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The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent.
J Bone Miner Res. 2017 Dec; 32(12):2489-2499.JB

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by episodic yet cumulative heterotopic ossification (HO) in skeletal muscles, tendons, and ligaments over a patient's lifetime. FOP is caused by missense mutations in the type I bone morphogenetic protein (BMP) receptor ACVR1. We have determined that the formation of heterotopic bone in FOP requires activation of mutant ACVR1 by Activin A, in part by showing that prophylactic inhibition of Activin A blocks HO in a mouse model of FOP. Here we piece together a natural history of developing HO lesions in mouse FOP, and determine where in the continuum of HO Activin A is required, using imaging (T2-MRI, μCT, 18 F-NaF PET/CT, histology) coupled with pharmacologic inhibition of Activin A at different times during the progression of HO. First, we show that expansion of HO lesions comes about through growth and fusion of independent HO events. These events tend to arise within a neighborhood of existing lesions, indicating that already formed HO likely triggers the formation of new events. The process of heterotopic bone expansion appears to be dependent on Activin A because inhibition of this ligand suppresses the growth of nascent HO lesions and stops the emergence of new HO events. Therefore, our results reveal that Activin A is required at least up to the point when nascent HO lesions mineralize and further demonstrate the therapeutic utility of Activin A inhibition in FOP. These results provide evidence for a model where HO is triggered by inflammation but becomes "self-propagating" by a process that requires Activin A. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Authors+Show Affiliations

Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.InviCRO, LLC, Boston, MA, USA.InviCRO, LLC, Boston, MA, USA.InviCRO, LLC, Boston, MA, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.InviCRO, LLC, Boston, MA, USA.InviCRO, LLC, Boston, MA, USA.InviCRO, LLC, Boston, MA, USA.College of Holy Cross, Worcester, MA, USA.InviCRO, LLC, Boston, MA, USA.InviCRO, LLC, Boston, MA, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA. Regeneron Genetics Center, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28782882

Citation

Upadhyay, Jaymin, et al. "The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 32, no. 12, 2017, pp. 2489-2499.
Upadhyay J, Xie L, Huang L, et al. The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent. J Bone Miner Res. 2017;32(12):2489-2499.
Upadhyay, J., Xie, L., Huang, L., Das, N., Stewart, R. C., Lyon, M. C., Palmer, K., Rajamani, S., Graul, C., Lobo, M., Wellman, T. J., Soares, E. J., Silva, M. D., Hesterman, J., Wang, L., Wen, X., Qian, X., Nannuru, K., Idone, V., ... Hatsell, S. J. (2017). The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 32(12), 2489-2499. https://doi.org/10.1002/jbmr.3235
Upadhyay J, et al. The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent. J Bone Miner Res. 2017;32(12):2489-2499. PubMed PMID: 28782882.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent. AU - Upadhyay,Jaymin, AU - Xie,LiQin, AU - Huang,Lily, AU - Das,Nanditha, AU - Stewart,Rachel C, AU - Lyon,Morgan C, AU - Palmer,Keryn, AU - Rajamani,Saathyaki, AU - Graul,Chris, AU - Lobo,Merryl, AU - Wellman,Tyler J, AU - Soares,Edward J, AU - Silva,Matthew D, AU - Hesterman,Jacob, AU - Wang,Lili, AU - Wen,Xialing, AU - Qian,Xiaobing, AU - Nannuru,Kalyan, AU - Idone,Vincent, AU - Murphy,Andrew J, AU - Economides,Aris N, AU - Hatsell,Sarah J, Y1 - 2017/09/22/ PY - 2017/05/05/received PY - 2017/07/23/revised PY - 2017/08/03/accepted PY - 2017/8/8/pubmed PY - 2018/7/24/medline PY - 2017/8/8/entrez KW - ACTIVIN A KW - ANTI-ACTIVIN A ANTIBODY KW - FIBRODYSPLASIA KW - HETEROTOPIC OSSIFICATION SP - 2489 EP - 2499 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 32 IS - 12 N2 - Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by episodic yet cumulative heterotopic ossification (HO) in skeletal muscles, tendons, and ligaments over a patient's lifetime. FOP is caused by missense mutations in the type I bone morphogenetic protein (BMP) receptor ACVR1. We have determined that the formation of heterotopic bone in FOP requires activation of mutant ACVR1 by Activin A, in part by showing that prophylactic inhibition of Activin A blocks HO in a mouse model of FOP. Here we piece together a natural history of developing HO lesions in mouse FOP, and determine where in the continuum of HO Activin A is required, using imaging (T2-MRI, μCT, 18 F-NaF PET/CT, histology) coupled with pharmacologic inhibition of Activin A at different times during the progression of HO. First, we show that expansion of HO lesions comes about through growth and fusion of independent HO events. These events tend to arise within a neighborhood of existing lesions, indicating that already formed HO likely triggers the formation of new events. The process of heterotopic bone expansion appears to be dependent on Activin A because inhibition of this ligand suppresses the growth of nascent HO lesions and stops the emergence of new HO events. Therefore, our results reveal that Activin A is required at least up to the point when nascent HO lesions mineralize and further demonstrate the therapeutic utility of Activin A inhibition in FOP. These results provide evidence for a model where HO is triggered by inflammation but becomes "self-propagating" by a process that requires Activin A. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/28782882/The_Expansion_of_Heterotopic_Bone_in_Fibrodysplasia_Ossificans_Progressiva_Is_Activin_A_Dependent_ L2 - https://doi.org/10.1002/jbmr.3235 DB - PRIME DP - Unbound Medicine ER -