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骼疾病， 导致骨骼脆弱，增加骨折的风险。骨量受到骨偶联的严格控制 吸收到骨形成，这是由骨破坏细胞之间的细胞通讯调节的， 破骨细胞(OCs)、骨形成细胞、成骨细胞(OBS)。在这项拟议的研究中，我们将演示如何 OCS通过一种新出现的细胞-细胞通讯机制来调节OC-to-OB通讯，即 隧道纳米管(TNT)，并探索潜在的骨骼疾病预防治疗解决方案。我们 先前报道了OCS中由1A型受体(BMPR1A)介导的BMP信号的干扰 通过促进成骨细胞分化来促进骨形成。结合我们的初步数据，我们假设 OCS中的BMP信号调节TNT的形成，从而局部抑制成熟成骨细胞的功能。我们会 识别通过TNT从OCS转移到OBS的分子以及OCS如何识别成熟的机制，但 不是不成熟的笨蛋来交流。我们还将在动物身上建立一个活体成像系统来演示 类骨质疏松条件下TNTs形成和功能的变化及药物的影响 甲状旁腺素等治疗。拟议研究的成功完成将开创一种全新的治疗方法 骨质疏松症通过抑制TNT的形成/功能而不影响骨钙素数量而增加骨量 队形。

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.