Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva

John B. Lees-Shepard, Masakazu Yamamoto, Arpita A. Biswas, Sean J. Stoessel, Sarah-Anne E. Nicholas, Cathy A. Cogswell, Parvathi M. Devarakonda, Michael J. Schneider, Samantha M. Cummins, Nicholas P. Legendre, Shoko Yamamoto, Vesa Kaartinen, Jeffrey W. Hunter and David J. Goldhamer ()
Additional contact information
John B. Lees-Shepard: University of Connecticut Stem Cell Institute, University of Connecticut
Masakazu Yamamoto: University of Connecticut Stem Cell Institute, University of Connecticut
Arpita A. Biswas: University of Connecticut Stem Cell Institute, University of Connecticut
Sean J. Stoessel: University of Connecticut Stem Cell Institute, University of Connecticut
Sarah-Anne E. Nicholas: University of Connecticut Stem Cell Institute, University of Connecticut
Cathy A. Cogswell: University of Connecticut Stem Cell Institute, University of Connecticut
Parvathi M. Devarakonda: University of Connecticut Stem Cell Institute, University of Connecticut
Michael J. Schneider: University of Connecticut Stem Cell Institute, University of Connecticut
Samantha M. Cummins: University of Connecticut Stem Cell Institute, University of Connecticut
Nicholas P. Legendre: University of Connecticut Stem Cell Institute, University of Connecticut
Shoko Yamamoto: University of Connecticut Stem Cell Institute, University of Connecticut
Vesa Kaartinen: University of Michigan
Jeffrey W. Hunter: Alexion Pharmaceuticals
David J. Goldhamer: University of Connecticut Stem Cell Institute, University of Connecticut

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-02872-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02872-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-02872-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().