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Newly-discovered bone cells may become target for osteoporosis treatment

Reuters Health - 01/03/2021 - Researchers have discovered a new type of bone cells, called "osteomorphs," which may be targeted for osteoporosis and other skeletal diseases.

The discovery came when Dr. Tri Giang Phan of the Garvan Institute of Medical Research in Darlinghurst, New South Wales and colleagues were studying osteoclasts, cells that resorb bone.

"The dogma until now was that osteoclasts died after they finished resorbing bone," Dr. Phan told Reuters Health by email. However, he said, "intravital imaging revealed that the bone-resorbing osteoclasts split up into daughter cells, which we called osteomorphs. This had never been seen before and was totally unexpected. The new finding suggests that the dogma is wrong."

The osteomorphs were able to fuse together to form osteoclasts in a process the team calls "cellular recycling."

As reported in Cell, the researchers performed single cell RNA sequencing to profile the genes that were highly expressed by osteomorphs. Those genes were shown to be important in bone structure and function in mice.

"Working with colleagues at Imperial College in London," Dr. Phan said, "we showed that when 17 of these genes were knocked out, the mice developed abnormal bones." Specifically, the deletions impacted the amount of bone, as well as bone strength.

Genes upregulated by osteomorphs also were shown to be important in human bone diseases. Specifically, investigation of human orthologues of osteomorph-upregulated genes were found to be involved in rare skeletal dysplasias caused by single-gene defects. Seventy-one of the genes also were found to be involved in the regulation of bone mineral density in a large population cohort, the UK Biobank Study, and may therefore be important in osteoporosis.

Summing up, the authors state that osteoclasts fission into daughter cells called osteomorphs; osteomorphs fuse and recycle back into osteoclasts; osteomorph-upregulated genes control bone structure and function in mice, and are implicated in both rare and common bone diseases in humans.

Dr. Phan said the team also modeled the use of denosumab, which induces a paradoxical rebound increase in bone resorption and spontaneous fractures in some patients when treatment is stopped.

"Our data suggest that this may be due to the accumulation of osteomorphs that are poised to resorb bone once the drug is withdrawn," he explained. "If this is the case, then it may be possible to test ways to prevent this using our model - for example, by giving bisphosphonate drugs such as zoledronic acid before withdrawing patients from denosumab."

Dr. Theresa Guise, Section Chief, Bone and Mineral Disorders in the Department of Endocrine Neoplasia and Hormonal Disorders at MD Anderson Cancer Center in Houston, commented in an email to Reuters Health, "These compelling findings have important implications for the clinic. The transcriptionally distinct nature of osteomorphs suggest that these cells will be identifiable in the blood of patients."

Questions that then arise, she noted, include:

- Will detection and quantification of osteomorphs predict bone loss from denosumab withdrawal?

- Could identification, spacial and temporal characterization lead to modalities to prevent the accelerated bone loss associated with denosumab withdrawal?

- How do other osteoporosis therapies, such as bisphosphonates, teriparatide, abaloparatide or romozosumab affect the osteomorph population?

- Does the osteomorph represent a new target for osteoporosis treatment?

- What is the role of osteomorphs in the setting of bone metastases? We know that accelerated bone destruction can stimulate cancer growth in bone by release of bone-derived growth factors. Is cancer growth in bone accelerated in the presence of increased osteomorphs?

- Are there other regulators of osteomorph activity and osteoclast recycling? How can these be exploited to improve bone health?

"The work raises many new questions to answer in so many clinical settings," Dr. Guise said. "Thanks to (the authors), our work is cut out for us for years to come!"

SOURCE: https://bit.ly/3q08cjS Cell, online February 25, 2021

By Marilynn Larkin

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