Slowing down and improving the treatment of osteoarthritis through molecular cartilage research
Prof. Tim Welting (CAPHRI) knew early on that he wanted to use his fundamental molecular knowledge to create societal impact. Today, he is just doing that through his research into osteoarthritis. As he explains: “Osteoarthritis is already a major issue and it’s only going to grow. It has a tremendous impact on our society. I hope that my research will help to slow down the progression of osteoarthritis. If we can delay the course of the disease, it would be a huge win for both individual patients and society as a whole. Here in Maastricht, our Department of Orthopaedics is making real strides in molecular cartilage research to really make a difference in this area”.
About osteoarthritis
Tim Welting: “The number of patients with osteoarthritis is skyrocketing. Right now, there are around 1.5 million patients with osteoarthritis in the Netherlands, and that number is set to double over the next 25 years. We still don’t fully understand what’s driving this dramatic rise. It is often said that osteoarthritis is simply a wear and tear disease: that as we age, joint deterioration inevitably leads to it. But this is a misconception. Certainly, ageing plays an important role in the risk of developing osteoarthritis, but unlike 20 years ago, we are now seeing people developing the condition at much younger ages. We don’t yet understand why. It could be linked to environmental factors, lifestyle, genetics and many other influences.
At present, we have no medicines to offer people with osteoarthritis that can slow the progression of the disease. We can use a number of treatments to temporarily manage symptoms such as pain, but ultimately most patients will require a joint replacement. However, it is best to delay this surgical procedure for as long as possible to maximize the lifespan of the prosthesis. Actively slowing the progression of the disease and preserving the patient’s own joint for longer will therefore bring significant health benefits and have a major impact on both patients and society”.
Seeking other forms of treatment
Welting: “Mechanical stress, particularly overloading due to unhealthy body weight or lifestyle is a key factor in the development of osteoarthritis. And if you view osteoarthritis purely as a ‘mechanical wear-and-tear condition’, then an orthopaedic prosthesis is a logical solution to address the mechanical problem and associated pain. For many patients, it is therefore an excellent treatment. But osteoarthritis isn’t just a mechanical issue, it is primarily a biomolecular and cell-driven disease. If we want to slow down osteoarthritis and help patients keep their natural joints for longer, we need to develop additional and alternative treatments. In the Department of Orthopaedics, we work with clinicians and researchers across the entire spectrum, from molecules and cells right through to the individual patient and the population.
My research focuses on three pillars: gaining a molecular understanding of osteoarthritis, developing drugs that inhibit osteoarthritis, and refining molecular diagnostics: we are increasingly discovering that osteoarthritis is not a single disease. There is a lot of variation in the course of the disease”.
My hypothesis is that it is possible to slow down osteoarthritis; everything I do is based on that.
Molecular understanding
Welting: “My chair is entitled ‘Experimental Orthopaedics, with a particular focus on the molecular biology of cartilage’. The molecular aspect is my expertise: truly understanding and unravelling osteoarthritis at a molecular level. My hypothesis is that it is possible to slow down osteoarthritis. Everything I do is built on that belief. Biology gives us the foundation to support this. Over the past years, I have seen multiple examples where we can steer cartilage cells in a direction that gives them a healthier profile. This molecular understanding enables me to develop drugs and more refined diagnostics”.
Developing drugs
Welting: “For drug development, we’re working on two main tracks. The first involves peptides: these are small fragments of protein. Over the past 15 years, our lab has developed four peptides that target different disease processes in osteoarthritis. Two of these form the basis of patents; they are now being further developed by a company so that, hopefully, they can reach patients. The second track is small molecules. Here, we are exploring new compounds and repurposed drugs. Repurposed drugs involve well-known medicinal compounds that were discovered some time ago and have already been proven safe. We’re tackling this on a large-scale approach in so-called high-throughput drug screens1, where we simultaneously test hundreds of different drug conditions in high-capacity laboratory plates. If any of these give cartilage cells a healthier profile, that compound could be a candidate for further investigation. The major advantage of working with existing medicines is that, if a successful candidate is identified, there is a greater chance that it can reach patients relatively quickly. But that will have to be assessed on a case-by-case basis”.
Diagnostics: identifying subtypes
Welting: “Finally, we are also trying to develop molecular diagnostics. As mentioned, we currently have no medicinal treatments that can slow, halt or reverse osteoarthritis. If we want to develop such treatments, it is important to know which patients respond to which medicines. We are therefore trying to identify patient groups (subtypes) in order to match them with the most suitable treatments for them. In this research, we are looking at (for example) the fluid in a knee joint: what molecules are present? Can we identify subtypes of osteoarthritis based on this? The fascinating part is that we do not interpret the composition the fluid’s composition and biological consequences ourselves: we let the cell do it. After all, the cell is naturally best at this. Using technology we are developing in our lab, we take cartilage cells, equip them with a kind of molecular ‘thermometer’ and then expose them to the joint fluid. The cell then emit a light signal indicating how it is reacting to its environment. From this, we can determine whether the cell interprets its environment as ‘diseased’ and whether different reactions are observed. Thanks to this technology, we may be on the trail of subtypes of osteoarthritis. With knowledge of these groups, we aim to better tailor future treatments for osteoarthritis”.
By developing models of this kind, we are working towards a future where we need to use fewer animal models.
Animal-free
Welting: “We have quite recently launched a major grant-funded project through the Growth Fund (Groeifonds). The aim is to develop animal-free models that will enable us to develop and validate osteoarthritis medicines. To achieve this, we use cell models with relevant cells from osteoarthritis patients to mimic the natural patient situation as closely as possible. That is why we are also collaborating with companies that are developing, for example, ‘cartilage-on-a-chip’ technology, which allows cartilage cells to be subjected to stress in a natural way. By developing models of this kind, we are working towards a future where we need to use fewer animal models. This is important for many reasons, but certainly also because the predictive value of animal experiments is limited in the field of osteoarthritis. After all, our ultimate aim is to be able to treat patients”.
Making an impact
Welting: “As the Department of Orthopaedics, we want to make a difference for orthopaedic patients. We recognise and feel a social responsibility not only to develop biomedical innovations, but also to ensure that these have a tangible impact for osteoarthritis patients at MUMC+. We hope that our department’s activities in research, care and education will contribute to this”.
“I often think back to the decision I made quite deliberately 20 years ago to use my knowledge of fundamental biology to tackle significant societal medical challenges. Literally using your science to try to solve a major healthcare problem. Back then, I couldn’t have imagined how it would turn out, but now I’m right in the middle of it. Together with many inspiring colleagues, highly committed research funding bodies and patient organisations, I’m determined to create impact”.
1 High-throughput screening is an automated process in which thousands of substances (in this case, small molecules) are screened for their effectiveness in order to discover new medicines.
Text: Eline Dekker
Photo: Joey Roberts
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