STUDIES ON THE REGULATION OF OSTEOCLAST PRECURSOR CELLS

描述(申请人提供)：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到骨的影响。原理：破骨细胞是吸收骨骼的独特细胞，是骨转换、骨量和骨质量的共同调节者(与成骨细胞)。然而，我们对它们成熟所涉及的步骤知之甚少。具体地说，这一应用程序将重点研究破骨细胞前体细胞迁移到骨骼的途径。目前尚不清楚起源于骨髓的破骨细胞前体细胞是1)直接从骨髓迁移到邻近的骨，在那里成熟并发挥吸收细胞的功能，还是2)首先从骨髓迁移到循环中，经历髓外成熟步骤，然后返回骨骼成为吸收细胞。目前还不清楚甲状旁腺素等全身骨稳态调节剂是否会改变骨髓微环境，增加破骨细胞前体对骨的循环和归巢。也有可能这两条途径都是重要的，而且邻近骨髓部位的骨内和骨小梁重建受途径1的调节，而非骨髓部位的骨膜吸收和破骨细胞的形成依赖于途径2。通过研究正常和病理条件下破骨细胞前体细胞归巢到骨的谱系进程、迁移模式和因素，我们希望更好地了解循环细胞在骨生理中的作用，循环细胞保持向破骨细胞发展的能力。预计这一知识将确定干预措施的新目标，可用于创造逆转骨丢失、改善骨质量和预防与骨质疏松症和其他代谢性骨疾病发展相关的疾病的治疗方法。具体目标1：确定破骨细胞前体细胞在骨髓和外周(血液和脾)中的数量，并确定体内甲状旁腺激素(PTH)治疗是否改变了它们在小鼠体内的相对比例或绝对数量。特定目的2：确定甲状旁腺激素治疗后或基础状态下破骨细胞前体细胞是否向髓外迁移，然后回到骨中。公共卫生相关性：这些研究将检验髓外循环与破骨细胞成熟的相关性，破骨细胞是唯一能够有效吸收骨的细胞。通过研究破骨细胞前体细胞在正常和病理条件下的传代过程、迁移模式和调节其归巢到骨的因素，我们希望更好地了解具有向破骨细胞发展能力的循环细胞在骨生理中的作用。预计这一知识将确定干预措施的新目标，可用于创造逆转骨丢失、改善骨质量和预防与骨质疏松症和其他代谢性骨疾病发展相关的疾病的治疗方法。

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.