Fibrodysplasia ossificans progressiva (FOP) also known as münchmeyer disease is a rare condition that causes substantial bone growth outside of the normal skeleton, generally termed as Second skeleton, preventing the body from responding normally to even mild traumas.

It causes the formation of a “second skeleton,” which restricts joint movement and may make breathing difficult. However, new research in mice by a team at the University of Pennsylvania’s Perelman School of Medicine suggests that extra-skeletal bone formation isn’t the main cause of the condition.

After injuries, it appears that impaired and inefficient muscle tissue regeneration allows the undesired bone to develop in regions where new muscle should form. This study, which was reported today in NPJ Regenerative Medicine, brings up the possibility of developing new therapeutics for FOP.

“While we have made great strides toward better understanding this disease, this work shows how basic biology can provide great insights into appropriate regenerative medicine therapies,” says Foteini Mourkioti, the study’s lead author. “From the lab, we’re now able to show that there is potential for a whole new realm of therapies for patients with this devastating condition.”

Around 15 years ago, Penn researchers – including this study’s co-author, Eileen Shore, PhD, professor of Orthopaedic Surgery and Genetics and co-director of the Center for Research in FOP and Related Disorders – determined that FOP was caused by a mutation in the ACVR1 gene. The researchers discovered that the mutation caused cells in muscles and connective tissues to behave like bone cells, leading to the formation of new and superfluous extra-skeletal bone in the body.

“However, while investigations of how the FOP mutation alters the regulation of cell fate decisions have been extensively pursued in recent years, little attention has been paid to the effects of the genetic mutation on muscle and its impact on the cells that repair muscle injuries,” Shore add. “We were convinced that pursuing research in this area could provide clues not only for preventing extra bone formation but also for improving muscle function and regeneration, bringing new clarity to FOP as a whole.”

The researchers looked at muscle from mice with the identical ACVR1 gene mutation as patients with FOP. They studied fibro-adipogenetic progenitors (FAPs) and muscle stem cells, two types of muscle tissue stem cells (MuSCs). Muscle damage recovery usually necessitates a delicate balance of these two cell types. Injured tissue responds by enlarging FAP cells, which are tasked with attracting muscle stem cells and regenerating the injured muscle tissue. FAPs die out after roughly three days, and their role is done. At the same time, MuSCs evolve into a more mature, differentiated state known as muscle fiber, which is required for organized muscle activity.

Apoptosis – the process by which FAP cells die as part of regular muscle regeneration – had delayed greatly in the mice with the ACVR1 mutation that Mourkioti, Shore, and their co-authors analyzed, resulting in a high presence of FAPs past their normal lifespan. This tipped the scales in their favor with the MuSCs. Muscle fibers in mice with the ACVR1 mutation were much smaller than muscle fibers in mice without the mutation, indicating that the wounded tissue had a reduced ability for muscle stem cell development.

“The prolonged persistence of diseased FAPs within the regenerating muscle contributes to the altered muscle environment in FOP, which reduces muscle regeneration and allows the over-abundant FAPs to contribute to the formation of extra-skeletal bone,” Mourkioti adds. “This provides a completely new perspective on how excess extra-skeletal bone is formed – and how it could be prevented.”

The current treatment goals for FOP are to slow extra-skeletal bone development. This study could pave the way for a significant new direction.

“We propose that therapeutic interventions should consider promoting the regenerating potential of muscles together with the reduction of ectopic bone formation,” Shore and Mourkioti add. “By addressing both stem cell populations and their roles in the origin of FOP, there is the possibility of greatly enhanced therapies.”

Image credit: Getty

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