Fibrodysplasia+Ossificans+Progressiva

**Name of the Disease:** Fibrodysplasia Ossificans Progressi va

**The Root Cause of the Disease:** A mutation in the ACVR1 gene that “breaks” repair mechanisms of the body. It alters the structure and activity of Bone Morphogenic Protein type.

**Affected Cell types/tissues/organs/systems:** It is a disorder of the connective tissue of the body. Skeletal system is greatly modified/altered as well. [2]

**Historical Background:** The first case of Fibrodysplasia Ossificans Progressiva was documented by Guy Patin in 1692, though a more accurate description of the disease was actually written by John Freke, a London surgeon, in 1740. He was writing a letter to a friend, and was writing about a boy who had come to him to fix his back. There were many large swellings which had been there for three years and continued to grow; they arose from every rib and from all along the vertebrae of the neck and spine. The definitive symptom, Monophalangism of the great toe, was discovered by Frnankel in 1871. Unlike normal skeletons after death in which have to be pieced back together due to the loss of connective tissue that held them together his did not have to be reconstructed due to his disease which virtually fused his back together and the ossification of the connective tissue aided in holding the skeleton together. By the time he had died, the only thing he was able to move was his lips, everything else was immobilized by FOP.His upper arms were connected to his chest bone, ribbons of bone joined the spine to the joints and limbs, his jaw was locked to his skull and his skull to his spine. [1]  The most famous individual that is associated with the disease, and was also a victim of it, is a man named Henry Eastlack. He was born with the disease in 1933 and died because of it in 1973. His skeleton is an exhibit at The Mutter Museum in Philadelphia and its one of the best FOP skeletons in the world.

**Common symptoms & Definitive Features:** Two clinical features define FOP: malformation of great toes and progressive heterotropic ossification. Children within their first decade of life exhibit painful and highly inflammatory soft tissue swellings (that usually resemble tumors) that eventually turn into bone. Immobility is often a result as stiffness occurs due to ossification of connective tissue until the point where one becomes “turned into stone”. It often begins in the neck and shoulders and progresses along the back, trunk, and limbs of the body. Flareups of bone formation can occur spontaneously of following body trauma and surgeries to remove bone only encourage it to grow faster [4].

**Standard Treatment:** There is currently no cure for this condition and treatments are limited. Prevention of flareups are most recommended in which the individual afflicted with the disease should avoid any instances or situations where injury or trauma have a high chance of happening. However, research being done for the treatment and prevention is looking in several directions including the disruption of relevant inductive signaling, suppression of immunological and inflammatory triggers, alteration of the osteoprogenitor cells in target tissues, and the modification of the environment that causes it to proliferate.

**Current Research:** Ultimately, the only way that FOP will ever be cured is by some sort of gene therapy that can correct the misexpressed or altered gene: all patients with classical FOP carry the same heterozygous mutation in the in activin A type I receptor/activin-like kinase 2 which is a bone morphogenetic protein (BMP) type I receptor [3]. BMP signaling has been being researched in FOP in order to find some sort of treatment or therapy. BMP’s are very important as they are seen to regulate cell differentiation fates and have major roles in many different cells and tissue types during embryonic development and throughout life. BMP signaling is mediated through three known type I receptors which are BMPRIA, BMPRIB,and ACVR1. In 2006 it was discovered that this mutation was being cause by the same recurrent nucleotide change in ACVR1 that alters the shape and consequentially the sensitivity and activity of the receptor [3]. In 2010 this notion was reaffirmed through research and experimentation done on mice. The data showed that intramuscular expression in mice of an inducible transgene that coded for a permanently activated form of ALK2 leads to formation of ectopic endochondral bone formation, joint fusion, and functional impairment. The mouse was treated with a selective inhibitor of BMP type I receptor kinases that inhibit activation of specific BMP signaling effectors; this treatment showed success as it lead to a reduction in ectopic ossification and functional impairment [5]. In FOP cells it is commonly seen that BMP transcriptional targets are enhanced and overexpressed which lead to ankylosis of the joints, this stiffness remains and progressively gets worse as the continued overexpression (and very dangerous flareups) keeps signaling for the ossification to occur [3]. It can also be due to defect in the production of BMP antagonists in which the patient is unable to synthesize the proteins that regulate the process through a negative feedback loop. This is seen with the BMP4 signaling pathway which is a type of cascade in with BMP’s activate BMPR’s and in turn those BMPR’s form complexes which activate receptors further downstream in order to amplify the process that is happening. Without an antagonist to tell it to slow down (by binding to receptors or proteins and deactivating them) then overexpression occurs and in the case of this disease it entails the uncontrollable growth of bone at the sight of the injury in which the body is trying to repair [6]. Through studies done on the BMP pathways involved with uncontrolled bone growth in patients, new therapies and treatments are becoming more of a reality. Such a method could be the controlled administration of BMP antagonists (such as noggin in BMP4 pathways) to the patient that would put functional forms of the BMP antagonists into the cells, allowing bone growth and formation to be regulated. There could also be the possibility of the alteration of the receptor itself and when antagonistic factors attempt to bind with it to prevent signaling it cannot do so correctly and thus not be able to achieve inhibition of the signal that begins the cascade resulting in bone growth. None of these treatments would be permanent and would require reoccurring treatments throughout the rest of the victim’s life. Gene therapy that corrected the mutation or supplied a working copy of the gene would be required for complete removal of the disease.



 A. Fibrodysplasia Ossificans Progressiva B. Mutation in the ACVR1 gene that “breaks” repair mechanisms of the body. It alters the structure and activity of Bone Morphogenic Protein type. C. It is a disorder of the connective tissue of the body. Skeletal system is greatly modified/altered as well. [2] D. The first case of Fibrodysplasia Ossificans Progressiva was documented by Guy Patin in 1692, though a more accurate description of the disease was actually written by John Freke, a London surgeon, in 1740. He was writing a letter to a friend, and was writing about a boy who had come to him to fix his back. There were many large swellings which had been there for three years and continued to grow; they arose from every rib and from all along the vertebrae of the neck and spine. The definitive symptom, Monophalangism of the great toe, was discovered by Frnankel in 1871. Unlike normal skeletons after death in which have to be pieced back together due to the loss of connective tissue that held them together his did not have to be reconstructed due to his disease which virtually fused his back together and the ossification of the connective tissue aided in holding the skeleton together. By the time he had died, the only thing he was able to move was his lips, everything else was immobilized by FOP.His upper arms were connected to his chest bone, ribbons of bone joined the spine to the joints and limbs, his jaw was locked to his skull and his skull to his spine. [1] The most famous individual that is associated with the disease, and was also a victim of it, is a man named Henry Eastlack. He was born with the disease in 1933 and died because of it in 1973. His skeleton is an exhibit at The Mutter Museum in Philadelphia and its one of the best FOP skeletons in the world. = E. Two clinical features define FOP: malformation of great toes and progressive heterotropic ossification. Children within their first decade of life exhibit painful and highly inflammatory soft tissue swellings (that usually resemble tumors) that eventually turn into bone. Immobility is often a result as stiffness occurs due to ossification of connective tissue until the point where one becomes “turned into stone”. It often begins in the neck and shoulders and progresses along the back, trunk, and limbs of the body. Flareups of bone formation can occur spontaneously of following body trauma and surgeries to remove bone only encourage it to grow faster [4]. =  F. There is currently no cure for this condition and treatments are limited. Prevention of flareups are most recommended in which the individual afflicted with the disease should avoid any instances or situations where injury or trauma have a high chance of happening. However, research being done for the treatment and prevention is looking in several directions including the disruption of relevant inductive signaling, suppression of immunological and inflammatory triggers, alteration of the osteoprogenitor cells in target tissues, and the modification of the environment that causes it to proliferate.  G. Ultimately, the only way that FOP will ever be cured is by some sort of gene therapy that can correct the misexpressed or altered gene: all patients with classical FOP carry the same heterozygous mutation in the in activin A type I receptor/activin-like kinase 2 which is a bone morphogenetic protein (BMP) type I receptor [3]. BMP signaling has been being researched in FOP in order to find some sort of treatment or therapy. BMP’s are very important as they are seen to regulate cell differentiation fates and have major roles in many different cells and tissue types during embryonic development and throughout life. BMP signaling is mediated through three known type I receptors which are BMPRIA, BMPRIB,and ACVR1. In 2006 it was discovered that this mutation was being cause by the same recurrent nucleotide change in ACVR1 that alters the shape and consequentially the sensitivity and activity of the receptor [3]. In 2010 this notion was reaffirmed through research and experimentation done on mice. The data showed that intramuscular expression in mice of an inducible transgene that coded for a permanently activated form of ALK2 leads to formation of ectopic endochondral bone formation, joint fusion, and functional impairment. The mouse was treated with a selective inhibitor of BMP type I receptor kinases that inhibit activation of specific BMP signaling effectors; this treatment showed success as it lead to a reduction in ectopic ossifica tion and functional impairment  [5]. In FOP cells it is commonly seen that BMP transcriptional targets are enhanced and overexpressed which lead to ankylosis of the joints, this stiffness remains and progressively gets worse as the continued overexpression (and very dangerous flareups) keeps signaling for the ossification to occur [3]. It can also be due to defect in the production of BMP antagonists in which the patient is unable to synthesize the proteins that regulate the process through a negative feedback loop. This is seen with the BMP4 signaling pathway which is a type of cascade in with BMP’s activate BMPR’s and in turn those BMPR’s form complexes which activate receptors further downstream in order to amplify the process that is happening. Without an antagonist to tell it to slow down (by binding to receptors or proteins and deactivating them) then overexpression occurs and in the case of this disease it entails the uncontrollable growth of bone at the sight of the injury in which the body is trying to repair [6] . Through studies done on the BMP pathways involved with uncontrolled bone growth in patients, new therapies and treatments are becoming more of a reality. Such a method could be the controlled administration of BMP antagonists (such as noggin in BMP4 pathways) to the patient that would put functional forms of the BMP antagonists into the cells, allowing bone growth and formation to be regulated. There could also be the possibility of the alteration of the receptor itself and when antagonistic factors attempt to bind with it to prevent signaling it cannot do so correctly and thus not be able to achieve inhibition of the signal that begins the cascade resulting in bone growth. None of these treatments would be permanent and would require reoccurring treatments throughout the rest of the victim’s life. Gene therapy that corrected the mutation or supplied a working copy of the gene would be required for complete removal of the disease. References: <span style="font-family: 'Times New Roman','serif'; font-size: 12pt; line-height: 115%;">1. Kaplan, F. S. (2005). Fibrodysplasia Ossificans Progressiva An Historical Perspective. //<span style="font-family: 'Calibri','sans-serif';">Clinical Reviews in Bone and Mineral Metabolism //, //<span style="font-family: 'Calibri','sans-serif';">3 //(3-4), 179-181. <span style="font-family: 'Times New Roman','serif'; font-size: 12pt; line-height: 115%;">2. Shore, E. M., Feldman, G. J., Xu, M., & Kaplan, F. S. (2005). The Genetics of Fibrodysplasia Ossificans Progressiva. //<span style="font-family: 'Calibri','sans-serif';">Clinical Reviews in Bone and Mineral Metabolism //, //<span style="font-family: 'Calibri','sans-serif';">3 //(3-4), 201-204. <span style="font-family: 'Times New Roman','serif'; font-size: 12pt; line-height: 115%;">3. Kaplan, F. S., Xu, M., Seemann, P., Connor, M., Glaser, D. L., Carroll, L., Delai, P., Fastnacht-Urban, E., Forman, S. J., Gillessen-Kaesbach, G., Hoover-Fong, J., Koster, B., Pauli, R. M., Reardon, W., Zaidi, S., Zasloff, M., Morhart, R., Mundlos, S., Groppe, J., & Shore, E. M. (2009). Classic and Atypical FOP Phenotypes are Caused by Mutations in the BMP Type I Receptor ACVR1. //<span style="font-family: 'Calibri','sans-serif';">Hum. Mutat //, //<span style="font-family: 'Calibri','sans-serif';">30 //(3), 379-390. Retrieved from [] <span style="font-family: 'Times New Roman','serif'; font-size: 12pt; line-height: 115%;">4. Kaplan, F. S., Merrer, M. L., Glaser, D. L., Pignolo, R. J., Goldsby, R., Kitterman, J. A., Groppe, J., & Shore, E. M. (2009). Fibrodysplasia ossificans progressiva. //<span style="font-family: 'Calibri','sans-serif';">PMC //, //<span style="font-family: 'Calibri','sans-serif';">22 //(1), 191-205. Retrieved from [] <span style="font-family: 'Times New Roman','serif'; font-size: 12pt; line-height: 115%;">5. Yu, P. B., Deng, D. Y., Lai, C. S., Hong, C. C., Cuny, G. D., Bouxsein, M. L., Hong, D. W., McManus, P. M., Katagiri, T., Sachidanandan, C., Kamiya, N., Fukada, T., Mishina, Y., Peterson, R. T., & Bloch, K. D. (2008). BMP type I receptor inhibition reduces heterotopic ossification. //<span style="font-family: 'Calibri','sans-serif';">Nat Med //, //<span style="font-family: 'Calibri','sans-serif';">14 //(12), 1363-1369. Retrieved from [] <span style="font-family: 'Times New Roman','serif'; font-size: 12pt; line-height: 115%;">6. Kaplan, F. S., Fiori, J. L., De la Pena, L. S., Ahn, J., Billings, P. C., & Shore, E. M. (2005). Dysregulation of BMP4 receptor trafficking and signaling in fibrodysplasia ossificans progressiva. //<span style="font-family: 'Calibri','sans-serif';">Clinical Reviews in Bone and Mineral Metabolism //, //<span style="font-family: 'Calibri','sans-serif';">3 //(3-4), 217-223. Retrieved from http://link.springer.com/article/10.1385/BMM%3A3%3A3-4%3A217
 * <span style="font-family: 'Times New Roman',Times,serif;">References: **
 * 1) <span style="font-family: 'Times New Roman',Times,serif;">Kaplan, F. S. (2005). Fibrodysplasia Ossificans Progressiva An Historical Perspective. Clinical Reviews in Bone and Mineral Metabolism, 3(3-4), 179-181.
 * 2) <span style="font-family: 'Times New Roman',Times,serif;">Shore, E. M., Feldman, G. J., Xu, M., & Kaplan, F. S. (2005). The Genetics of Fibrodysplasia Ossificans Progressiva. Clinical Reviews in Bone and Mineral Metabolism, 3(3-4), 201-204.
 * 3) <span style="font-family: 'Times New Roman',Times,serif;">Kaplan, F. S., Xu, M., Seemann, P., Connor, M., Glaser, D. L., Carroll, L., Delai, P., Fastnacht-Urban, E., Forman, S. J., Gillessen-Kaesbach, G., Hoover-Fong, J., Koster, B., Pauli, R. M., Reardon, W., Zaidi, S., Zasloff, M., Morhart, R., Mundlos, S., Groppe, J., & Shore, E. M. (2009). Classic and Atypical FOP Phenotypes are Caused by Mutations in the BMP Type I Receptor ACVR1. Hum. Mutat, 30(3), 379-390. Retrieved from []
 * 4) <span style="font-family: 'Times New Roman',Times,serif;">Kaplan, F. S., Merrer, M. L., Glaser, D. L., Pignolo, R. J., Goldsby, R., Kitterman, J. A., Groppe, J., & Shore, E. M. (2009). Fibrodysplasia ossificans progressiva. PMC, 22(1), 191-205. Retrieved from []
 * 5) <span style="font-family: 'Times New Roman',Times,serif;">Yu, P. B., Deng, D. Y., Lai, C. S., Hong, C. C., Cuny, G. D., Bouxsein, M. L., Hong, D. W., McManus, P. M., Katagiri, T., Sachidanandan, C., Kamiya, N., Fukada, T., Mishina, Y., Peterson, R. T., & Bloch, K. D. (2008). BMP type I receptor inhibition reduces heterotopic ossification. Nat Med, 14(12), 1363-1369. Retrieved from []
 * 6) <span style="font-family: 'Times New Roman',Times,serif;">Kaplan, F. S., Fiori, J. L., De la Pena, L. S., Ahn, J., Billings, P. C., & Shore, E. M. (2005). Dysregulation of BMP4 receptor trafficking and signaling in fibrodysplasia ossificans progressiva. Clinical Reviews in Bone and Mineral Metabolism, 3(3-4), 217-223. Retrieved from http://link.springer.com/article/10.1385/BMM%3A3%3A3-4%3A217
 * 7) <span style="font-family: 'Times New Roman',Times,serif;">Diagram adapted from http://www.springerimages.com/Images/RSS/1-10.1007_s00264-011-1301-z-1