Trap+ Mononuclear Cells in Periosteal Bone Formation

捕获骨膜骨形成中的单核细胞

• 批准号: 9902330
• 负责人: Xu Cao
• 金额: $ 36.03万
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902330
• 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.

项目摘要/摘要 骨膜骨生长和建模发生在皮质骨外表面的骨膜中。 薄膜覆盖了整个骨表面，除了包含关节的骨骼的一部分 软骨，是体内最成骨的组织之一，在皮质膨胀中起着至关重要的作用 在生长期间。骨膜骨形成与骨表面其他区域具有不同的机制 作为内接，继发性海绵和小梁骨头的重塑等。尽管有生理 意义上，骨膜通常在底层中发生的过程中被忽略 皮质骨。骨膜生物学的研究很少，理解不足。在结构上， 骨膜由两层组成。在骨膜骨表面附近是一层松散的堆积 细胞对于基础骨的生长和修复必不可少的细胞。进一步的是一层密集的包装 骨膜衍生的干细胞（PDSC）散布在淋巴管，血管和神经末端。这 外层的微环境用作维持PDSC的利基市场，而内层提供 用于骨膜骨形成的成骨微环境。我们已经表明没有面孔 CSF-1 OP/OP小鼠（CSF-1 - / - ）中的巨噬细胞和陷阱+单核细胞，有趣的是，没有明显的 皮质骨形成。单一注射RHM-CSF足以挽救破骨细胞招募和 CSF-1 - / - 小鼠的生存。这些结果表明骨膜巨噬细胞在维持中至关重要 骨膜微环境的骨膜骨形成。而且，我们已经证明了陷阱+ mononuclear cells derived from wild WT mice secrete PDGF-BB to induce migration of mesenchymal 基质/干细胞。陷阱+细胞谱系中PDGF-BB的敲除可减少骨膜血管生成和 骨形成，但PDSC和基质蛋白仍然存在于骨膜中，表明骨膜 巨噬细胞在维持骨膜稳态中起着更重要的作用。此外，我们还有 发现机械应力诱导骨膜陷阱+单核细胞分泌PDGF-BB血管生成 和我们的初步数据中的骨形成。因此，我们假设骨膜巨噬细胞保持 骨膜和陷阱+单核细胞的稳态从外层募集PDSC 用于血管生成和骨形成的骨膜表面。在此提案中，我们将首先确定 骨膜巨噬细胞在骨膜稳态中的作用。然后，我们将确定陷阱+的功能 单核细胞，具体是由TRAP+单核细胞募集PDSC的机制 用于骨膜骨形成。最后，我们将验证陷阱+单核细胞在机械中的作用 应力诱导的骨膜骨形成。