Researchers have discovered that an existing drug can be redeployed to target "sleeping" or senescent osteoclasts to significantly reduce hypersensitivity in the spine. "Osteoclasts are the primary bone-resorbing cells necessary for bone remodeling and skeletal development, but we have shown that osteoclasts in the spinal endplates undergo senescence, leading to nerve proliferation and spinal pain," said senior author Xu Cao, professor of orthopedics at the Johns Hopkins University School of Medicine.
"Our findings suggest that perhaps depleting these senescent osteoclasts using existing drugs could be a new strategy for treating low back pain."
The drug in question is the experimental anti-cancer drug Navitoclax, a Bcl-2 inhibitor formerly known as ABT263 and produced by the US pharmaceutical company AbbVie. In earlier studies, the drug has shown promise beyond cancer treatment, rejuvenating skin cells and fighting Alzheimer's disease.
Cellular senescence is a focus of research in the emerging field of geriatrics, or age-related diseases. Senescent cells are cells that stop dividing but also don't die when they should, which can lead to inflammation and, as we're learning, contribute to a host of age-related chronic diseases.
It is also one of the main targets of a new class of drugs known as "senolytics," which are designed to combat the cellular dysfunction that occurs with age to extend health and lifespan. Nativoclax is also an aging agent.
Speaking of osteoclasts, these types of senescent cells are "sleeping" instead of doing their job of breaking down bone to remodel new tissue.
"Aging induces age-related musculoskeletal diseases such as osteoporosis, and removing senescent cells from degenerated discs can restore disc structure," explains first author Dayu Pan from Johns Hopkins University. "We previously found that osteoclasts cause low back pain by causing the endplates between each vertebra and the disc to become porous, allowing new nerves to infiltrate. In this study, we set out to test whether this was caused by a specific group of senescent osteoclasts, and whether eliminating these osteoclasts could reduce pain."
Using mouse models, the researchers tested whether senescent osteoclasts were found in the porous inner lamina of animals with two types of pain problems, one age-related and one caused by lumbar instability.
After determining the cause, they used Navitoclax to target senescent cells and remove them from the "construction site." Compared with the control group, they effectively reduced pain and increased their mobility in both groups of mice.
Analysis of the bone tissue showed less degradation and porosity of the inner plates, as well as less separation between the inner plates. They also found that without senescent cells, a lack of porosity means new nerves cannot grow into the bone and cause sensitivity and pain.
This is a promising result for the researchers, who hope to further evaluate it in clinical trials.
The research results were released as a peer-reviewed preprint before being published in the journal eLife.