Osteoarthritis is a painful and progressive joint disorder that affects hundreds of millions of people worldwide. Typically, the options for treating the condition involve exercise or medication to reduce pain. However, these methods do not target the underlying structural problems in the joints of patients. Recently, researchers have uncovered a genetic susceptibility to osteoarthritis associated with a protein called GDF5, which is involved in skeletal growth and development. Alongside a team of scientists across Europe, Dr Kerstin Kleinschmidt-Doerr at Merck has explored a modified form of the GDF5 protein, named R399E, which showed effects in animal models and in-vitro experiments for treating pain and the underlying structural problems in osteoarthritis. More
Osteoarthritis is a debilitating condition that can become extremely painful and significantly affect a patient’s mobility, sleep, and ability to work. As it reduces physical activity and sleep quality, the disease is also associated with many mental and physical health conditions, including depression, anxiety, cardiovascular disease and diabetes.
Knee and hip osteoarthritis currently affect more than 300 million people worldwide. Around one in five women over the age of 60 live with the condition, and this prevalence is expected to rise as our life-expectancy increases.
In osteoarthritis, there is a disturbance in the balance between build-up and degradation processes in the joint. When these processes become unbalanced, more cartilage is destroyed than is produced. The result is the incurable and progressive break-down of cartilage, as well as inflammatory and painful changes in the synovial membrane and the adjacent bone structures.
At present, treatments for osteoarthritis remain limited. General medical recommendations centre around exercise and drugs, which work to reduce inflammation and relieve pain. However, there are currently no treatments available that can stop the disease from progressing or repair the damaged structure of the joints. According to the American College of Rheumatology and the Arthritis Foundation, the search for a treatment that can reduce the pain of osteoarthritis and treat the affected tissues and joint structures remains a ‘substantial unmet medical need’.
Growth and Differentiation Factor 5, or ‘GDF5’ for short, is a protein known to be associated with susceptibility to osteoarthritis. It is involved in the development of bones and joints in humans and other mammals. If this protein is under-expressed, individuals are more likely to develop the disease. In fact, studies have revealed that supplementation with GDF5 could be a beneficial treatment for osteoarthritis.
Dr Kerstin Kleinschmidt-Doerr of Merck Healthcare and her colleagues have built on this research. To mitigate the undesirable bone-activating effects of this protein, the team used molecular-based tools to create modified forms of GDF5. They investigated different variants of the protein and ultimately chose the one that performed best in various tests. They named this modified protein molecule R399E.
The researchers characterised the protein in detail in isolated cells and tissues, as well as in animals. They first tested the effects of R399E on joint tissues they had collected from osteoarthritis patients. Interestingly, the protein had measurable effects on the biochemical processes within these samples.
For instance, R399E reduced the production of cartilage-destroying enzymes and therefore decreased the degradation of cartilage. Surprisingly, it also reduced the release of inflammatory mediators and pain messengers. At the same time, treatment with R399E for only one week per month in cartilage cultures resulted in an increase in the number of cartilage cells and cartilage matrix formation. The researchers also discovered an accumulation of the protein in cartilage cultures, which raised their hope that the effect would last long enough in a patient’s knee after injection.
Dr Kleinschmidt-Doerr and her colleagues then tested R399E on rabbits with osteoarthritis for its effect on the altered joint tissue and pain caused by the disease. However, unlike human patients, knee pain in rabbits cannot be measured using questionnaires. Therefore, the researchers needed to devise a method for measuring the comparatively weak knee pain experienced by the animals in a reliable and reproducible way.
When osteoarthritis is triggered only in the right knee, as in this study, the animals put less weight on this limb and more weight on the left limb. Therefore, the team developed a method to objectively measure how much weight a rabbit puts on each knee voluntarily. The bigger the difference between right and left, the more pain the rabbits feel, which is a fair assumption.
Dr Kleinschmidt-Doerr’s team showed that rabbits who received R399E injections into the diseased knee put significantly more weight on that limb compared to animals who received a placebo injection. This result indicates that the treatment reduces osteoarthritis-related knee pain in rabbits. Importantly, the pain reduction was observed as early as six hours after the first injection of R399E. In their rabbit study, the pain-relieving effect was greater and longer lasting than when the team administered triamcinolone – a common pain medication for osteoarthritis.
The team is particularly proud of their knee pain examination method, which was only possible thanks to the particularly species-appropriate and stress-free handling of the animals. The animals, which were very relaxed during the measurement, could be reliably tested without being influenced by the observer. This makes the results particularly meaningful and robust.
Finally, examination of the tissues of the knee after 13 weeks showed that structural damage was also significantly less in the treated knees than in those of the placebo control groups.
Dr Kleinschmidt-Doerr and her colleagues then confirmed the pain-relieving and tissue-protective effects of the same doses of R399E in sheep with osteoarthritis.
The team’s experiments with sheep, rabbits and human patient tissue samples clearly demonstrate the potential of R399E in both relieving pain and reducing damage to joint tissues. Based on these data, it appears justified to test effectiveness and safety of R399E in human patients.
If clinical studies were to prove the assumed potential of R339E, it could become the first treatment that both reduces the debilitating pain of osteoarthritis while actually rebuilding damaged joints. Given that there are over 300 million people suffering with the condition worldwide, the impact of such a treatment on global health and wellbeing would be revolutionary.