Fibrodysplasia Ossificans Progressiva: New Hope

Researchers are making headway on a very rare genetic disease that causes muscle, tendons, and ligaments to turn into bone. Shinya Yamanaka, M.D., Ph.D., who first created induced pluripotent stem cells (iPSCs), and his colleagues at the Gladstone Institutes have, according to the October 24, 2016 news release, “found a way to increase the efficiency of stem cell reprogramming through research on a rare genetic disease…” the condition—fibrodysplasia ossificans progressiva (FOP).

“Surprisingly, the scientists discovered that they could create more iPSCs from cells taken from FOP patients than those taken from healthy individuals. They believe this is because BMP [bone morphogenetic proteins] signaling enhances cell renewal—a cell’s ability to replicate—and keeps them in a pluripotent state, able to turn into any type of cell. These two traits are key characteristics of stem cells. To confirm their hunch, the researchers prevented BMP signaling, which resulted in fewer iPSCs being generated from FOP patients’ cells. Conversely, activating the signaling pathway yielded more iPSCs.”

Edward Hsiao, M.D., Ph.D., a former postdoctoral scholar at Gladstone and current associate professor at the University of California, San Francisco, who specializes in stem cells and bone, told OTW, “Our research team wants to understand what factors control the formation of human bone. The project described in the PNAS [Proceedings of the National Academy of Sciences] paper is related to other work using human iPS cells to model skeletal diseases, including FOP. The primary inspiration was an initial observation that the genetic mutation that leads to FOP also changes the cell fate and stability of the cell lines.”

“We were extremely surprised to find that the ACVR1 R206H mutation leads to an increased ability to form human iPS cells from skin fibroblasts. When we see this in light of other data suggesting an increased ability to form other types of cells, it suggests that the ACVR1 gene is important for regulating cell stability, and that part of the FOP disease mechanism may be a loss of the ability to retain a particular cell fate. This may account for the development of heterotopic ossification at inappropriate sites such as skeletal muscle and connective tissues.”

“There are two things I think orthopedic surgeons should know:

• Making or suspecting the diagnosis in FOP when they see great toe malformations (particularly bilaterally) or unusual limb swellings, so as to avoid potential surgical procedures that could worsen FOP.
• That understanding the genetic roles of ACVR1 will help elucidate what regulates normal bone formation, hopefully identify mechanisms for FOP, and shed light on other conditions of heterotopic ossification such as neurogenic, trauma, and burn-induced heterotopic ossification. It may also help us understand some of the complications that occur with BMP-infused scaffolds current in the market.”

“We hope that this report helps surgeons think about FOP as a potential diagnosis if patients come into their practice with this condition. We also hope in the long run that the mechanisms will help us develop better regenerative medicine treatments for bone diseases.”