During a trip to China in 2012, Paul Yu, MD, PhD, had an eye-opening experience. For the first time, he met patients with fibrodysplasia ossificans progressiva (FOP) at a specialty clinic at Shanghai Tongji Hospital. FOP, which affects roughly 1 in 1.5 million people worldwide, is a rare connective tissue disorder that begins in childhood and turns one’s soft tissues into bone either spontaneously or after injury.
Yu was already committed to researching FOP, among other diseases, but he says that meeting patients in person for the first time made him realize the importance of early intervention in their lives. He met a man in his 40s who had made lifestyle adjustments to compensate for his lack of mobility. He met a 6-year-old girl who was still able to run and play, and a boy only two years older, who was already experiencing some of the effects of the disease.
“The boy’s neck was so stiff that he couldn’t move his head; he had to turn his whole body to face me,” said Yu, of the Division of Cardiovascular Medicine. “Meeting young children who were mildly affected and adults with more severe disease impressed upon me that using an effective preventative treatment early could preserve a great deal of patients’ function.”
FOP is not obvious at birth, says Yu. Children with FOP have subtle skeletal abnormalities of their cervical spine and big toes, and while the disease is usually discovered in the first six months of life, it could present as late as 10 years old.
In patients with FOP, bone formation occurs after an injury, such as a bump into a wall or an infection. Instead of the body repairing the muscles, tendons or ligaments that were injured, the body replaces them with bone. The only tissues that routinely tend to be spared are the muscles of the diaphragm and the eyes, a mystery that Yu and his team are investigating. Another puzzle of the disease is that bone formation can also spontaneously occur without injury.
“The first two decades of patients’ lives may include spontaneous episodes and injury-related episodes,” said Yu, who joined the Brigham in 2011 from Massachusetts General Hospital. “The burden of soft tissue turning to bone becomes greater and more debilitating. By 18, a person is often immobilized in many of their joints.”
Yu focuses on bone morphogenetic proteins (BMP) – groups of signaling molecules that are vital to tissue development – and how a BMP receptor mutation signals the body to grow bone where it does not belong. Yu and his team tried to recreate the disease in mouse models to gain more insight into how it occurs and its cells of origin. Though targeting bone marrow and several blood vessel-associated cells in mice with the mutation did not produce the intended result, focusing on other types of cells did.
Targeting expression of the mutant receptor to skeletal muscle interstitial cells – the cells that lie between muscle fiber cells – didn’t immediately produce bone formation, but once there was an injury to the muscle, bone began to develop.
“This was very reminiscent of some of the observations we had from people who experienced the replacement of muscle tissue with bone following injury,” said Yu.
When the team targeted expression of the mutant receptor to tendon and ligament cells of mice, they also saw bone formation in those tissues, but this time without an injury needing to occur.
“The mice developed spontaneous replacement of ligaments, tendons and fascia with bone progressively, which looked just like the CT scans of some FOP patients,” said Yu. These studies identifying multiple populations of stem cells driving FOP disease were recently published by Yu and collaborators at Harvard, the biotechnology company Regeneron Pharmaceutical, Inc., and internationally in Science Translational Medicine (Dey et al, 2015).
Since there was no obvious injury required to trigger bone formation in tendon and ligament cells in those mice, the team has started to look at other potential modifiers of disease.
“While it is clear that muscle injury should be avoided, patients and their physicians have long wondered whether participating in sports and regular exercise would aggravate or improve this condition,” said Yu.
The group is now testing whether or not allowing mice to exercise regularly by running on treadmill wheels might change the spontaneous bone formation seen in ligaments. When left to their own instincts and given the opportunity, mice like to run and can clock in up to 6 kilometers per night. The research group is hoping that the results of these studies can help answer this longstanding question about the benefit or harm of exercise, acknowledging that caution will be needed in extrapolating a mouse experiment to people.
Down the road, there could be implications of these investigations for more common issues, such as the immobility that affects individuals with hip fractures and joint surgeries, a phenomenon that may be driven by some of the same processes as FOP.
“The field of heterotopic ossification is teaching us a lot of interesting new biology, not only in how tissue repair can go wrong in a disease like FOP, but also what these reparative cells do in normal biology and the signals by which their activities are regulated,” said Yu. “We and several other groups are working on treatment strategies, some of which are starting to look promising. I’m hopeful that we as a field will have something useful to offer these patients in the near future.”