BROKEN: The skeleton of this man who had fibrodysplasia ossificans progressiva (FOP) shows the extensive bone growth that happens when soft tissue cells get the wrong message. Image: A.B. SHAFRITZ ET AL./NEW ENGLAND JOURNAL OF MEDICINE/MUTTER MUSEUM
What would happen if some soft tissue cells in your body randomly got the message to transform into stiff bone cells? Patients born with a disease called fibrodysplasia ossificans progressiva (FOP) are locked into this fate, often becoming severely disabled before adulthood.
The disease first manifests itself at birth, when a baby appears normal but has bent big toes. By early childhood, however, some of the body's connective tissues—including muscles, ligaments and tendons—have begun ossifying into skeletal bone, locking the joints and distorting posture and movement. Some bone formation appears to be spontaneous, while some can be brought on by trauma from surgery or even a mild impact.
FOP is one of the most rare genetic diseases known, occurring in about one in two million people, but spontaneous bone development is relatively common in the broader population. This bizarre shift of tissue systems, known as heterotopic ossification in most cases, can be brought on with spinal cord injury, amputation and even hip surgery.
Eileen Shore, a research associate professor of orthopedic surgery at the University of Pennsylvania, has been studying the disease since 1991. "I always had been interested in development on a cellular level," she says. "What changes a cell, or what regulates a cell to follow certain cell fate decisions? We usually think about development on an organism level, but it was more a question of what determines the personality of the cell?"
When she discovered FOP and the work of Frederick Kaplan, a professor of orthopedic surgery at Penn, she realized she had found a puzzle that was "a disease of misregulated cell differentiation," she says.
Three years ago, she and Kaplan identified the genetic mutation that causes the disease in a paper published in Nature Genetics (Scientific American is part of the Nature Publishing Group). This year, Shore and her team found some of the key biochemical steps that lead soft tissue cells to turn to bone. The results were published in the Journal of Clinical Investigation in November.
The progress bodes well for the development of new therapies for people imprisoned by this genetic abnormality, and suggests that "we have a very, very good possibility of being able to treat other types of ossification, as well," Shore says.
[An edited transcript of the interview follows.]
Is fibrodysplasia ossificans progressiva (FOP) caused by a genetically inherited mutation or is it random?
It can be inherited, but it's random in the sense [that] it is a random occurrence of a new mutation. The main reason for that is even though the mutation could be inherited, most of the people who have it don't have children. There have been some instances where people have had children—often at a very young age—and have passed it on to one or more child.
When does it start?
When someone with FOP is born, we don't have any evidence that there is any of the extraskeletal bone that has started. Their embryonic development is pretty normal—except for a bent great toe. The bone formation typically starts by the age of five. There have been some cases where it starts in the first month and others where someone is 10 or a little older.
Is every case similar?
The majority of them are very similar. We've analyzed a number of patients' DNA to look for the mutation in the gene we [found]. The vast majority of them have the same identical nucleotide change. All of these patients are pretty similar in the way their FOP develops—in terms of malformation of the big toe that we see at birth. So far, less than 10 percent of the people we've examined have variations of that mutation. All of them still have mutations in the same gene, but mutations occur in different parts of the gene. They have cases that are more severe or less severe.
How is the bone formation response triggered?
The mutation occurs in the gene ACVR1, and this gene produces a protein that is a receptor that spans the cell membrane—so part of the receptor is outside of the cell, and part is on the inside. Cell receptors will receive a signal from outside, and when it binds, that information is transmitted through the receptor to other proteins within the cell, [creating] a chain of events to change how the gene works in the cell. The pathway that ACVR1 is on is part of the BMP (bone morphogenetic protein) pathway, and that pathway has been known for a long time to stimulate cells to differentiate into cartilage and bone.
So is the bone formation just spontaneous?
It seems to be spontaneous in that many instances of the bone formation are not associated with any obvious trauma. Or maybe it's a relatively minor event like a stretched tendon or muscle. It could be something that in most other people wouldn't elicit any other obvious response—these patients could be more sensitive to something like that.