Interview with dr. N. Bravenboer
Dr Nathalie Bravenboer is an associate professor at Amsterdam UMC and leads a laboratory research group focusing on bone and calcium metabolism. Among other things, she is searching for possible treatments for osteogenesis imperfecta, also known as brittle bone disease. The Power of Reflection Foundation assists in this endeavour in several ways.
Can you explain what collagen connective tissue disorders are?
It's all about collagen, the molecule that acts as the “glue” of our connective tissue and gives strength to bones, skin, tendons and organs. If you zoom in on collagen, you can see that it consists of a kind of rope made up of three strands twisted together – we call this the triple helixA large number of these fibres, which are connected to each other in three dimensions, form a strong matrix. In bone, this matrix becomes even harder because calcium phosphate binds to it.
There are 28 different types of collagen, each with a specific function. Type 1 is found in bone, type 2 in cartilage. When there is a genetic abnormality in collagen, it does not function properly and problems arise. The tissue becomes weaker or, conversely, too stiff. In bone, this can mean that it becomes too brittle and breaks more easily. And in tendons and joints, it can cause hypermobility, as in some forms of Ehlers-Danlos syndrome. Often, different genetic abnormalities can underlie a single disease. In osteogenesis imperfecta alone, some thirty different errors in the DNA have been described that lead to the disease.
What exactly can go wrong during collagen formation?
“Sometimes the triple helix is not formed properly, creating too much space for calcium phosphate. The bone then becomes overmineralised. This means that the bone is hard, but not strong. It breaks easily, just like a piece of chalk. It is also possible that cells produce only half the normal amount of collagen, which means that the bone grows less quickly and also binds too much calcium phosphate.
In addition, things can go wrong in what we call processing : the entire process by which the collagen strands are linked together. This requires many auxiliary proteins. If one of those links fails, things will still go wrong.”
How do you search for treatments for osteogenesis imperfecta?
“At the moment, we are mainly investigating substances that can improve the balance between bone resorption and bone formation. In type 1 osteogenesis imperfecta, the milder form we are currently focusing on, patients produce about half the normal amount of collagen. These people do not have impaired growth or bone deformities, but they do suffer from fractures much more often. Their bones are simply less strong. Among other things, we are looking at a substance that inhibits bone resorption while bone formation continues. This could potentially make the bone stronger."
But can such a medicine still work when people are already fully grown?
Yes, because bone formation and resorption is a lifelong process. Every eight to ten years, all your bones are replaced.
How long will patients have to wait for such a medicine?
“That is difficult to estimate, but expect at least ten years. We are still working at a very basic level – at the tissue level, not even with animal testing yet. After that, studies with patients will follow, and those can easily take five years or more.”
Can you envisage any other future treatments?
“Certainly. There are three types of enzymes that cause the triple helix to form and collagen to bind together. If you stimulate those enzymes, you get stronger collagen with less space for calcium phosphate, which can counteract overmineralisation. And for other connective tissue disorders where the collagens are connected too haphazardly, you could actually inhibit those enzymes. That could be interesting for fibrous disorders. Chemically, this has already been partially researched, but it still needs to be proven in practice. We need more funding for that.”
You just mentioned another connective tissue disorder that also falls under the umbrella of Power of Reflection. How did your collaboration with this foundation begin?
“Through Cindy Wan, the founder. She knew me from her previous chairmanship of the patient association for osteogenesis imperfecta. When she set up Power of Reflection, she asked me to contribute my ideas and help build a multidisciplinary scientific team.”
What does the foundation mean for your work?
Cindy opens doors. That is truly her strength. She has ensured that we now have a core team of scientists from various disciplines: in addition to myself, these include Dr Ibrahim Korkmaz, who conducts burn research, internist-endocrinologist Prof. Carola Zillekens, mathematician Prof. Fred Vermolen, and chemist Prof. Ruud Bank. By combining our knowledge, we learn from each other. We work on different conditions, but we can make use of each other's knowledge and tools. For example, the burn researchers work with skin, which is much more accessible than bone. They have developed techniques and methods that we can adapt for our bone research. That exchange of knowledge is extremely valuable.
Equally important, Cindy has established contacts with investment companies and pharmaceutical firms. If this leads to funding, it will provide our scientific team with a significant boost. We will then be able to pursue research into enzymes that no one else is currently investigating.
What are your hopes for the future?
“That we raise enough funding to really make progress, so that we will soon have a new medicine for osteogenesis imperfecta. And Power of Reflection can certainly contribute to that. It's a long road, but with the networks and contacts that Cindy is establishing, we are getting closer and closer. All exposure helps: the more people know about these conditions and the research we are doing, the better.”
Towards effective medicines for Osteogenesis Imperfecta
Written by: Diana de Veld, science journalist
English (UK) 
Nederlands