THE GENETIC MODEL OF THE DISEASE FIBRODYSPLASIA OSSIFICANS PROGRESSIVA AND ITS POTENTIAL TREATMENTS – A REVIEW.
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Published
Sep 8, 2021
Ritwija Bhattacharjee
Abstract
“Fibrodysplasia ossificans progressiva” is genetically very uncommon disease, autosomally inherited, of a connective tissue which is responsible for unusual bone development, where bone should not develop, this condition is called “heterotopic ossification”. This mostly affects in ligament, soft tissues, tendons, muscles and it get converted into hard like bone structure through metamorphosis. The disorder is caused by a single mutation in ACVR1 gene, due to a particular substitution of an amino acid, arginine with a histidine at 206 positions. It is a congenital disease so its first sign is seen in early childhood. Children with this disorder is seen to have smaller great toe and abnormal distal first metatarsal. Still there are no evidence of any particular effective treatment for FOP but there are many clinical trials going on. Few drugs mainly corticosteroids for reducing pain and inflammations. The patients are mostly given occupational therapies and genetic counselling. Currently researches are going on that includes BMP pathway inhibition, immunosuppressants.
How to Cite
Bhattacharjee, R. (2021). THE GENETIC MODEL OF THE DISEASE FIBRODYSPLASIA OSSIFICANS PROGRESSIVA AND ITS POTENTIAL TREATMENTS – A REVIEW. SPAST Abstracts, 1(01). Retrieved from https://spast.org/techrep/article/view/174
Article Details
Keywords
Fibrodysplasia, Ossificans, Progressiva, ACVR1 gene, BMP, Amino acids, Heterotopic Ossification (HO), Immunosuppressants.
References
[1] Qi Z, Luan J, Zhou X, Cui Y, Han J. Fibrodysplasia ossificans progressiva: basic understanding and experimental models. Intractable & rare diseases research. 2017 Nov 30;6(4):242-8.
[2] Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best practice & research Clinical rheumatology. 2008 Mar 1;22(1):191-205.
[3] Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, Zhang Q, Ye J, Yan Z, Denduluri S, Idowu O. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes & diseases. 2014 Sep 1;1(1):87-105
[4] Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature genetics. 2006 May;38(5):525-7.
[5] Di Rocco M, Baujat G, Bertamino M, Brown M, De Cunto CL, Delai PL, Eekhoff EM, Haga N, Hsiao E, Keen R, Morhart R. International physician survey on management of FOP: a modified Delphi study. Orphanet journal of rare diseases. 2017 Dec;12(1):1-5.
[6] Kaplan FS, Shore EM, Glaser DL, Emerson S. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. InClin Proc intl clin consort FOP 2011 May (Vol. 4, pp. 1-100).
[7] Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet journal of rare diseases. 2011 Dec;6(1):1-6.
[8] Rocke DM, Zasloff M, Peeper J, Cohen RB, Kaplan FS. Age-and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clinical Orthopaedics and Related Research. 1994 Apr 1(301):243-8.
[9] Schaffer AA, Kaplan FS, Tracy MR, O'Brien ML, Dormans JP, Shore EM, Harland RM, Kusumi K. Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome: clues from the BMP signaling pathway. Spine. 2005 Jun 15;30(12):1379-85.
[10] Deirmengian GK, Hebela NM, O’Connell M, Glaser DL, Shore EM, Kaplan FS. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. The Journal of bone and joint surgery. American volume. 2008 Feb 1;90(2):366.
[11] Pignolo RJ, Suda RK, Kaplan FS. The fibrodysplasia ossificans progressiva lesion. Clinical Reviews in Bone and Mineral Metabolism. 2005 Sep;3(3):195-200.
[12] Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva.
[13] Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai P, Fastnacht‐Urban E, Forman SJ, Gillessen‐Kaesbach G, Hoover‐Fong J. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Human mutation. 2009 Mar;30(3):379-90.
[14] Hüning I, Gillessen-Kaesbach G. Fibrodysplasia ossificans progressiva: clinical course, genetic mutations and genotype-phenotype correlation. Molecular syndromology. 2014;5(5):201-11.
[15] Haupt J, Xu M, Shore EM. Variable signaling activity by FOP ACVR1 mutations. Bone. 2018 Apr 1;109:232-40.
[16] Kaliya-Perumal AK, Carney TJ, Ingham PW. Fibrodysplasia ossificans progressiva: current concepts from bench to bedside. Disease Models & Mechanisms. 2020 Sep 1;13(9).
[17] Wolken DM, Idone V, Hatsell SJ, Paul BY, Economides AN. The obligatory role of activin A in the formation of heterotopic bone in fibrodysplasia ossificans progressiva. Bone. 2018 Apr 1;109:210-7.
[18] Gregson CL, Bergen DJ, Leo P, Sessions RB, Wheeler L, Hartley A, Youlten S, Croucher PI, McInerney‐Leo AM, Fraser W, Tang JC. A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD‐Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis. Journal of Bone and Mineral Research. 2020 Jan;35(1):92-105.
[19] Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Science translational medicine. 2015 Sep 2;7(303):303ra137-.
[20] Sanchez-Duffhues G, de Gorter DJ, Ten Dijke P. Towards a cure for fibrodysplasia ossificans progressiva. Annals of translational medicine. 2016 Oct;4(Suppl 1).
[21] Sheng N, Xie Z, Wang C, Bai G, Zhang K, Zhu Q, Song J, Guillemot F, Chen YG, Lin A, Jing N. Retinoic acid regulates bone morphogenic protein signal duration by promoting the degradation of phosphorylated Smad1. Proceedings of the National Academy of Sciences. 2010 Nov 2;107(44):18886-91.
[22] Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Machiya A, Jimi E, Kokabu S. Smad9 is a new type of transcriptional regulator in bone morphogenetic protein signaling. Scientific reports. 2014 Dec 23;4(1):1-1.
[23] Wang H, Shore EM, Pignolo RJ, Kaplan FS. Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone. 2018 Apr 1;109:218-24.
[24] Petrie KA, Lee WH, Bullock AN, Pointon JJ, Smith R, Russell RG, Brown MA, Wordsworth BP, Triffitt JT. Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients. PloS one. 2009 Mar 30;4(3):e5005.
[25] Macı́as-Silva M, Hoodless PA, Tang SJ, Buchwald M, Wrana JL. Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. Journal of Biological Chemistry. 1998 Oct 2;273(40):25628-36.
[26] Katagiri T, Tsukamoto S, Kuratani M. Heterotopic bone induction via BMP signaling: Potential therapeutic targets for fibrodysplasia ossificans progressiva. Bone. 2018 Apr 1;109:241-50.
[27] Furuya H, Ikezoe K, Wang L, Ohyagi Y, Motomura K, Fujii N, Kira JI, Fukumaki Y. A unique case of fibrodysplasia ossificans progressiva with an ACVR1 mutation, G356D, other than the common mutation (R206H). American Journal of Medical Genetics Part A. 2008 Feb 15;146(4):459-63.
[28] Liu H, Sawyer SL, Gos M, Grynspan D, Issa K, Ramphal R, Rotaru C, Consortium FC, Majewski J, Boycott KM, Graham G. Atypical fibrodysplasia ossificans progressiva diagnosed by whole‐exome sequencing. American Journal of Medical Genetics Part A. 2015 Jun;167(6):1337-41.
[29] Glaser D, Rocke D, Kaplan FS. Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clinical orthopaedics and related research. 1998;346.
[30] Kaplan FS, Shore EM, Connor JM. Fibrodysplasia ossificans progressiva. Connective tissue and its heritable disorders: molecular, genetic, and medical aspects. 2nd ed. New York: John Wiley and Sons. 2002 May 10;2002:827-40.
[31] Glaser DL, Kaplan FS. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clinical Reviews in Bone and Mineral Metabolism. 2005 Sep;3(3):243-50.
[32] Kaplan, Frederick & Mukaddam, M & Baujat, G & Cali, Amanda & Cho, Tae-Joon & Crowe, C & Cunto, C & Delai, Patricia & Diecidue, R & Di Rocco, Maja & Eekoff, EMW & Friedman, C & Grunwald, Z & Haga, N & Hsiao, E & Keen, R & Kitterman, Joseph & Levy, Charles & Morhart, Rolf & Pignolo, Robert. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. InClin Proc intl clin consort FOP 2019 June (Vol. 12, pp. 1-111).
[33] Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics. 2005 Nov 1;116(5):e654-61.
[34] Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacological reviews. 2004 Sep 1;56(3):387-437.
[35] Schuetz P, Mueller B, Christ-Crain M, Dick W, Haas H. Amino-bisphosphonates in heterotopic ossification: first experience in five consecutive cases. Spinal cord. 2005 Oct;43(10):604-10.
[36] Connor JM, Evans DA. Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. The Journal of bone and joint surgery. British volume. 1982 Feb;64(1):76-83.
[37] Delatycki M, Rogers JG. The Genetics of Fibrodysplasia Ossificans Progressiva. Clinical Orthopaedics and Related Research (1976-2007). 1998 Jan 1;346:15-8.
[38] Altschuler EL. Question: Bone marrow transplant for fibrodysplasia ossificans progressiva: has the hour arrived?. Clinical Orthopaedics and Related Research®. 2001 Nov 1;392:450-1.
[39] Kaplan FS, Glaser DL, Shore EM, Emerson SG. Bone marrow transplantation in a patient with fibrodysplasia ossificans progressiva. Clin Orthop. 2004, 422:278.
[40] Langenfeld EM, Langenfeld J. Bone Morphogenetic Protein-2 Stimulates Angiogenesis in Developing Tumors11NIH K22 grant CA91919-01A1 and UMDNJ Foundation to J. Langenfeld. Molecular Cancer Research. 2004 Mar 1;2(3):141-9.
[41] Kaplan FS, Tabas JA, Gannon FH, Finkel G, Hahn GV, Zasloff MA. The histopathology of fibrodysplasia ossificans progressiva. An endochondral process. The Journal of bone and joint surgery. American volume. 1993 Feb 1;75(2):220-30.
[42] Kaplan FS, Sawyer JR, Connors S, Keough K, Shore E, Gannon F, Glaser D, Rocke D, Zasloff MA, Folkman J. Urinary Basic Fibroblast Growth Factor: A Biochemical Marker for Preosseous Fibroproliferative Lesions in Patients Who Have Fibrodysplasia Ossificans Progressiva. Clinical orthopaedics and related research. 1998;346.
[43] Botman E, Netelenbos JC, Rustemeyer T, Schoonmade LJ, Nieuwenhuijzen JA, Teunissen BP, Visser M, Raijmakers P, Lammertsma AA, Dahele M, Eekhoff M. Radiotherapy in fibrodysplasia ossificans progressiva: A case report and systematic review of the literature. Frontiers in endocrinology. 2020 Feb 12;11:6.
[44] Chaikuad A, Alfano I, Kerr G, Sanvitale CE, Boergermann JH, Triffitt JT, von Delft F, Knapp S, Knaus P, Bullock AN. Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. Journal of Biological Chemistry. 2012 Oct 26;287(44):36990-8.
[45] Dey D, Bagarova J, Hatsell SJ, Armstrong KA, Huang L, Ermann J, Vonner AJ, Shen Y, Mohedas AH, Lee A, Eekhoff EM. Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification. Science translational medicine. 2016 Nov 23;8(366):366ra163-.
[46] Hamasaki M, Hashizume Y, Yamada Y, Katayama T, Hohjoh H, Fusaki N, Nakashima Y, Furuya H, Haga N, Takami Y, Era T. Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance: mechanisms of reprogramming and strategy for drug identification. Stem Cells. 2012 Nov;30(11):2437-49.
[47] Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert opinion on orphan drugs. 2017 Apr 3;5(4):291-4.
[48] Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, Whitehead B, Jacobs B, Siegel DM, Keen R, Hsiao E. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone. 2018 Apr 1;109:276-80.
[2] Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best practice & research Clinical rheumatology. 2008 Mar 1;22(1):191-205.
[3] Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, Zhang Q, Ye J, Yan Z, Denduluri S, Idowu O. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes & diseases. 2014 Sep 1;1(1):87-105
[4] Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature genetics. 2006 May;38(5):525-7.
[5] Di Rocco M, Baujat G, Bertamino M, Brown M, De Cunto CL, Delai PL, Eekhoff EM, Haga N, Hsiao E, Keen R, Morhart R. International physician survey on management of FOP: a modified Delphi study. Orphanet journal of rare diseases. 2017 Dec;12(1):1-5.
[6] Kaplan FS, Shore EM, Glaser DL, Emerson S. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. InClin Proc intl clin consort FOP 2011 May (Vol. 4, pp. 1-100).
[7] Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet journal of rare diseases. 2011 Dec;6(1):1-6.
[8] Rocke DM, Zasloff M, Peeper J, Cohen RB, Kaplan FS. Age-and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clinical Orthopaedics and Related Research. 1994 Apr 1(301):243-8.
[9] Schaffer AA, Kaplan FS, Tracy MR, O'Brien ML, Dormans JP, Shore EM, Harland RM, Kusumi K. Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome: clues from the BMP signaling pathway. Spine. 2005 Jun 15;30(12):1379-85.
[10] Deirmengian GK, Hebela NM, O’Connell M, Glaser DL, Shore EM, Kaplan FS. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. The Journal of bone and joint surgery. American volume. 2008 Feb 1;90(2):366.
[11] Pignolo RJ, Suda RK, Kaplan FS. The fibrodysplasia ossificans progressiva lesion. Clinical Reviews in Bone and Mineral Metabolism. 2005 Sep;3(3):195-200.
[12] Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva.
[13] Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai P, Fastnacht‐Urban E, Forman SJ, Gillessen‐Kaesbach G, Hoover‐Fong J. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Human mutation. 2009 Mar;30(3):379-90.
[14] Hüning I, Gillessen-Kaesbach G. Fibrodysplasia ossificans progressiva: clinical course, genetic mutations and genotype-phenotype correlation. Molecular syndromology. 2014;5(5):201-11.
[15] Haupt J, Xu M, Shore EM. Variable signaling activity by FOP ACVR1 mutations. Bone. 2018 Apr 1;109:232-40.
[16] Kaliya-Perumal AK, Carney TJ, Ingham PW. Fibrodysplasia ossificans progressiva: current concepts from bench to bedside. Disease Models & Mechanisms. 2020 Sep 1;13(9).
[17] Wolken DM, Idone V, Hatsell SJ, Paul BY, Economides AN. The obligatory role of activin A in the formation of heterotopic bone in fibrodysplasia ossificans progressiva. Bone. 2018 Apr 1;109:210-7.
[18] Gregson CL, Bergen DJ, Leo P, Sessions RB, Wheeler L, Hartley A, Youlten S, Croucher PI, McInerney‐Leo AM, Fraser W, Tang JC. A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD‐Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis. Journal of Bone and Mineral Research. 2020 Jan;35(1):92-105.
[19] Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Science translational medicine. 2015 Sep 2;7(303):303ra137-.
[20] Sanchez-Duffhues G, de Gorter DJ, Ten Dijke P. Towards a cure for fibrodysplasia ossificans progressiva. Annals of translational medicine. 2016 Oct;4(Suppl 1).
[21] Sheng N, Xie Z, Wang C, Bai G, Zhang K, Zhu Q, Song J, Guillemot F, Chen YG, Lin A, Jing N. Retinoic acid regulates bone morphogenic protein signal duration by promoting the degradation of phosphorylated Smad1. Proceedings of the National Academy of Sciences. 2010 Nov 2;107(44):18886-91.
[22] Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Machiya A, Jimi E, Kokabu S. Smad9 is a new type of transcriptional regulator in bone morphogenetic protein signaling. Scientific reports. 2014 Dec 23;4(1):1-1.
[23] Wang H, Shore EM, Pignolo RJ, Kaplan FS. Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone. 2018 Apr 1;109:218-24.
[24] Petrie KA, Lee WH, Bullock AN, Pointon JJ, Smith R, Russell RG, Brown MA, Wordsworth BP, Triffitt JT. Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients. PloS one. 2009 Mar 30;4(3):e5005.
[25] Macı́as-Silva M, Hoodless PA, Tang SJ, Buchwald M, Wrana JL. Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. Journal of Biological Chemistry. 1998 Oct 2;273(40):25628-36.
[26] Katagiri T, Tsukamoto S, Kuratani M. Heterotopic bone induction via BMP signaling: Potential therapeutic targets for fibrodysplasia ossificans progressiva. Bone. 2018 Apr 1;109:241-50.
[27] Furuya H, Ikezoe K, Wang L, Ohyagi Y, Motomura K, Fujii N, Kira JI, Fukumaki Y. A unique case of fibrodysplasia ossificans progressiva with an ACVR1 mutation, G356D, other than the common mutation (R206H). American Journal of Medical Genetics Part A. 2008 Feb 15;146(4):459-63.
[28] Liu H, Sawyer SL, Gos M, Grynspan D, Issa K, Ramphal R, Rotaru C, Consortium FC, Majewski J, Boycott KM, Graham G. Atypical fibrodysplasia ossificans progressiva diagnosed by whole‐exome sequencing. American Journal of Medical Genetics Part A. 2015 Jun;167(6):1337-41.
[29] Glaser D, Rocke D, Kaplan FS. Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clinical orthopaedics and related research. 1998;346.
[30] Kaplan FS, Shore EM, Connor JM. Fibrodysplasia ossificans progressiva. Connective tissue and its heritable disorders: molecular, genetic, and medical aspects. 2nd ed. New York: John Wiley and Sons. 2002 May 10;2002:827-40.
[31] Glaser DL, Kaplan FS. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clinical Reviews in Bone and Mineral Metabolism. 2005 Sep;3(3):243-50.
[32] Kaplan, Frederick & Mukaddam, M & Baujat, G & Cali, Amanda & Cho, Tae-Joon & Crowe, C & Cunto, C & Delai, Patricia & Diecidue, R & Di Rocco, Maja & Eekoff, EMW & Friedman, C & Grunwald, Z & Haga, N & Hsiao, E & Keen, R & Kitterman, Joseph & Levy, Charles & Morhart, Rolf & Pignolo, Robert. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. InClin Proc intl clin consort FOP 2019 June (Vol. 12, pp. 1-111).
[33] Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics. 2005 Nov 1;116(5):e654-61.
[34] Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacological reviews. 2004 Sep 1;56(3):387-437.
[35] Schuetz P, Mueller B, Christ-Crain M, Dick W, Haas H. Amino-bisphosphonates in heterotopic ossification: first experience in five consecutive cases. Spinal cord. 2005 Oct;43(10):604-10.
[36] Connor JM, Evans DA. Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. The Journal of bone and joint surgery. British volume. 1982 Feb;64(1):76-83.
[37] Delatycki M, Rogers JG. The Genetics of Fibrodysplasia Ossificans Progressiva. Clinical Orthopaedics and Related Research (1976-2007). 1998 Jan 1;346:15-8.
[38] Altschuler EL. Question: Bone marrow transplant for fibrodysplasia ossificans progressiva: has the hour arrived?. Clinical Orthopaedics and Related Research®. 2001 Nov 1;392:450-1.
[39] Kaplan FS, Glaser DL, Shore EM, Emerson SG. Bone marrow transplantation in a patient with fibrodysplasia ossificans progressiva. Clin Orthop. 2004, 422:278.
[40] Langenfeld EM, Langenfeld J. Bone Morphogenetic Protein-2 Stimulates Angiogenesis in Developing Tumors11NIH K22 grant CA91919-01A1 and UMDNJ Foundation to J. Langenfeld. Molecular Cancer Research. 2004 Mar 1;2(3):141-9.
[41] Kaplan FS, Tabas JA, Gannon FH, Finkel G, Hahn GV, Zasloff MA. The histopathology of fibrodysplasia ossificans progressiva. An endochondral process. The Journal of bone and joint surgery. American volume. 1993 Feb 1;75(2):220-30.
[42] Kaplan FS, Sawyer JR, Connors S, Keough K, Shore E, Gannon F, Glaser D, Rocke D, Zasloff MA, Folkman J. Urinary Basic Fibroblast Growth Factor: A Biochemical Marker for Preosseous Fibroproliferative Lesions in Patients Who Have Fibrodysplasia Ossificans Progressiva. Clinical orthopaedics and related research. 1998;346.
[43] Botman E, Netelenbos JC, Rustemeyer T, Schoonmade LJ, Nieuwenhuijzen JA, Teunissen BP, Visser M, Raijmakers P, Lammertsma AA, Dahele M, Eekhoff M. Radiotherapy in fibrodysplasia ossificans progressiva: A case report and systematic review of the literature. Frontiers in endocrinology. 2020 Feb 12;11:6.
[44] Chaikuad A, Alfano I, Kerr G, Sanvitale CE, Boergermann JH, Triffitt JT, von Delft F, Knapp S, Knaus P, Bullock AN. Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. Journal of Biological Chemistry. 2012 Oct 26;287(44):36990-8.
[45] Dey D, Bagarova J, Hatsell SJ, Armstrong KA, Huang L, Ermann J, Vonner AJ, Shen Y, Mohedas AH, Lee A, Eekhoff EM. Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification. Science translational medicine. 2016 Nov 23;8(366):366ra163-.
[46] Hamasaki M, Hashizume Y, Yamada Y, Katayama T, Hohjoh H, Fusaki N, Nakashima Y, Furuya H, Haga N, Takami Y, Era T. Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance: mechanisms of reprogramming and strategy for drug identification. Stem Cells. 2012 Nov;30(11):2437-49.
[47] Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert opinion on orphan drugs. 2017 Apr 3;5(4):291-4.
[48] Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, Whitehead B, Jacobs B, Siegel DM, Keen R, Hsiao E. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone. 2018 Apr 1;109:276-80.
Section
NB:Biology