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Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva.
Lees-Shepard, John B; Yamamoto, Masakazu; Biswas, Arpita A; Stoessel, Sean J; Nicholas, Sarah-Anne E; Cogswell, Cathy A; Devarakonda, Parvathi M; Schneider, Michael J; Cummins, Samantha M; Legendre, Nicholas P; Yamamoto, Shoko; Kaartinen, Vesa; Hunter, Jeffrey W; Goldhamer, David J.
Afiliação
  • Lees-Shepard JB; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Yamamoto M; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Biswas AA; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Stoessel SJ; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Nicholas SE; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Cogswell CA; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Devarakonda PM; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Schneider MJ; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Cummins SM; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Legendre NP; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Yamamoto S; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
  • Kaartinen V; Department of Biological and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Hunter JW; Alexion Pharmaceuticals, 100 College St, New Haven, CT, 06510, USA.
  • Goldhamer DJ; Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA. david.goldhamer@uconn.edu.
Nat Commun ; 9(1): 471, 2018 02 02.
Article em En | MEDLINE | ID: mdl-29396429
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco / Ativinas / Receptores de Ativinas Tipo I / Modelos Animais de Doenças / Miosite Ossificante Tipo de estudo: Etiology_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco / Ativinas / Receptores de Ativinas Tipo I / Modelos Animais de Doenças / Miosite Ossificante Tipo de estudo: Etiology_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article