Osteoclast precursors in bone homeostasis and inflammatory arthritis

描述（由申请人提供）：骨在整个生命过程中不断重塑，估计人类每十年发生一次完整的骨骼更新。破骨细胞是稳态骨重建中的关键细胞，但破骨细胞过度活性导致骨病理学，包括高度流行的疾病骨质疏松症。在类风湿性关节炎中，炎症环境激活破骨细胞，导致骨侵蚀和全身性骨丢失。虽然在过去的二十年中，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，但对OC前体细胞（OCP）的产生、迁移和定型的了解却少得多。在这项资助中，我们寻求扩大我们对OCP功能和体内稳态和炎症性骨重建的理解。我们最近已经确定了骨髓CD 11b-/lo Ly 6Chi人口与体外破骨细胞前体（OCP）的活动。我们提出的实验将确定骨髓CD 11b-/lo Ly 6Chi OCP是否是多能骨髓前体或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诱导OCP中的细胞内在变化，从而改变其祖细胞特性，并检查OCP向发炎关节运输的要求。为了建立小鼠模型研究OCP是否可以应用于了解人类OCP，我们建议定义人骨髓破骨细胞前体。这项资助将促进我们对小鼠和人类破骨细胞谱系的基本理解，并有助于了解炎症性关节炎中的骨骼重塑和关节破坏。我们预计我们的数据将直接适用于了解RA，骨质疏松症和相关炎症性疾病的骨破坏。 公共卫生相关性：骨质破坏是类风湿性关节炎、骨质疏松症、原发性和转移性骨癌致残的主要原因。体内只有一种细胞能够破坏骨骼：破骨细胞。目前，这种细胞如何在这些疾病中产生还知之甚少。拟议的研究将研究破骨细胞如何在小鼠和人类中产生，它们如何导致炎症性关节炎中的骨质流失和关节破坏，以及我们如何将这些知识应用于类风湿性关节炎，骨质疏松症和相关骨骼疾病。

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. PUBLIC HEALTH RELEVANCE: Destruction of bone is a major cause of disability in rheumatoid arthritis, osteoporosis and primary and metastatic bone cancer. Only one cell in the body is capable of destroying bone: the osteoclast. Currently, how this cell arises in these diseases is poorly understood. The proposed studies will examine how osteoclasts are generated in mice and humans, how they contribute to bone loss and joint destruction in inflammatory arthritis, and how we can apply that knowledge to rheumatoid arthritis, osteoporosis and related skeletal diseases.