Fibrodysplasia Ossificans Progressiva: Annotated Bibliography

Al Kaissi, Ali, Vladimir Kenis, Maher Ben Ghachem, Jochen Hofstaetter, Franz Grill, Rudolf Ganger, and Susanne Gerit Kircher. 2016. “The Diversity of the Clinical Phenotypes in Patients With Fibrodysplasia Ossificans Progressiva.” Journal of Clinical Medicine Research 8 (3): 246–53. doi:10.14740/jocmr2465w.

  • Describes the clinical presentation of FOP 11 patients from 0-16 years of age. The deformed big toe (congenital hallux valgus) is usual first sign of FOP.

Billings, Paul C, Jennifer L Fiori, Jennifer L Bentwood, Michael P O’Connell, Xiangyang Jiao, Burton Nussbaum, Robert J Caron, Eileen M Shore, and Frederick S Kaplan. 2008. “Dysregulated BMP Signaling and Enhanced Osteogenic Differentiation of Connective Tissue Progenitor Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP).” Journal of Bone and Mineral Research 23 (3): 305–13. doi:10.1359/JBMR.071030.

  • The authors were obtained connective tissue progenitor cells from the teeth of FOP and control patients. The FOP cells were hyperresponsive to BMP4 signaling. Dysregulation of the MAPK and Smad parts of the BMP signaling was also observed.

Cai, Jie, Valeria V. Orlova, Xiujuan Cai, Elisabeth M.W. Eekhoff, Keqin Zhang, Duanqing Pei, Guangjin Pan, Christine L. Mummery, and Peter ten Dijke. 2015. “Induced Pluripotent Stem Cells to Model Human Fibrodysplasia Ossificans Progressiva.Stem Cell Reports 5 (6): 963–70. doi:10.1016/j.stemcr.2015.10.020.

  • The authors evaluated hiPSCs as a model for FOP. The mineralization of hiPSC pericytes due to ACVR1 R206H provides evidence that this could be used as a model for testing potential drugs.

Culbert, Andria L., Salin A. Chakkalakal, Edwin G. Theosmy, Tracy A. Brennan, Frederick S. Kaplan, and Eileen M. Shore. 2014. “Alk2 Regulates Early Chondrogenic Fate in Fibrodysplasia Ossificans Progressiva Heterotopic Endochondral Ossification.” Stem Cells (Dayton, Ohio) 32 (5): 1289–1300. doi:10.1002/stem.1633.

  • The effect of Alk2 with the FOP R206H mutation on mesenchymal progenitor cells was examined. Increased Alk2 signaling (as in FOP) results in differentiation of those progenitor cells to cartilage.

de la Peña, Lourdes Serrano, Paul C Billings, Jennifer L Fiori, Jaimo Ahn, Frederick S Kaplan, and Eileen M Shore. 2005. “Fibrodysplasia Ossificans Progressiva (FOP), a Disorder of Ectopic Osteogenesis, Misregulates Cell Surface Expression and Trafficking of BMPRIA.” Journal of Bone and Mineral Research 20 (7): 1168–76. doi:10.1359/JBMR.050305.

  • This article explored BMP signaling in FOP. Significantly more BMPRIA is found on the cell surface in FOP than in non-FOP cells. Additionally, BMPRIA not being internalized properly by the FOP cells.

Feldman, George, Ming Li, Shelden Martin, Margrit Urbanek, J. Andoni Urtizberea, Michel Fardeau, Martine LeMerrer, et al. 2000. “Fibrodysplasia Ossificans Progressiva, a Heritable Disorder of Severe Heterotopic Ossification, Maps to Human Chromosome 4q27-31.” American Journal of Human Genetics 66 (1): 128–35.

  • The location of the genetic mutation that causes FOP was narrowed down to 4q27-31, a region on chromosome 4. We now know exactly where the mutation occurs, but this was the paper that was originally able to determine roughly where it is.

Fiori, Jennifer L, Paul C Billings, Lourdes Serrano de la Peña, Frederick S Kaplan, and Eileen M Shore. 2006. “Dysregulation of the BMP-p38 MAPK Signaling Pathway in Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP).” Journal of Bone and Mineral Research 21 (6): 902–9. doi:10.1359/jbmr.060215.

  • The BMP-p38 MAPK pathway is favored in lymphocytes due to the presence of BMP4. There is an increase in phosphorylation of p38  The p38 MAPK pathway plays a role in the transcription of ID1 and ID3.

Gannon, Francis H., David Glaser, Robert Caron, Lester D. R. Thompson, Eileen M. Shore, and Frederick S. Kaplan. 2001. “Mast Cell Involvement in Fibrodysplasia Ossificans Progressiva.” Human Pathology 32 (8): 842–48. doi:10.1053/hupa.2001.26464.

  • Inflammatory mast cells were found to be present in high levels during lesion development in FOP. The authors describe a potential pathway of the combination of inflammation from mast cells, hyperactive BMP4 production, and the eventual TGF-β that results in ossification.

Giacopelli, Francesca, Serena Cappato, Laura Tonachini, Marzia Mura, Simona Di Lascio, Diego Fornasari, Roberto Ravazzolo, and Renata Bocciardi. 2013. “Identification and Characterization of Regulatory Elements in the Promoter of ACVR1, the Gene Mutated in Fibrodysplasia Ossificans Progressiva.” Orphanet Journal of Rare Diseases 8 (September): 145. doi:10.1186/1750-1172-8-145.

  • The authors identified transcription factors the regulate the ACVR1 Hey-1 was a transcription factor that acts as an inhibitor that is regulated by BMP signaling, the pathway that is affected by the FOP-causing mutation.

Haupt, Julia, Alexandra Deichsel, Katja Stange, Cindy Ast, Renata Bocciardi, Roberto Ravazzolo, Maja Di Rocco, et al. 2014. “ACVR1 p.Q207E Causes Classic Fibrodysplasia Ossificans Progressiva and Is Functionally Distinct from the Engineered Constitutively Active ACVR1 p.Q207D Variant.” Human Molecular Genetics 23 (20): 5364–77. doi:10.1093/hmg/ddu255.

  • These authors explored a different model for FOP than the typical ACVR1 R206H mutation. The mutation was made at position 207 instead of 206. Of the different mutations, ACVR1 Q207E was most like R206H while Q207E was not as good of a model.

Hino, Kyosuke, Makoto Ikeya, Kazuhiko Horigome, Yoshihisa Matsumoto, Hayao Ebise, Megumi Nishio, Kazuya Sekiguchi, et al. 2015. “Neofunction of ACVR1 in Fibrodysplasia Ossificans Progressiva.Proceedings of the National Academy of Sciences of the United States of America 112 (50): 15438–43. doi:10.1073/pnas.1510540112.

  • A new mechanism of mutant ACVR1 is proposed in which BMP signaling occurs in response to Activin-A. Activin-A was also found to stimulate TGF-β signaling. Activin-A helped to stimulate the differentiation of chondrocytes.

Kaplan, Frederick S., Robert J. Pignolo, and Eileen M. Shore. 2013. “From Mysteries to Medicines: Drug Development for Fibrodysplasia Ossificans Progressive.” Expert Opinion on Orphan Drugs 1 (8): 637–49. doi:10.1517/21678707.2013.825208.

  • A review of potential treatment options for FOP. Key drug targets include inhibiting the activity of the mutant ACVR1, inhibiting flare-up triggers, preventing stem cells from ossifying, stopping the body from responding to lesion forming signals.

Kaplan, Frederick S., Robert J. Pignolo, and Eileen M. Shore. 2016. “Granting Immunity to FOP and Catching Heterotopic Ossification in the Act.” Seminars in Cell & Developmental Biology, Bone development and diseaseMechanisms of vertebrate embryo segmentation, 49 (January): 30–36. doi:10.1016/j.semcdb.2015.12.013.

  • The article explores hypotheses for what exactly causes the periodic flare-ups of FOP that lead to ossification. Evidence points to the involvement of the immune response and inflammatory factors.

Kaplan, Frederick S., and Eileen M. Shore. 1998. “Encrypted Morphogens of Skeletogenesis: Biological Errors and Pharmacologic Potentials.” Biochemical Pharmacology 55 (4): 373–82. doi:10.1016/S0006-2952(97)00559-5.

  • This paper was one of the first to establish the connection between of BMPs and FOP, and, more specifically, it highlighted the overexpression of BMP-4 in FOP patients. This paper led to later research that discovered where exactly in the BMP signaling pathway the FOP mutation occurs.

Luo, Jinyong, Min Tang, Jiayi Huang, Bai-Cheng He, Jian-Li Gao, Liang Chen, Guo-Wei Zuo, et al. 2010. “TGFβ/BMP Type I Receptors ALK1 and ALK2 Are Essential for BMP9-Induced Osteogenic Signaling in Mesenchymal Stem Cells.” Journal of Biological Chemistry 285 (38): 29588–98. doi:10.1074/jbc.M110.130518.

  • This article studies how stem cells are differentiated into bone through the BMP signaling pathway. ALK2 (ACVR1) is demonstrated to be vital to BMP9 signaling, backed up by its role in FOP. How the FOP mutant of ALK2 effects BMP9 signaling is not reported.

Mao, Li, Masato Yano, Naoyuki Kawao, Yukinori Tamura, Kiyotaka Okada, and Hiroshi Kaji. 2013. “Role of Matrix Metalloproteinase-10 in the BMP-2 Inducing Osteoblastic Differentiation.” Endocrine Journal 60 (12): 1309–19. doi:10.1507/endocrj.EJ13-0270.

  • MMP-10 interacts with the BMP signaling pathway to induce the differentiation of myoblasts to osteoblasts. MMP-10 expression is increased in the presence of hyperactive ALK2 R206H.

Martelli, Anderson, and Arnaldo Rodrigues Santos. 2014. “Cellular and Morphological Aspects of Fibrodysplasia Ossificans Progressiva.” Organogenesis 10 (3): 303–11. doi:10.4161/org.29206.

  • A review of the mutation and mechanism behind FOP. Also gives detail on the normal bone formation pathway.

Matsumoto, Yoshihisa, Yohei Hayashi, Christopher R Schlieve, Makoto Ikeya, Hannah Kim, Trieu D Nguyen, Salma Sami, et al. 2013. “Induced Pluripotent Stem Cells from Patients with Human Fibrodysplasia Ossificans Progressiva Show Increased Mineralization and Cartilage Formation.” Orphanet Journal of Rare Diseases 8 (December): 190. doi:10.1186/1750-1172-8-190.

  • The authors establish an in vitro model for FOP using induced pluripotent stem cells. The cells can replicate mineralization that occurs after injury in FOP patients, but they do not go as far as full bone formation.

Micha, Dimitra, Elise Voermans, Marelise E. W. Eekhoff, Huib W. van Essen, Behrouz Zandieh-Doulabi, Coen Netelenbos, Thomas Rustemeyer, E. A. Sistermans, Gerard Pals, and Nathalie Bravenboer. 2016. “Inhibition of TGFβ Signaling Decreases Osteogenic Differentiation of Fibrodysplasia Ossificans Progressiva Fibroblasts in a Novel in Vitro Model of the Disease.” Bone 84 (March): 169–80. doi:10.1016/j.bone.2016.01.004.

  • This article focused on the role of TGFβ in osteogenic differentiation. Due to the near impossibility of obtaining biopsy samples due to the health risks to the patient, the researchers focused on markers of osteoblasts (Runx2 and Alp). A TGFβ inhibitor, GW788388 was resulted in a lower expression of those markers.

Pacifici, Maurizio, and Eileen M. Shore. 2016. “Common Mutations in ALK2/ACVR1, a Multi-Faceted Receptor, Have Roles in Distinct Pediatric Musculoskeletal and Neural Orphan Disorders.” Cytokine & Growth Factor Reviews, Special Issue:Bone/Body Morphogenetic Proteins, 27 (February): 93–104. doi:10.1016/j.cytogfr.2015.12.007.

  • The role of ACVR1 in FOP is discussed, in addition to its role in another disease, Diffuse Intrinsic Pontine Gliomas.

Shafritz, Adam B., Eileen M. Shore, Francis H. Gannon, Michael A. Zasloff, Rebecca Taub, Maximilian Muenke, and Frederick S. Kaplan. 1996. “Overexpression of an Osteogenic Morphogen in Fibrodysplasia Ossificans Progressiva.” New England Journal of Medicine 335 (8): 555–61. doi:10.1056/NEJM199608223350804.

  • One of the early papers that identified the overexpression of BMP-4 as a common trait of FOP patients.

Shen, Qi, Shawn C. Little, Meiqi Xu, Julia Haupt, Cindy Ast, Takenobu Katagiri, Stefan Mundlos, et al. 2009. “The Fibrodysplasia Ossificans Progressiva R206H ACVR1 Mutation Activates BMP-Independent Chondrogenesis and Zebrafish Embryo Ventralization.” Journal of Clinical Investigation, October. doi:10.1172/JCI37412.

  • The FOP mutant R206H ACVR1 was expressed in zebrafish, a model used to study BMP signaling. FKBP1A binds to BMP in the absence of a ligand and acts to inhibit BMP. The R206H mutant displayed decreased binding activity to FKBP1A.

Shi, SongTing, Jie Cai, David J. J. de Gorter, Gonzalo Sanchez-Duffhues, Dwi U. Kemaladewi, Willem M. H. Hoogaars, Annemieke Aartsma-Rus, Peter A. C. ’t Hoen, and Peter ten Dijke. 2013. “Antisense-Oligonucleotide Mediated Exon Skipping in Activin-Receptor-Like Kinase 2: Inhibiting the Receptor That Is Overactive in Fibrodysplasia Ossificans Progressiva.” PLoS ONE 8 (7). doi:10.1371/journal.pone.0069096.

  • A new method of reducing the signaling of BMP is developed. ALK2 AON is designed to skip exon 8. It was successful in preventing osteoblast differentiation in some cells, but more work is needed.

ten Dijke, Peter, Olexander Korchynskyi, Gudrun Valdimarsdottir, and Marie-José Goumans. 2003. “Controlling Cell Fate by Bone Morphogenetic Protein Receptors.” Molecular and Cellular Endocrinology, First International Meeting on Anti-Mullerian Hormone/Mullerian Inhibiting Substance, 211 (1–2): 105–13. doi:10.1016/j.mce.2003.09.016.

  • Discusses the mechanism of BMPs. Id proteins are shown to be involved with the determination of cell fate.

van den Wijngaard, Arthur, Marie-Antonette Pijpers, Paul H. L. J. Joosten, José M. A. Roelofs, Everardus J. J. Van Zoelen, and Wiebe Olijve. 1999. “Functional Characterization of Two Promoters in the Human Bone Morphogenetic Protein-4 Gene.” Journal of Bone and Mineral Research 14 (8): 1432–41. doi:10.1359/jbmr.1999.14.8.1432.

  • Two promoters of the human BMP-4 gene were characterized. The regulation of the promoter activity was observed. It was noted that BMP-4 promoter 1 had higher activity in the presence of the transcript BMP2.1ab or BMP4.2.

Yadin, David, Petra Knaus, and Thomas D. Mueller. 2016. “Structural Insights into BMP Receptors: Specificity, Activation and Inhibition.” Cytokine & Growth Factor Reviews, Special Issue:Bone/Body Morphogenetic Proteins, 27 (February): 13–34. doi:10.1016/j.cytogfr.2015.11.005.

  • Overview of BMP receptors. Contains important structural information and images.

Yano, Masato, Naoyuki Kawao, Katsumi Okumoto, Yukinori Tamura, Kiyotaka Okada, and Hiroshi Kaji. 2014. “Fibrodysplasia Ossificans Progressiva-Related Activated Activin-like Kinase Signaling Enhances Osteoclast Formation during Heterotopic Ossification in Muscle Tissues.” Journal of Biological Chemistry 289 (24): 16966–77. doi:10.1074/jbc.M113.526038.

  • Another article that highlights the importance of TGF-β in osteoblast differentiation and formation. Successful inhibition of TGF-β results in lessening of osteoblast formation.