Osteomorphs are found in the blood and bone marrow, and fuse together to form osteoclasts, the cells that are specialized in resorbing bone. Osteomorph upregulated genes are implicated in rare and common bone diseases in humans.
Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete; By intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Image credit: McDonald et al., doi: 10.1016/j.cell.2021.02.002.
“This discovery is a game-changer, which not only helps us understand bone biology but presents significant new in-roads for osteoporosis therapy,” said Professor Tri Phan, a researcher at the Garvan Institute of Medical Research and the University of New South Wales.
“Osteomorphs express several genes that seem to be linked to bone disease, which could lead scientists to entirely new ways to target osteoporosis.”
At a microscopic level, our skeleton is constantly changing. To support bone growth, maintenance and repair damage, specialized cells on the bone surface break down old bone tissue and build it back up.
A change to that balance can lead to bone fragility, including osteoporosis.
To better understand bone resorption and how to treat it, Professor Phan and colleagues investigated osteoclasts in an experimental model.
Using intravital imaging technology that allows a deep look inside living bone tissue, they noticed that osteoclasts did something unusual — they split up into smaller cells, and then joined back to form osteoclasts again.
“This process was completely new to us,” said Dr. Michelle McDonald, also from the Garvan Institute of Medical Research and the University of New South Wales.
“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.”
Using cutting-edge single cell RNA sequencing technology, the team found that osteomorphs 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 Dr. Weng Hua Khoo, also from the Garvan Institute of Medical Research and the University of New South Wales.
“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.”
The scientists then deleted 40 of the genes switched on in osteomorphs in experimental models.
They found that for 17 of these genes, the deletion impacted on the amount of bone and bone strength, indicating a critical role in controlling bone.
“When we further investigated human genomic data in publicly available databases, we found that genes switched on in osteomorphs were linked to human gene variants that lead to skeletal dysplasia and control bone mineral density,” said Professor Peter Croucher, also from the Garvan Institute of Medical Research and the University of New South Wales.
Beyond revealing new avenues for treatment, findings provide a possible explanation of a commonly observed clinical phenomenon.
“Some individuals who discontinue the osteoporosis treatment denosumab experience a reduction in bone mass and an increase in so-called rebound vertebral fractures,” Professor Phan said.
“Denosumab blocks a molecule that we found is needed for the osteomorphs to form osteoclasts.”
“We 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.”
“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.”
A paper on the findings was published in the journal Cell.
_____
Michelle M. McDonald et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell, publihsed online February 25, 2021; doi: 10.1016/j.cell.2021.02.002
This article is based on text provided by the University of New South Wales.
