endosteal and trabecular bone remodeling at sites adjacent to bone marrow are regulated by the pathway 1, while periosteal resorption and osteoclast formation at sites not adjacent to bone marrow are dependent on pathway 2. By studying the lineage progression, migration patterns and factors that regulate the homing of osteoclast precursor cells to bone in normal and pathologic conditions, we hope to better understand the role that circulating cells, which retain the capacity to develop into osteoclasts, have in bone physiology. It is anticipated that this knowledge will identify new targets for interventions, which can be used to create therapies to reverse bone loss, improve bone quality and prevent the morbidities that are associated with the development of osteoporosis and other metabolic bone diseases. Specific Aim 1: Define the population of osteoclast precursor cells in the bone marrow and periphery (blood and spleen) and determine if parathyroid hormone (PTH) treatment in vivo alters their relative proportions or absolute number in mice. Specific Aim 2: Determine if osteoclast precursor cells migrate extramedullarily and then home to bone in the basal state or after treatment of mice with parathyroid hormone. PUBLIC HEALTH RELEVANCE: These studies will examine the relevance of extramedullary circulation in the maturation of osteoclasts, which are the only cells capable of efficiently resorbing bone. By studying the lineage progression, migration patterns and factors that regulate the homing of osteoclast precursor cells to bone in normal and pathologic conditions, we hope to better understand the role that circulating cells, which retain the capacity to develop into osteoclasts, have in bone physiology. It is anticipated that this knowledge will identify new targets for interventions, which can be used to create therapies to reverse bone loss, improve bone quality and prevent the morbidities that are associated with the development of osteoporosis and other metabolic bone diseases.