Holy Grail: Professor Tri Phan introduces osteomorphs

Can you sum up the goals of this project in 10 words?
To image osteoclast formation, function and fate in living bone.

You’ve described these new cells called osteomorphs. What do you know about them?
Not very much! This is only the beginning. So far we have seen that multinucleated osteoclasts break up into daughter cells that we have called osteomorphs, during bone resorption. The osteomorphs are not attached to bone and can move around to fuse with each other and form new osteoclasts. They upregulate a number of genes which are important in bone structure and function in mice and humans.

The discovery involved intravital imaging. What are the strengths – and promise – of this technique?
Intravital microscopy has the potential to uncover hidden biology. In this case, the discovery of osteomorphs and cellular recycling was completely unexpected and has challenged the prevailing dogma that osteoclasts are short-lived and die once they have completed their task of resorbing bone. The ability to see something with our own eyes in real-time is incredibly powerful and compelling.

What aspect of this research excites you the most?
The undiscovered country! Intravital microscopy has opened up so many new and exciting vistas and we are literally only just scratching the surface. The next generation of intravital microscopes promise to give us even better quality high-resolution images at depth inside live experimental models.

What have you previously discovered in the area of bone homeostasis or metabolism?
We previously showed that osteoclasts play an important role in cancer relapse in bone. Disseminated cancer cells that lodge in the bone can lie dormant for many years before re-awakening to cause metastatic relapse. By resorbing bone and disrupting this bone niche, osteoclasts can reactivate these dormant cancer cells. This is one of the drivers for our quest to understand more about osteoclasts that led to the discovery of osteomorphs.

How might this research impact on patient care?
One of the things we modelled in the mice was a blockbuster drug called denosumab used to treat osteoporosis. We found that when mice were treated with the equivalent of denosumab this blocked the fusion of osteomorphs back into osteoclasts. When the drug was stopped, the osteomorphs rapidly fused and this rebound led to accelerated osteoclastic bone resorption. This seems to also happen in some patients in whom denosumab is stopped – they paradoxically develop spontaneous vertebral fractures. So our model can be used to study how bone active drugs work and also how to predict and prevent complications. Osteomorphs are present in the blood, unlike osteoclasts so they may also be a useful biomarker of the state of your bone health. In the longer term, we hope that by identifying a new cell type and its gene expression profile we have uncovered a new target for treating bone diseases such as osteoporosis and bone cancers. But this will likely take many years.

What’s your Holy Grail – the one thing you’d like to achieve in your research career?
Discover something that my kids will be proud of. Naming the cells after Power Rangers only earned me eye rolls. They are a tough crowd…

What is your biggest research hurdle?
We are in an incredibly difficult funding climate and there is little appetite for risk and basic science research. This saddens me as a clinician because basic science is the wellspring of transformative knowledge.

Who has inspired you in work or life?
My mother and father. They brought me up wanting to change the lives of people around me for the better.

There’s an app for that. What’s new on your phone?
Vivino. Only because I’m hopeless and can’t decide without datapoints.

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