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性骨病，其特征是骨量和骨质量进行性下降，导致骨骼脆弱并增加骨折风险。骨量受到骨耦合的严格控制吸收骨形成，这是由骨破坏细胞之间的细胞通讯调节的，破骨细胞（OC）和骨形成细胞，成骨细胞（OB）。在这项拟议的研究中，我们将展示如何 OC 通过一种新出现的细胞间通讯机制来调节 OC 到 OB 的通讯，即隧道纳米管（TNT），并探索骨骼疾病的潜在预防治疗解决方案。我们之前报道过 OC 中 1A 型受体 (BMPR1A) 介导的 BMP 信号传导中断通过促进 OB 分化来刺激骨形成。结合我们的初步数据，我们假设 OC 中的 BMP 信号传导可调节 TNT 形成，从而局部抑制成熟成骨细胞的功能。我们将识别通过 TNT 从 OC 转移到 OB 的分子以及 OC 如何识别成熟的机制，但是不成熟的OB无法沟通。我们还将建立一个动物活体成像系统来证明在模拟骨质疏松症的情况下，TNT 的形成和功能发生变化以及药物的影响治疗如PTH。拟议研究的成功完成将开创一种全新的治疗方法通过抑制 TNT 形成/功能来治疗骨质疏松症，不影响 OC 数量，但会增加骨量形成。