Osteoclast precursors in bone homeostasis and inflammatory arthritis

描述(由申请人提供)：骨骼在一生中不断重塑，据估计，人类每十年就会发生一次完整的骨骼转换。破骨细胞是动态平衡性骨重建的关键细胞，但破骨细胞活性过高会导致骨病理，包括高发的骨质疏松症。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。在过去的二十年里，调控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已经得到了深入的研究，但对OC前体细胞(OCP)的产生、迁移和承诺的了解却很少。在这项资助中，我们寻求扩大我们对OCP功能以及体内内稳态和炎症性骨重建的运输的理解。我们最近发现了一个具有体外破骨细胞前体(OCP)活性的骨髓CD11b-/lo Ly6chi群体。我们提出的实验将确定骨髓CD11b-/lo Ly6chi OCP是多潜能的髓系前体，还是仅限于体内的破骨细胞系。在此基础上，我们将确定炎症是否诱导OCP中细胞的内在变化，从而改变其祖细胞特性，并检查OCP对交通到发炎关节的要求。为了确定研究OCP的小鼠模型是否可以应用于理解人类OCP，我们建议定义人骨髓破骨细胞前体。这笔赠款将促进我们对小鼠和人类破骨细胞谱系的基本了解，并有助于了解炎症性关节炎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类风湿性关节炎、骨质疏松症和相关炎症性疾病的骨破坏。

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.