A new model for spatio-temporal coupling of bone formation and bone resorption governed by osteoclasts

破骨细胞控制的骨形成和骨吸收时空耦合的新模型

基本信息

批准号：
10905262
负责人：
Yuji MISHINA
金额：
$ 39.35万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10905262
关键词：
Address Affect Age-Related Bone Loss Albers-Schonberg disease Animals Apoptosis Biology Bone Diseases Bone Formation Stimulation Bone Morphogenetic Proteins Bone Resorption Bone remodeling Cell Communication Cell Death Cell Death Induction Cell physiology Cells Cessation of life Clinical Code Communication Coupling Data Disease Distal Elderly Failure Fracture Homeostasis Human In Vitro Intervention Mediating Metabolic Bone Diseases Modeling Molecular Nanotubes Organ Osteoblasts Osteoclasts Osteogenesis Osteoporosis Osteoporosis prevention Pathologic Pattern Pharmacotherapy Pharmacy (field)Play Population Preventive Process Production Proteins Public Health Regimen Reporting Risk Role Shapes Signal Transduction Signaling Protein Site Skeletal system System TNFSF11 gene Therapeutic Tissues bone bone fragility bone loss bone mass bone morphogenetic protein receptors bone quality druggable target fracture risk imaging system improved in vivo innovation insight morphogens nano new therapeutic target novel osteoblast differentiation prevent programs receptor recruit skeletal skeletal disorder spatiotemporal transcriptome

项目摘要

ABSTRACT Osteoporosis is a metabolic bone disorder characterized by progressive decline of bone mass and bone quality, leading to bone fragility and an increased risk of fracture. Bone mass is tightly controlled by coupling of bone resorption to bone formation, which is regulated by a cellular communication between bone-destroying cells, osteoclasts (OCs), and bone-forming cells, osteoblasts (OBs). In this proposed study, we will demonstrate how OCs regulate OC-to-OB communication by a newly emerged mechanism of cell-cell communication, namely tunneling nanotube (TNT), and explore the potential preventive therapeutic solutions in skeletal diseases. We previously reported that disruption of BMP signaling mediated by type 1A receptor (BMPR1A) in OCs stimulates bone formation by promoting OB differentiation. Together with our preliminary data, we hypothesize that BMP signaling in OCs regulate TNT formation to locally suppress functions of mature osteoblasts. We will identify molecules transferred from OCs to OBs via TNT and mechanisms of how OCs recognize mature, but not immature OBs to communicate. We will also establish a live imaging system in animals to demonstrate alterations in formation and function of TNTs in conditions mimicking osteoporosis and impacts of drug treatment such as PTH. Successful completion of the proposed study will pioneer a totally new treatment for osteoporosis by suppression of TNT formation/function without affecting OC number but to increase bone formation.

抽象的骨质疏松症是一种代谢骨疾病，其特征是骨骼质量和骨质质量的逐渐下降，导致骨骼脆弱性和骨折风险增加。骨头通过骨头耦合严格控制吸收骨形成，骨形成受骨破坏细胞之间的细胞通信的调节，破骨细胞（OC）和骨形成细胞，骨细胞（OBS）。在这项拟议的研究中，我们将证明 OCS通过新出现的细胞电池通信机制来调节OC-OB通信，即隧道纳米管（TNT），并探索骨骼疾病中潜在的预防治疗溶液。我们先前报道了OCS中由1A受体（BMPR1A）介导的BMP信号的破坏通过促进OB分化刺激骨形成。与我们的初步数据一起，我们假设 OC中的BMP信号传导调节TNT形成以局部抑制成熟成骨细胞的功能。我们将鉴定通过TNT转移到OBS的分子以及OC如何识别成熟的机制，但是并非不成熟地沟通。我们还将在动物中建立一个实时成像系统以证明在模仿骨质疏松症的条件下，TNT的形成和功能改变了药物的影响诸如PTH之类的治疗。拟议的研究成功完成将开拓全新的待遇通过抑制TNT形成/功能而不会影响OC数，而是增加骨骼，骨质疏松症形成。