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Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva.
Nat Commun. 2018 02 02; 9(1):471.NC

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1 tnR206H). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1 R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.

Authors+Show Affiliations

Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.Department of Biological and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, 48109, USA.Alexion Pharmaceuticals, 100 College St, New Haven, CT, 06510, USA.Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA. david.goldhamer@uconn.edu.

Pub Type(s)

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

Language

eng

PubMed ID

29396429

Citation

Lees-Shepard, John B., et al. "Activin-dependent Signaling in Fibro/adipogenic Progenitors Causes Fibrodysplasia Ossificans Progressiva." Nature Communications, vol. 9, no. 1, 2018, p. 471.
Lees-Shepard JB, Yamamoto M, Biswas AA, et al. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun. 2018;9(1):471.
Lees-Shepard, J. B., Yamamoto, M., Biswas, A. A., Stoessel, S. J., Nicholas, S. E., Cogswell, C. A., Devarakonda, P. M., Schneider, M. J., Cummins, S. M., Legendre, N. P., Yamamoto, S., Kaartinen, V., Hunter, J. W., & Goldhamer, D. J. (2018). Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nature Communications, 9(1), 471. https://doi.org/10.1038/s41467-018-02872-2
Lees-Shepard JB, et al. Activin-dependent Signaling in Fibro/adipogenic Progenitors Causes Fibrodysplasia Ossificans Progressiva. Nat Commun. 2018 02 2;9(1):471. PubMed PMID: 29396429.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. AU - Lees-Shepard,John B, AU - Yamamoto,Masakazu, AU - Biswas,Arpita A, AU - Stoessel,Sean J, AU - Nicholas,Sarah-Anne E, AU - Cogswell,Cathy A, AU - Devarakonda,Parvathi M, AU - Schneider,Michael J,Jr AU - Cummins,Samantha M, AU - Legendre,Nicholas P, AU - Yamamoto,Shoko, AU - Kaartinen,Vesa, AU - Hunter,Jeffrey W, AU - Goldhamer,David J, Y1 - 2018/02/02/ PY - 2017/06/06/received PY - 2018/01/04/accepted PY - 2018/2/4/entrez PY - 2018/2/6/pubmed PY - 2018/7/10/medline SP - 471 EP - 471 JF - Nature communications JO - Nat Commun VL - 9 IS - 1 N2 - Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1 tnR206H). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1 R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/29396429/Activin_dependent_signaling_in_fibro/adipogenic_progenitors_causes_fibrodysplasia_ossificans_progressiva_ L2 - http://dx.doi.org/10.1038/s41467-018-02872-2 DB - PRIME DP - Unbound Medicine ER -