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Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva.
J Bone Miner Res. 2018 02; 33(2):269-282.JB

Abstract

Heterotopic ossification (HO) is a clinical condition that often reduces mobility and diminishes quality of life for affected individuals. The most severe form of progressive HO occurs in those with fibrodysplasia ossificans progressiva (FOP; OMIM #135100), a genetic disorder caused by a recurrent heterozygous gain-of-function mutation (R206H) in the bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2. In individuals with FOP, episodes of HO frequently follow injury. The first sign of active disease is commonly an inflammatory "flare-up" that precedes connective tissue degradation, progenitor cell recruitment, and endochondral HO. We used a conditional-on global knock-in mouse model expressing Acvr1R206H (referred to as Acvr1cR206H/+) to investigate the cellular and molecular inflammatory response in FOP lesions following injury. We found that the Acvr1 R206H mutation caused increased BMP signaling in posttraumatic FOP lesions and early divergence from the normal skeletal muscle repair program with elevated and prolonged immune cell infiltration. The proinflammatory cytokine response of TNFα, IL-1β, and IL-6 was elevated and prolonged in Acvr1cR206H/+ lesions and in Acvr1cR206H/+ mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury-induced HO in Acvr1cR206H/+ mice, reducing injury-induced HO volume by ∼50% with depletion of each cell population independently, and ∼75% with combined depletion of both cell populations. Together, our data show that the immune system contributes to the initiation and development of HO in FOP. Further, the expression of Acvr1R206H in immune cells alters cytokine expression and cellular response to injury and unveils novel therapeutic targets for treatment of FOP and nongenetic forms of HO. © 2017 American Society for Bone and Mineral Research.

Authors+Show Affiliations

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28986986

Citation

Convente, Michael R., et al. "Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 33, no. 2, 2018, pp. 269-282.
Convente MR, Chakkalakal SA, Yang E, et al. Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva. J Bone Miner Res. 2018;33(2):269-282.
Convente, M. R., Chakkalakal, S. A., Yang, E., Caron, R. J., Zhang, D., Kambayashi, T., Kaplan, F. S., & Shore, E. M. (2018). Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 33(2), 269-282. https://doi.org/10.1002/jbmr.3304
Convente MR, et al. Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva. J Bone Miner Res. 2018;33(2):269-282. PubMed PMID: 28986986.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva. AU - Convente,Michael R, AU - Chakkalakal,Salin A, AU - Yang,EnJun, AU - Caron,Robert J, AU - Zhang,Deyu, AU - Kambayashi,Taku, AU - Kaplan,Frederick S, AU - Shore,Eileen M, Y1 - 2018/01/03/ PY - 2017/02/22/received PY - 2017/09/27/revised PY - 2017/10/05/accepted PY - 2017/10/8/pubmed PY - 2019/9/29/medline PY - 2017/10/8/entrez KW - ACVR1 KW - BMP KW - BONE MORPHOGENETIC PROTEIN SIGNALING KW - CHRONIC INFLAMMATION KW - FIBRODYSPLASIA OSSIFICANS PROGRESSIVA KW - FOP KW - HETEROTOPIC OSSIFICATION KW - TISSUE INJURY SP - 269 EP - 282 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 - 33 IS - 2 N2 - Heterotopic ossification (HO) is a clinical condition that often reduces mobility and diminishes quality of life for affected individuals. The most severe form of progressive HO occurs in those with fibrodysplasia ossificans progressiva (FOP; OMIM #135100), a genetic disorder caused by a recurrent heterozygous gain-of-function mutation (R206H) in the bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2. In individuals with FOP, episodes of HO frequently follow injury. The first sign of active disease is commonly an inflammatory "flare-up" that precedes connective tissue degradation, progenitor cell recruitment, and endochondral HO. We used a conditional-on global knock-in mouse model expressing Acvr1R206H (referred to as Acvr1cR206H/+) to investigate the cellular and molecular inflammatory response in FOP lesions following injury. We found that the Acvr1 R206H mutation caused increased BMP signaling in posttraumatic FOP lesions and early divergence from the normal skeletal muscle repair program with elevated and prolonged immune cell infiltration. The proinflammatory cytokine response of TNFα, IL-1β, and IL-6 was elevated and prolonged in Acvr1cR206H/+ lesions and in Acvr1cR206H/+ mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury-induced HO in Acvr1cR206H/+ mice, reducing injury-induced HO volume by ∼50% with depletion of each cell population independently, and ∼75% with combined depletion of both cell populations. Together, our data show that the immune system contributes to the initiation and development of HO in FOP. Further, the expression of Acvr1R206H in immune cells alters cytokine expression and cellular response to injury and unveils novel therapeutic targets for treatment of FOP and nongenetic forms of HO. © 2017 American Society for Bone and Mineral Research. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/28986986/Depletion_of_Mast_Cells_and_Macrophages_Impairs_Heterotopic_Ossification_in_an_Acvr1R206H_Mouse_Model_of_Fibrodysplasia_Ossificans_Progressiva_ L2 - https://doi.org/10.1002/jbmr.3304 DB - PRIME DP - Unbound Medicine ER -