What is currently known about osteoarthritis and genetics?
Joints are lined by articular cartilage, loss of which is one of the hallmarks of osteoarthritis. Articular cartilage is made up of a number of proteins, such as type II collagen. In rare forms of osteoarthritis, one of these structural proteins is defective as a result of a genetic mutation.
A number of large scale studies have also attempted to identify more common genetic factors which affect the risk of developing osteoarthritis, as opposed to causing this condition outright.
Though the precise function of many of these genetic risk factors remains unclear, it seems that they largely act by altering the function of chondrocytes, which are the cells involved in the production and maintenance of articular cartilage.
These alterations may also manifest themselves in early life during the initial formation of cartilage, when subtle alterations in cell function may affect characteristics such as overall joint shape.
Is osteoarthritis thought to be caused more by environmental factors or underlying genetic factors?
I think it's probably a combination. There are obvious environmental factors such as if you’ve had an injury. Menisectomy, when a cartilage in the knee is removed for example after a footballing injury, is an important risk factor for developing osteoarthritis of the knee for example.
Other factors which affect the mechanical functioning and load bearing of joints, such as obesity and occupation, also play an important role. However genetic factors also clearly influence mechanical functioning of the joint, such as those acting through altered joint shape.
There may well be an interaction between genetic and environmental factors, such that individuals with certain predisposing genetic factors are more likely to develop osteoarthritis when exposed to abnormal mechanical loading.
You have recently received a grant from medical research charity Arthritis Research UK to study which genes can lead to people developing osteoarthritis of the hip. How do you plan to spend this money?
The project is about understanding genetic factors that influence hip shape because there is thought to be a relationship between abnormalities of hip shape and the risk of developing hip osteoarthritis. There are certain shapes abnormalities already known to be associated with osteoarthritis of the hip.
In order to examine the role of common genetic factors in hip shape, one needs access to very large normal populations. There aren't such populations of people with hip x-rays, because these are generally associated with quite large x-ray doses.
However, there are large normal populations of people who have had hip DXA scans, which is a low radiation method for diagnosing osteoporosis.
It turns out that although they are look at bone density, these scans can also provide information about hip shape. The resolution of the image is not as good as on an ordinary x-ray, but it's still enough to get useful measures of hip shape.
The group in Aberdeen, led by Professor Richard Aspden, have recently developed a computer assisted image analysis method, based on principle components analysis, to analyse hip shape on hip DXA scans.
During this project, they will develop this method so as to make it automated, and then use it to measure hip shape in a large group of people in whom hip DXA scans have previously been obtained.
What are the main aims of this research?
The Aberdeen group will first develop their method for looking at hip shape on DXA scans so as to automate it. This method will then be applied to hip DXA scans previously obtained in around thirty eight thousand individuals from Europe and the US.
We already have information on the genes of these thirty eight thousand individuals. So finally we will aim to identify genetic risk factors associated with measures of hip shape in these people.
What techniques will you use to understand the genes which lead to people developing osteoarthritis of the hip?
So the question is how are these aspects of hip shape that we're identifying related to hip osteoarthritis?
In order to examine this, we're going to be looking at the relationship between the genetic markers of hip shape which we identify, and the presence of hip osteoarthritis, in a further group of patients with hip osteoarthritis and unaffected controls.
What hurdles do you expect to face and how do you plan to overcome them?
Although we've got access to very large numbers of hip DXA scans, some of them were carried out quite a few years ago with older versions of scanners. Until we get the scans, we're not completely certain how many are going to be feasible to get good measures of hip shape, because the images might lack sufficient resolution.
However with the large number of scans we have access to, even if we are unable to obtain accurate measures of hip shape in a small proportion, we should still have enough individuals to see interesting relationships.
What impact do you hope your study will have?
If we can identify factors that predict osteoarthritis, that would help to identify people to whom to offer preventative strategies.
For example if you have an abnormal hip shape, it might be that the load is abnormally distributed on the hip. So if you can pick that up you might be able to overcome this by exercises, having different types of footwear and so on.
How do you think the future of osteoarthritis research will develop and what are you further research plans?
Understanding genetics also provides insights into some of the biological mechanisms involved in the disease, which can then lead to new drug treatments. People have been trying to develop drug treatments for osteoarthritis for many years, so far without much success.
Arthritis Research UK is funding us in another study related to osteoarthritis in which we've gone around the country collecting people with very dense bones, picked up from DXA scans. Mainly it's a study to look at osteoporosis because we felt if we can identify factors that make bones stronger that can also help tell you what makes bones weaker.
Interestingly, it turns out that these people with very dense bones and also seem to have an increased risk of osteoarthritis. This suggests that there might be some genetic factors involved in making dense bones that might also predispose to having osteoarthritis. So this might prove to be another way to identify genetic risk factors for osteoarthritis.
Do you think it will ever be possible to prevent osteoarthritis of the hip?
Osteoarthritis is in part an age related condition. I wouldn't hold too much hope in terms of preventing it. I think the best one can hope for is having better ways of picking up people at risk and developing prevention methods that might be able to slow the progression.
We might also get better at drug treatment. Drugs might help not just in terms of preventing progression, but also by better targeted pain control.
At the end of the day when patients get osteoarthritis the thing they complain of most is pain. There is quite a lot research around looking at pain pathways in osteoarthritis, which might lead to new ways of treating it symptomatically.
Where can readers find more information?
Arthritis Research UK’s website has further information on osteoarthritis: https://www.versusarthritis.org/
About Professor Jonathan Tobias
Jonathan Tobias is professor of rheumatology at the University of Bristol, and consultant rheumatologist at North Bristol Trust.
Following undergraduate studies in medicine at Cambridge University and London University from where he qualified in 1984, he completed MD and PhD theses in bone biology in 1990 and 1994, at St George’s Hospital in London.
He was appointed as consultant senior lecturer at the University of Bristol in 1995, and is currently head of section (Clinical Sciences and Methods) of the School of Clinical Sciences, and co-director of the Musculoskeletal Research Unit (Avon Orthopaedic Centre, Southmead Hospital).
He manages a diverse research program into the causes and treatment of musculoskeletal disorders such as osteoporosis and osteoarthritis, with around 130 peer-reviewed research papers in this field.
He has served on the editorial board of Calcified Tissue International, the Heberden committee of the British Society for Rheumatology, the program committee of the National Osteoporosis Society, the research committee of Arthritis Research UK, NICE appraisal and guideline committees, and was President of the UK Bone Research Society (2010-12).
He is currently on the editorial board of the Journal of Bone and Mineral Research and Rheumatology, and editor of Frontiers in Bone Research.
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