Researchers at the Garvan Institute of Medical Research have discovered a new type of bone cell that may yield novel therapeutic targets and strategies for osteoporosis and other skeletal diseases.
The cells, which the researchers have called osteomorphs, are found in the blood and bone marrow, and fuse together to form osteoclasts, which are specialized cells that break down bone tissue. The newly identified osteomorphs have a unique genomic profile that indicates potentially promising, and as yet unexplored targets for therapy.
“This discovery is a game-changer, which not only helps us understand bone biology but presents significant new in-roads for osteoporosis therapy,” said co-senior author Tri Giang Phan, PhD, who heads the Intravital Microscopy and Gene Expression Lab at the Garvan Institute. “Osteomorphs express several genes that seem to be linked to bone disease, which could lead scientists to entirely new ways to target osteoporosis.”
Phan is co-senior author of the team’s paper, which is published in Cell, and titled, “Ostoclasts recycle via osteomorphs during RANKL-stimulated bone resorption.”
The skeleton acts as the body’s scaffold, supporting our weight, allowing us to move, protecting vital organs, and controlling mineral homeostasis, the authors explained. It is also the site where blood cell components are formed. “Accordingly, it is a dynamic organ that is continuously remodeled throughout life in response to diverse environmental stimuli.”
At the microscopic level, the skeleton is constantly changing. To support bone growth, maintenance, and repair from damage, specialized cells on the bone surface break down old bone tissue (a process known as bone resorption) and then build it back up. “… remodeling is achieved by the coordinated action of osteoclasts that resorb old bone and osteoblasts that form new bone, activities that are coupled in both time and space,” the team noted. A change to that balance of resorption and rebuilding can lead to bone fragility, including osteoporosis, which is estimated to affect over 900,000 people in Australia alone.
While the importance of osteoclasts in bone homeostasis and health is evident in diseases, such as osteoporosis and rheumatoid arthritis, in which osteoclast formation and function is dysregulated, “ … the pivotal role of osteoclasts in health and disease, the biology of this cell type, particularly their life cycle in vivo, remains elusive,” the authors acknowledged.
To better understand bone resorption and potentially how to treat it, the Garvan researchers looked more closely at osteoclasts in an experimental mouse model. Using intravital imaging technology that allows a deep look inside living bone tissue, the researchers noticed that osteoclasts did something unusual—they split up into smaller cells, and then joined back to form osteoclasts again. These smaller cells the scientists named osteomorphs. “These studies reveal an unexpected cell fate in which osteoclasts recycle by fissioning into smaller more motile cells, which we have termed osteomorphs.”
“This process was completely new to us,” said Michelle McDonald, PhD, first author of the paper and leader of the bone microenvironment group at Garvan. “The consensus until now has been that osteoclasts undergo cell death after they’ve done their job, but we saw they were recycling by splitting up and joining back together again, a process which we hypothesize may increase their lifespan. We also found these cells in the blood and bone marrow, suggesting they can travel to other parts of the skeleton, as a likely ‘reserve’ of cells that are ready to fuse and deploy when osteoclasts are needed again.”
The investigators also used cutting-edge single-cell RNA sequencing technology—which they developed specifically for studying these cells in bone—to reveal that the newly identified cells switched on a number of genes. “The profile of genes that were switched on in these cells was really interesting—while many genes were also expressed by osteoclasts, several were unique, said co-author Weng Hua Khoo, PhD. “This, together with the evidence of the new re-fusion processes observed by intravital imaging, convinced us that we had discovered a new cell type, which we called osteomorphs, after the Mighty Morphin Power Rangers.”
In collaboration with colleagues at Imperial College London, the researchers investigated, using mouse models, the effects of deleting 40 of the genes switched on in osteomorphs. They found that for 17 of these genes, deletion impacted on the amount of bone and bone strength, indicating they played a critical role in controlling bone. Further investigation of human genomic data in publicly available databases found that genes switched on in osteomorphs were linked to human gene variants that lead to skeletal dysplasia and control bone mineral density, explained co-senior author Peter Croucher, PhD, deputy director of the Garvan Institute and head of the Bone Biology Lab. “Together, these findings revealed just how crucial osteomorphs are in bone maintenance, and that understanding these cells and the genes that control them may reveal new therapeutic targets for skeletal disease.”
The authors further stated, “… our analysis shows that osteomorph genes cause monogenic skeletal diseases and that some of these genes are also strongly associated with eBMD [estimated bone mineral density], indicating that osteomorph genes play a role in the pathogenesis of both rare monogenic and common polygenic skeletal diseases like osteoporosis,” the authors noted. They concluded, “Our study has revealed a suite of genes upregulated by osteomorphs, many of which have not been previously known to be involved in bone resorption. The bone phenotypes when these genes are deleted in mice and their role in monogenic skeletal dysplasias and association with eBMD confirm the important role of osteomorphs in bone homeostasis and disease and mark them as a valuable resource for future drug discovery.”
Beyond revealing new possible avenues for treatment, the team’s findings provide a possible explanation of a commonly observed clinical phenomenon, Phan noted. “Some individuals who discontinue the osteoporosis treatment denosumab experience a reduction in bone mass and an increase in so-called ‘rebound vertebral fractures’.” The authors say that denosumab blocks a molecule that they found is needed for the osteomorphs to form osteoclasts. The investigators suspect that patients who receive denosumab accumulate osteomorphs in their body, and that these are released to form osteoclasts, which resorb bone, when treatment is stopped.
They further suggest that studying the effects of denosumab and other osteoporosis medication on osteomorphs may inform how those treatments could be improved and how their withdrawal effects could be prevented. “Osteoclast recycling therefore not only provides a paradigm for understanding the behavior of these cells in their physiological niche in vivo but also a framework for understanding drug effects on bone homeostasis,” the authors concluded. Croucher said, “While we don’t yet fully understand the role of osteomorphs, their existence has already led to a major step change in our understanding of the skeleton. “This research has been an enormous combined international effort across many scientific disciplines. We look forward to exploring how these cells may change the approach to osteoporosis and other skeletal diseases moving forward.”