Osteoclast precursors in bone homeostasis and inflammatory arthritis

骨稳态和炎症性关节炎中的破骨细胞前体

基本信息

批准号：
8497630
负责人：
Julia F Charles
金额：
$ 13.18万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8497630
关键词：
Adult Affect Arthritis Autoimmune Process Behavior Blood Circulation Bone Marrow Bone Resorption Bone remodeling CX3CL1 gene Cell Differentiation process Cell Lineage Cell physiology Cell surface Cells Characteristics Commit Data Disease Environment Generations Grant Homeostasis Human ITGAM gene Immigration In Vitro Inflammation Inflammatory Joints Knowledge Laboratories Life Ligands Macrophage Colony-Stimulating Factor Mediating Metastatic Neoplasm to the Bone Molecular Mus Myelogenous Myeloid Cells Osteoblasts Osteoclasts Osteoporosis Pathology Peripheral Phenotype Population Process Property Reporting Research Rheumatoid Arthritis Scheme Signal Pathway Site Source System TNFSF11 gene Tissues Work bone bone cell bone loss career development chemokine receptor cytokine disability in vivo innovation joint destruction migration monocyte mouse model precursor cell progenitor receptor research study skeletal skeletal disorder trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): Bone is continuously remodeled throughout life, with complete skeletal turnover estimated to occur every decade in humans. The osteoclast is a key cell in homeostatic bone remodeling, but excess osteoclast activity leads to bone pathology, including the highly prevalent disease osteoporosis. In rheumatoid arthritis, the inflammatory environment activates osteoclasts, resulting in bone erosions and generalized bone loss. While the signaling pathways, transcription factors and molecular machinery that govern osteoclast differentiation and resorptive activity have been studied intensively over the past two decades, much less is understood about the generation, migration and commitment of OC precursor cells (OCP). In this grant we seek to expand our understanding of OCP function and trafficking in homeostatic and inflammatory bone remodeling in vivo. We have recently identified a bone marrow CD11b-/lo Ly6Chi population with ex vivo osteoclast precursor (OCP) activity. The experiments we propose will establish whether bone marrow CD11b-/lo Ly6Chi OCP are multi-potent myeloid precursors or are restricted to the osteoclast lineage in vivo. Building on this we will determine if inflammation induces cell intrinsic changes in the OCP that alter its progenitor properties and examine the requirements for OCP to traffic to inflamed joints. To establish whether mouse models investigating OCP can be applied to understanding human OCP, we propose to define the human bone marrow osteoclast precursor. This grant will advance our basic understanding of the osteoclast lineage in mice and humans, and contribute to knowledge about skeletal remodeling and joint destruction in inflammatory arthritis. We anticipate our data will be directly applicable to understanding bone destruction in RA, osteoporosis and related inflammatory diseases.

描述（由申请人提供）：骨骼在整个生命中都经常重塑，完全骨骼周转估计每十年就会发生在人类中。破骨细胞是稳态骨重塑的关键细胞，但过量的破骨细胞活性导致骨病理学，包括高度普遍的疾病骨质疏松症。在类风湿关节炎中，炎症环境激活破骨细胞，导致骨侵蚀和普遍的骨质流失。在过去的二十年中，已经对控制破骨细胞分化和吸收活性的信号通路，转录因子和分子机制进行了深入研究，但了解OC前体细胞（OCP）的产生，迁移和承诺的了解少得多。在这笔赠款中，我们旨在扩大对体内稳态和炎症性骨骼重塑的OCP功能和贩运的理解。我们最近确定了具有离体破骨前体（OCP）活性的骨髓CD11b-/lo ly6chi种群。我们提出的实验将确定骨髓CD11b-/lo ly6chi OCP是多动髓样前体，还是仅限于体内破骨细胞谱系。在此基础上，我们将确定炎症是否会导致OCP的细胞内在变化，从而改变其祖细胞特性，并检查OCP对发炎关节的流量的要求。为了确定研究OCP的小鼠模型是否可以应用于理解人的OCP，我们建议定义人骨骨髓破骨细胞前体。这笔赠款将提高我们对小鼠和人类破骨细胞谱系的基本理解，并有助于了解骨骼重塑和炎症性关节炎的关节破坏。我们预计我们的数据将直接适用于理解RA，骨质疏松症和相关炎症性疾病的骨骼破坏。