In some heartening news for the 80% of Americans who will endure lower back pain in their lifetime, researchers have found that an existing drug can be redeployed to target ‘sleeping’, or senescent, osteoclast cells to significantly reduce spinal hypersensitivity.
"Osteoclasts are the principal bone-resorbing cells essential for bone remodeling and skeletal development, but we have shown that osteoclasts in the endplate of the spinal column undergo senescence, leading to nerve growth and spine pain," said senior author Xu Cao, professor of Orthopedic Surgery at Johns Hopkins University School of Medicine. "Our findings suggest that depletion of these senescent osteoclasts, perhaps by use of existing drugs, could represent a new strategy in the treatment of lower back pain."
The drug in question is experimental anticancer drug Navitoclax, a Bcl-2 inhibitor previously known as ABT263, made by US pharmaceutical company AbbVie. In earlier studies, the drug has shown promise beyond cancer treatment, rejuvenating skin cells and combatting Alzheimer's disease.
Cellular senescence is a key focus of research in the emerging area of geroscience, or age-related disease. Senescent cells are ones that stop dividing, but also don’t die off when they should, which can lead to inflammation and, as we are learning, a host of age-related chronic conditions.
It’s also one of the main targets of the new class of drugs known as senolytics, which aim to counter the cellular dysfunction that comes with age to extend healthspan and lifespan. Nativoclax is also a senolytic.
When it comes to osteoclasts, these types of senescent cells are ‘sleeping’ instead of doing their job of breaking down bone to be remodeled for new tissue.
"Senescence promotes age-related musculoskeletal diseases such as osteoporosis, and removing senescent cells from degenerated vertebral disks restores the intervertebral disk structure," explains lead author Dayu Pan, from Johns Hopkins. "We previously found that osteoclasts cause the endplates between each vertebra and disk to become porous, allowing infiltration of new nerves that cause lower back pain. In this study, we set out to test whether this is caused by a specific group of senescent osteoclasts and whether eliminating these osteoclasts could reduce the pain."
Using a mouse model, the researchers tested whether senescent osteoclasts were to be found in the porous endplates of animals with two types of pain issues – one age-related and the other the result of lumbar spine instability.
Once identified, they used Navitoclax, which targeted the senescent cells and removed them from the ‘construction site’, effectively reducing pain in both cohorts of mice and increasing activity, compared to a control group.
Analysis of bone tissue showed a reduced degeneration and porousness in the endplates, and reduced separation between them. They also found that without the senescent cells, the lack of porousness meant new nerves were unable to grow into the bones and trigger sensitivity and pain.
It’s a promising result for the researchers, who hope it can be further evaluated in a clinical trial.
The study is available as a peer-reviewed preprint ahead of publishing in the journal eLife.
Source: Johns Hopkins University via EurekAlert!
