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.