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

摘要 骨质疏松症是一种以骨量和骨质量进行性下降为特征的代谢性骨疾病， 导致骨骼脆弱和骨折风险增加。骨质量受骨耦合的严格控制 骨形成的再吸收，由骨破坏细胞之间的细胞通讯调节， 破骨细胞（OC）和骨形成细胞，成骨细胞（OB）。在这项研究中，我们将展示如何 OC通过一种新出现的细胞间通讯机制调节OC-OB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 先前报道，OC中1A型受体（BMPR 1A）介导的BMP信号传导的破坏 通过促进OB分化刺激骨形成。结合我们的初步数据，我们假设 OC中的BMP信号调节TNT的形成以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， 而不是不成熟的OB来交流我们还将在动物身上建立一个活体成像系统， 在类似骨质疏松症的情况下TNT的形成和功能的改变以及药物的影响 治疗如PTH。成功完成拟议的研究将开创一种全新的治疗方法， 通过抑制TNT形成/功能而不影响OC数量但增加骨密度的骨质疏松症 阵

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.