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

Dr Rob Layfield is a biochemist based at the University of Nottingham, who has researched Paget’s disease since 2002. Here he gives an overview of his work and an insight into the valuable role that organisations such as the Paget’s Association play in supporting research.

Labor ipse voluptas - “work itself is a pleasure” - was the family motto of Sir James Paget, the physician who first described the condition that we now know as Paget’s disease of bone. Indeed it was a genuine pleasure to receive an invitation to attend the Paget’s Association Information Day in Manchester on 13th September 2013, and to give a presentation about some of the work that goes on in my research laboratory at the University of Nottingham. For those members who were not able to attend (and those that were, and maybe, were baffled by the biochemistry!), I will try to summarise some of the main points that I covered on the day.

I will start by saying that I feel very fortunate to have received funding from the Paget’s Association for my group’s research and am of the firm belief that this has directly improved our understanding of the condition, specifically the molecular basis of Paget’s disease. In other words, the support has really helped towards answering the question that my research addresses - “what goes wrong inside bone cells in Paget’s disease?” At the outset it is probably also worth setting the context of which funding from the Association sits. In my role at the University I spend about half of my time teaching biochemistry to undergraduate (medical and science) students. The other half of my time is spent on research, and most of this researching Paget’s disease, a condition that has fascinated me for over 10 years. Whilst the teaching side is well supported, the total amount of funding that is allocated to research in this setting is very low (in fact nil!). So to do any research (not just in to Paget’s disease) requires that financial support is secured from outside agencies, be they government-funded or charities, and a large part of the job is in trying to raise such funds. That is why support for research from organisations such as the Paget’s Association is so important.

So to return to the question above, “what does go wrong inside bone cells in Paget’s disease?” Before we deal with this, we first need to think about the different types of cells that are found in bone, and a process they control that we know as ‘bone remodelling’. There are two types of bone cells that are important in Paget’s disease - so-called ‘osteoclasts’, whose normal job is to resorb or break down bone, on a microscopic scale, throughout the skeleton. Once they have done this a second type of bone cell, the ‘osteoblast’, replaces the bone that has been removed with new bone. This concerted action of osteoclasts and osteoblasts is known as ‘bone remodelling’. It might seem counter-intuitive to do this, but bone remodelling is vital to ensure that the skeleton is healthy. The analogy I give is DIY around the house. You might re-decorate your utility room just to spruce it up a bit. Then a few months later buy some new curtains in the living room and a new hall carpet. This might at the time seem futile and a waste of money. If you don’t do this however, in a few years your house will start falling into disrepair.

In Paget’s disease, this bone remodelling cycle goes wrong, at specific sites throughout the skeleton. The principal problem is with the osteoclasts - too many are produced and they are too active, resorbing bone too efficiently. So more osteoblasts are produced to counteract the problem, and we end up in a situation where bone remodelling is dramatically increased and the new bone formed is of the wrong structure. Buy why does this happen? Well in some, but not all cases, there are mutations (changes in the DNA) in one particular gene called the SQSTM1 gene that we think cause the disease. It is this genetic or familial ‘form’ of Paget’s disease that we research, as experimentally it is easier to study, but importantly what we learn is relevant for all cases of Paget’s disease. The mutant SQSTM1 gene produces what we will for simplicity call a ‘Paget’s protein’. My group investigate how this Paget’s protein is different from the normal (non-mutant) form and how the processes that the protein controls in osteoclasts are altered in the disease. With support from the Paget’s Association, we have already found that the Paget’s protein has a different shape to its normal counterpart, and that three different biological pathways in osteoclasts are affected when it is produced. In the longer term, information of this type could be used to devise new treatments. Your support has also helped us lever additional funding from other bodies to continue important aspects of this research.

You might ask why we need to know this sort of information, given that (as we heard at the Information Day) existing treatments for Paget’s disease (e.g. zoledronate) can be very effective, and in fact, epidemiological studies show that the incidence of Paget’s disease is falling in the UK? Well firstly, zoledronate is not appropriate for everybody, and as we move to a point where clinical trials will reveal whether pre-symptomatic treatment for those at higher risk of Paget’s disease may be considered, new forms of treatment might be needed. And secondly yes, the incidence is falling, but several hundred thousand people in the UK alone are still currently affected, and the fall in the incidence of Paget’s disease we see at present may not necessarily continue in the future.

I hope that in the same way that I was reminded of the human side of Paget’s disease at the Information Day, this piece gives you a small insight into the human side of basic medical research. One thing I was left with after the meeting was a strong feeling of community - whether we are doctors, scientists, staff at the Association or individuals directly and indirectly affected by Paget’s disease, we are all the same and we are linked by a common goal - a desire to improve the quality of life of those affected by Paget’s disease.

Published in Paget's News, 2013


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