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How Can a Genetic Mutation Cause Muscle to Turn into Bone?

A rare genetic disease leaves its victims debilitated by transforming soft tissue cells into bone cells, creating a strange second skeleton. A leading researcher explains how the disease works and what we can learn from it
muscle turn to bone genetic disease



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.

How does trauma spur bone development?
That's an area that we're very interested in. We don't know how it occurs, [but] we suspect that trauma induces a normal tissue repair response. The tissue either perceives the signal incorrectly or overstimulates [the response]. We know that even though this occurs at very low levels, the signaling triggers an event of bone formation.

Are there currently any treatments or therapies for those with the disease?

The treatments that seem to be effective in most patients with FOP are antinflammatory drugs. We think they're repressing some of the early events that are associated [with the bone formation]. It's not an ideal treatment because it doesn't work in all cases. Clearly better treatments are needed.

Are there other diseases or conditions that studying FOP might help us better understand or treat?
I think so because it's a disease that affects cartilage and bone cell differentiation. There are different conditions—osteoporosis is a clear example—where bone formation is no longer happening properly, so there is a possibility this could be applied to understand how to encourage cells to produce bone. We have also been talking with a number of people who are involved in tissue engineering to see: Can stimulating this pathway help heal broken bone?

There are more common instances of bone formation called heterotopic ossification. Extraskeletal bone is a relatively common occurrence following hip replacement surgery, head trauma or spinal cord trauma. It's been a very big issue in soldiers who have had certain types of war-related injuries. In many cases, heterotopic ossification has formed at amputation sites making it difficult to fit prostheses. It actually does affect a lot of people. Presumably the process is the same and has the same cellular process.

Your most recent research made use of zebrafish embryos to examine the molecular processes. What are the next steps in studying FOP?
The mouse model is going to be very important to understand the disease. We have been using cell culture models and zebrafish as an assay to determine the effects of BMP on signaling, but we also want to be able to understand what the effect of the mutation is in the tissue and organ systems. We need to be able to study this in vivo. We will continue to use the zebrafish to develop transgenic models. With mice, we can do a lot of studies to understand what will initiate heterotopic ossification.

We are interested in understanding the impacts of the mutation on tissues other than bone. It is also very important in development in other tissues or organs. It might be that there are other underlying health issues in these patients. It will also give us a better understanding of the process.

Being such a rare disease, has FOP been difficult to study?
It was difficult. Especially when trauma induces bone formation [so] we weren't able to take samples. Now that we've been able to identify the gene, we can use model systems to gain terrific insights. And we'll be able to take that information and verify and see that those processes are happening in patients. Identifying the gene mutation gives us tremendously greater opportunities.

[By] identifying the specific cells that are important in developing the disease, we can develop more targeted therapies and treatments.

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