Investigation of Cholinergic Signaling in Bone Mechanobiology

Bones constantly adapt to the stresses of daily activities like walking, running, and lifting. Specialized cells within bones, called osteocytes, play a crucial role in sensing mechanical forces and regulating bone mass and health. Recent discoveries suggest that acetylcholine-releasing nerves may functionally interact with osteocytes within bone tissue. This is a new paradigm in bone biology where neurotransmitters influence osteocytes directly. This work aims to define this paradigm. The research has the potential to lead to innovative treatments for osteoporosis and other bone diseases that affect millions of people. The project promotes scientific progress and enhances national health by improving the quality of life for aging populations. It will also generate activities that focus on biomechanics and bone health for a traveling interactive science exhibit that will serve rural communities. This project aims to investigate the role of acetylcholine signaling in osteocyte mechanotransduction and bone remodeling. Osteocytes are key mechanosensors in bone, using calcium signaling pathways to respond to mechanical loading. While acetylcholine is known for its role in parasympathetic nerve signaling and its ability to modulate calcium signaling, its specific impact on osteocyte function and interactions with cholinergic nerves remains unclear. Preliminary data suggest that osteocytes express acetylcholine signaling components, and that deletion of cholinergic receptors impairs load-induced calcium signaling in these cells. The project includes three specific aims: 1) Characterize the anatomical and functional relationship between cholinergic nerves and osteocytes in bone tissue using advanced imaging techniques. 2) Investigate the acute effects of local acetylcholine signaling modulation on osteocyte calcium responses to mechanical loading. 3) Examine the temporal effects of local acetylcholine signaling modulation on osteocyte mechanotransduction and bone remodeling over time. This research will provide insights into how acetylcholine signaling influences osteocyte function and bone health, with implications for developing new treatments for bone diseases like osteoporosis. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.