STUDIES ON THE REGULATION OF OSTEOCLAST PRECURSOR CELLS

破骨细胞前体细胞调控的研究

• 批准号: 8055018
• 负责人: Joseph A Lorenzo
• 金额: $ 30.95万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055018
• 关键词: Aftercare; Animals; Area; Blood; Blood Circulation; Bone Marrow; Bone remodeling; Cell surface; Cells; Development; Extramedullary; Goals; Health; Home environment; Homeostasis; Homing; Hormones; Intervention; Knowledge; Mature Bone; Metabolic Bone Diseases; Morbidity - disease rate; Mus; Myeloid Cells; Osteoblasts; Osteoclasts; Osteoporosis; Parathyroid gland; Pathologic; Pathway interactions; Pattern; Peripheral; Phenotype; Physiology; Population; Regulation; Relative (related person); Role; Site; Spleen; Tissues; bone; bone loss; bone mass; bone quality; bone turnover; improved; in vivo; migration; precursor cell; prevent; substantia spongiosa

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.

描述（由申请人提供）：这些研究的目的是了解系统性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剂（与成骨细胞）。然而，我们对它们成熟的步骤所知有限。具体来说，该应用将关注破骨细胞前体迁移到骨骼的途径。目前尚不清楚源自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骼，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系统，在髓外经历成熟步骤，然后返回骨骼成为吸收细胞。骨稳态的系统调节因子如甲状旁腺激素是否会改变骨髓微环境，增加破骨细胞前体的循环和归巢尚不清楚。也有可能这两种途径都很重要，靠近骨髓部位的骨内骨和骨小梁重构受途径1的调节，而非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。通过研究正常和病理条件下破骨细胞前体细胞的谱系进展、迁移模式和调节因子，我们希望更好地了解循环细胞在骨生理中的作用，这些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，可用于创造治疗方法，以逆转骨质流失，改善骨质量，预防与骨质疏松症和其他代谢性骨病的发展相关的发病率。特异性目的1：确定骨髓和外周血（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体内破骨细胞前体细胞的相对比例或绝对数量。特异性目的2：确定破骨细胞前细胞是否在基底状态或甲状旁腺激素治疗小鼠后迁移到髓外然后回到骨中。公共卫生相关性：这些研究将检查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。通过研究正常和病理条件下破骨细胞前体细胞的谱系进展、迁移模式和调节因子，我们希望更好地了解循环细胞在骨生理中的作用，这些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，可用于创造治疗方法，以逆转骨质流失，改善骨质量，预防与骨质疏松症和其他代谢性骨病的发展相关的发病率。

项目成果

Osteoclast precursor cells.

• DOI: 10.1007/978-0-387-72009-8_10
• 发表时间: 2007
• 期刊: Advances in experimental medicine and biology
• 作者: J. Lorenzo

Changes in bone sclerostin levels in mice after ovariectomy vary independently of changes in serum sclerostin levels.

• DOI: 10.1002/jbmr.1773
• 发表时间: 2013-03
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Jastrzebski, Sandra;Kalinowski, Judith;Stolina, Marina;Mirza, Faryal;Torreggiani, Elena;Kalajzic, Ivo;Won, Hee Yeon;Lee, Sun-Kyeong;Lorenzo, Joseph
• 通讯作者: Lorenzo, Joseph

Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery.

• DOI: 10.1002/jbmr.1822
• 发表时间: 2013-05
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Jacome-Galarza, Christian E.;Lee, Sun-Kyeong;Lorenzo, Joseph A.;Aguila, Hector Leonardo
• 通讯作者: Aguila, Hector Leonardo