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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Nic, 2018. "Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02872-2
    DOI: 10.1038/s41467-018-02872-2
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    Cited by:

    1. Yeon-Suk Yang & Jung-Min Kim & Jun Xie & Sachin Chaugule & Chujiao Lin & Hong Ma & Edward Hsiao & Jaehyoung Hong & Hyonho Chun & Eileen M. Shore & Frederick S. Kaplan & Guangping Gao & Jae-Hyuck Shim, 2022. "Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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