Cornell research could rebrand bone as an extension of the nervous system and reshape the understanding of its cellular signaling, thanks to a new grant from the National Science Foundation.
Bone is often thought of as a static part of the body, allowing us to stand and move, but the tissue is actually constantly changing, being built and resorbed over time in response to its environment. Researchers in the Meinig School of Biomedical Engineering will use the grant to investigate how osteocytes - specialized cells that respond to and regulate forces within bones - interact with and are impacted by the part of the nervous system that controls rest related involuntary functions such as digestion and heart rate.
Immunofluorescent staining was performed to produce 3D reconstructions of metatarsal bones for characterization of skeletal innervation, with close-ups at the distal, midshaft and proximal ends.
"I think an argument could be made that osteocytes are the nervous cells of bone," said Karl Lewis, an assistant professor of biomedical engineering and principle investigator on the grant. "If you look at an osteocyte and a nerve cell side by side, they look very similar. Osteocytes sense and then respond to the specific stimulus of force. Then they transduce that signal into biology. So in a lot of ways, they also function like nerve cells."
Titled "Investigation of Cholinergic Signaling in Bone Mechanobiology," the award will fund the Lewis Lab to investigate how osteocytes are regulated by acetylcholine - a chemical messenger that allows nerve cells to communicate with other cells responsible for involuntary bodily functions. Scientists want to know more about this regulation because it could reveal new pathways that influence bone formation and maintenance.
Scientists already understand how messengers that control nerve signaling in stressful situations - neurotransmitters like norepinephrine and adrenaline - affect bones, but they are still exploring acetylcholine's role.
"Increased norepinephrine in the blood is associated with decreased bone mass, which increases risk of fracture," said Lewis, who hypothesizes that the opposite may be true for signaling related to involuntary functions during rest.
Members of the Lewis Lab, from left: Karl Lewis, assistant professor of biomedical engineering; graduate students Melia Matthews, Samantha Bratcher, and Andi Garcia-Ortiz; and postdoctoral researcher Murtaza Wasi.
"In every other organ system we have a very full understanding of the balancing act that happens between nerves signaling during stressful and restful situations. For example, in the heart, norepinephrine increases the heart rate, acetylcholine decreases the heart rate. There is a similar pattern in the lungs, the gut, in muscles and in vasculature. We don't have that sort of clear picture of the balancing act or neurotransmitters happening in bone."
However, some hints have emerged that support the hypothesis.
"A class of drugs used to treat Alzheimer's disease increases the circulating acetylcholine by stopping their degradation. And those drugs have a marked anabolic effect on bone tissue, decreasing fracture risk by 20 to 30 percent by increasing bone mass," Lewis said, adding that this promising area of research may answer questions that provide new insight into treatments for bone disease. "I would like to identify a biological lever in osteocytes that we can use to combat osteoporosis and bone metabolic diseases."
Lewis is poised to change the baseline understanding of bone cells and said he hopes to use this research to set the foundation for a story that will have translational biomedical applications down the line.
The funding will span three years and will additionally support trainees in various stages. Murtaza Wasi, a postdoctoral researcher, was recently brought into the lab to take point on the project. Wasi said, "I am excited about the potential of this research to uncover the
mechanisms that connect osteocytes and nerves, and to contribute to a broader
understanding of bone biology and its interplay with systemic health."
Findings from the research will be used to inform subjects taught in Lewis's mechanobiology course and will help create workshop modules for biomedical-focused children's exhibit being produced for the Ithaca Sciencenter.
