The rare and debilitating disease known as fibrodysplasia ossificans progressiva (FOP) involves bone growth outside of the normal skeleton adversely affecting joint movement and even breathing.
New research (mouse model) from the Perelman School of Medicine at the University of Pennsylvania has found that the formation of extra-skeletal bone might not be the engine behind this disease. Specifically, say the Penn researchers, “Impaired and inefficient muscle tissue regeneration appears to open the door for unwanted bone to form in areas where new muscle should occur after injuries.”
Their work, “Dynamics of skeletal muscle-resident stem cells during myogenesis in fibrodysplasia ossificans progressiva,” was published in the January 14, 2022, edition of NPJ Regenerative Medicine.
“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,” said the study’s lead author, Foteini Mourkioti, Ph.D., an assistant professor of Orthopaedic Surgery and Cell and Developmental Biology, as well as the co-director of the Penn Institute for Regenerative Medicine, Musculoskeletal Program.
Roughly 15 years ago Penn researchers set the stage for this work, finding that a mutation in the ACVR1 gene was the driver behind FOP. Specifically, they discovered the mutation altered cells within muscles and connective tissues, “misdirecting cells within the tissue to behave like bone cells, resulting in new and unnecessary extra-skeletal bone within the body.”
Part of that team was this study’s co-author, Eileen Shore, Ph.D., a professor in Orthopaedic Surgery and Genetics and the co-director of the Center for Research in FOP and Related Disorders. She said, “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. 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.”
When OTW asked Dr. Shore what made them think there might be a problem in generating new muscle tissue, she responded, “The first clues came directly from people with FOP. Over time, we saw that as more and more ectopic bone formed, the muscle tissue where the bone formed was diminishing. Once we were able to model FOP in mice with the same ACVR1R206H mutation that occurs in people with FOP, we could examine the effects of FOP on muscle more closely. Detailed histology analysis readily revealed that the muscle tissue with the FOP mutation did not properly repair and regenerate during the healing process following injury. Our next steps were to design a study to investigate why this was occurring.”
Dr. Mourkioti added, “Our study revealed that there is a miscommunication between two specific types of muscle tissue stem cells: fibro-adipogenetic progenitors and muscle stem cells. Normally, muscle repair requires a careful balance between these two cell types. After injury, fibro-adipogenetic progenitors expand and help recruit and activate the muscle stem cells. As a result, muscle stem cells first start to make copies of themselves and then transform into mature muscle cells that will regenerate the muscle tissue. After about 3 days, fibro-adipogenetic progenitors die off as their job is completed. However, in mice with the ACVR1 mutation two things are not working properly: 1) the process by which fibro-adipogenetic progenitors die has been significantly slowed down. As a result, fibro-adipogenetic progenitors remain in high numbers past their usual lifetime and abnormally convert into bone within the muscle, and 2) due to the altered balance of the two types of stem cells, muscle stem cells receive the ‘wrong’ signals and do not mature properly, leading to smaller and incomplete muscles.”
“The current strategies and targets for treating FOP focus on slowing and preventing extra-skeletal bone growth—clearly a key process to target,” said Mourkioti to OTW. “This research may provide a different direction for future therapeutic interventions to ideally promote the regeneration potential of the muscles together with the reduction of the bone formation. This is an important consideration for health and quality of life: if the extra bone can be prevented from forming but the remaining muscles do not function properly, then the FOP problem is only partially resolved.”
Dr. Shore concluded, “A better understanding about how fibro-adipogenetic progenitors and muscle stem cells communicate during muscle repair will allow future therapies to address the specific molecules that induce these stem cells to diverge from their proper functions and by doing so, enhance tissue restoration. This understanding will not only benefit people with FOP but also has high potential to be applied to other needs for enhanced muscle repair and regeneration.”
