What goes wrong inside bone cells in Paget’s disease?

Prof Rob Layfield is a biochemist based at the University of Nottingham, who has researched Paget’s disease since 2002 and is Chair of the Paget's Association's Research Subcommittee. Here he gives an update on the valuable role that organisations such as the Paget’s Association play in supporting research. [2023]

I started this piece by looking back at something I wrote for the Paget's News magazine, under the same title, almost 10 years ago, after attending my first Paget’s Association Information Day in Manchester on 13 September 2013. As nearly a decade has passed, I thought it a good time to reflect and update not only on what we have learned in that time, but also to highlight the ongoing contribution of the Association in driving research into Paget’s disease.

The Paget’s Association is the only UK charity with sole focus on Paget’s disease. The Association continues to not only support those living with or affected by Paget’s disease, but also to promote awareness and high‑quality scientific research. Answering the question “what goes wrong” is one of the first steps in developing rational management approaches and treatments, and this is one critical aspect of the Association’s research focus. What we have learned in the last decade is much more about the genetics of Paget’s – several new genes that control susceptibility to Paget’s have been identified. This is really important as it helps us not only understand “why” Paget’s can develop, but it might also help us in the future to identify those most at risk. Related to this, clinical trials are just starting to reveal whether using existing therapies is beneficial in people at the highest risk of developing Paget’s before symptoms present i.e. can we ‘prevent’ Paget’s disease. 

This ‘people facing’ research is vital, for example in understanding the real-life experiences of living with Paget’s disease, such as the impact and causes of pain. In addition, so called ‘epidemiological’ research confirms that as we have suspected for some time, the incidence of Paget’s is definitely falling in the UK. Whilst clearly this is good news, we still don’t understand why, but this observation points to unknown environmental factors. Again, identifying these environmental factors that interact with our genetics remains a priority, as avoiding them clearly offers simple opportunities to manage and modulate progression of Paget’s without the dependence on drug treatments.

To come back to the original question of “what goes wrong”, despite some of the advances outlined above, in about the fundamental molecular mechanisms that underlie bone cell changes in Paget’s. In fact one of the reasons for this slow progress is that unlike many other diseases, Paget’s is incredibly difficult to study in the laboratory. This is in part because the bone cells affected –osteoclasts – are so highly specialised that growing them in a lab in order to establish ‘cell models’ is really challenging. 

Highlighted in the same issue of the Paget's News magazine, the Paget’s Association funded research of Prof Philippa Hulley and Dr Helen Knowles (Oxford) takes steps towards solving this problem, with development of new methods to grow human osteoclasts in controlled lab conditions. It is breakthroughs such as this which will ultimately allow us to understand and to beat Paget’s disease.

I will end where I started my piece 10 years ago, with the family motto of Sir James Paget, the physician who first described the condition. Labor ipse voluptas – “work itself is a pleasure”. 

Although we are acutely aware that Paget’s does still cause concern and impacts the quality of life for many of our members, it is certainly a privilege to be part of the research community that the Association supports, and the greatest pleasure will be in the future to improve the lives of those who are touched by Paget’s.

Prof Rob Layfield