Trap+ Mononuclear Cells in Periosteal Bone Formation

捕获骨膜骨形成中的单核细胞

• 批准号: 10196939
• 负责人: Xu Cao
• 金额: $ 34.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-14 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196939
• 关键词: Area; Biology; Blood Vessels; Bone Development; Bone Growth; Bone Regeneration; Bone Surface; Bone remodeling; Cell Lineage; Cells; Clinical; Collagen; Data; Endosteum; Fracture; Functional disorder; Goals; Growth; Growth and Development function; Homeostasis; Human; Impairment; Injections; Joints; Knock-out; Lymphatic; Macrophage Colony-Stimulating Factor; Maintenance; Marrow; Mechanical Stress; Mechanics; Mesenchymal; Metabolism; Minerals; Modeling; Mononuclear; Mus; Nerve; Nerve Endings; Organ; Osteocalcin; Osteoclasts; Osteocytes; Osteogenesis; Periosteal Cell; Periosteum; Physiological; Physiology; Play; Process; Proteins; Regulation; Rest; Role; Signal Transduction; Skeleton; Stimulus; Structure; Surface; TNFSF11 gene; Tissues; Vascular Endothelial Growth Factors; Weight; Wild Type Mouse; afferent nerve; angiogenesis; articular cartilage; bone; cortical bone; long bone; macrophage; mechanical load; migration; monocyte; nestin protein; osteogenic; periostin; platelet-derived growth factor BB; postnatal; public health relevance; recruit; repaired; response; sphingosine 1-phosphate; spine bone structure; stem cells; substantia spongiosa

Project Summary/ Abstract Periosteal bone growth and modeling take place in the periosteum at the outer surface of cortical bones. The perioseum, which covers the entire bone surface except the portion of bones that contains articular cartilage, is one of the most osteogenic tissues in the body and plays a critical role in cortical expansion during growth. Periosteal bone formation has different mechanisms from other areas of bone surface such as endosteum, secondary spongiosa and trabecular bone remodeling, etc. Despite its physiological significance, the periosteum is often overlooked when it comes to processes that occur in the underlying cortical bone. Periosteal biology remains little investigated and poorly understood. Structurally, the periosteum is composed of two layers; adjacent to the periosteal bone surface is a layer of loosely packed cells essential for growth and repair of the underlying bone. Further outward is a layer of densely packed periosteum derived stem cells (PDSCs) interspersed with lymphatics, blood vessels and nerve endings. The microenvironment of the outer layer serves as a niche to maintain the PDSCs whilst the inner layer provides an osteogenic microenvironment for periosteal bone formation. We have shown that there are no osteal macrophages and Trap+ mononuclear cells in CSF-1 op/op mice (CSF-1-/-), and interestingly, no obvious cortical bone formation. A single injection of rhM-CSF is sufficient for rescue of osteoclast recruitment and survival in CSF-1-/- mice. These results suggest that periosteal macrophages are essential in maintenance of periosteum microenvironment for periosteal bone formation. Moreover, we have shown that Trap+ mononuclear cells derived from wild WT mice secrete PDGF-BB to induce migration of mesenchymal stromal/stem cells. Knockout of PDGF-BB in the Trap+ cell lineage reduces periosteal angiogenesis and bone formation but PDSCs and matrix proteins are still present in the periosteum, suggesting periosteal macrophages play more important role in maintenance of periosteum homeostasis. In addition, we have found mechanical stress induces periosteal TRAP+ mononuclear cells to secrete PDGF-BB for angiogenesis and bone formation in our preliminary data. Thus, we hypothesize that periosteal macrophages maintain homeostasis of the periosteum and TRAP+ mononuclear cells recruit PDSCs from outward layer to the periosteal surface for angiogenesis and bone formation. In this proposal, we will first determine the role of periosteal macrophages in periosteum homeostasis. We will then determine the function of Trap+ mononuclear cells, specifically, the mechanisms by which PDSCs are recruited by Trap+ mononuclear cells for periosteal bone formation. Finally, we will validate the role of TRAP+ mononuclear cells in mechanical stress-induced periosteal bone formation.

项目概要/摘要 骨膜骨生长和建模发生在皮质骨外表面的骨膜中。 骨膜，覆盖整个骨表面，除了包含关节的部分骨外 软骨是体内最具成骨性的组织之一，在皮质扩张中起着至关重要的作用 在成长过程中。骨膜骨形成具有与骨表面其他区域不同的机制，例如 如骨内膜、继发性海绵体和骨小梁重塑等。 重要性，当涉及到发生在底层的过程时，骨膜经常被忽视 皮质骨。骨膜生物学仍然很少被研究和了解。从结构上来说， 骨膜由两层组成；与骨膜骨表面相邻的是一层松散堆积的 对于底层骨骼的生长和修复至关重要的细胞。再向外是一层密密麻麻的 骨膜衍生干细胞（PDSC）散布于淋巴管、血管和神经末梢。这 外层的微环境作为维持 PDSC 的利基，而内层则提供 骨膜骨形成的成骨微环境。我们已经证明不存在骨 CSF-1 op/op 小鼠 (CSF-1-/-) 中的巨噬细胞和 Trap+ 单核细胞，有趣的是，没有明显的变化 皮质骨形成。单次注射 rhM-CSF 足以挽救破骨细胞的募集和 CSF-1-/- 小鼠的存活率。这些结果表明骨膜巨噬细胞在维护中至关重要 骨膜骨形成的骨膜微环境。此外，我们还证明了 Trap+ 野生WT小鼠来源的单核细胞分泌PDGF-BB诱导间充质细胞迁移 基质/干细胞。 Trap+ 细胞谱系中 PDGF-BB 的敲除减少了骨膜血管生成， 骨形成，但骨膜中仍存在 PDSC 和基质蛋白，表明骨膜 巨噬细胞在维持骨膜稳态中发挥着更重要的作用。此外，我们还有 发现机械应力诱导骨膜 TRAP+ 单核细胞分泌 PDGF-BB 促进血管生成 和我们初步数据中的骨形成。因此，我们假设骨膜巨噬细胞维持 骨膜的稳态和 TRAP+ 单核细胞从外层招募 PDSC 骨膜表面用于血管生成和骨形成。在本提案中，我们将首先确定 骨膜巨噬细胞在骨膜稳态中的作用。然后我们将确定Trap+的功能 单核细胞，特别是 Trap+ 单核细胞招募 PDSC 的机制 用于骨膜骨形成。最后，我们将验证 TRAP+ 单核细胞在机械中的作用 应力诱导的骨膜骨形成。