Dysregulated BMP Signaling and Enhanced Osteogenic Differentiation of Connective Tissue Progenitor Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP)

Authors

  • Paul C Billings,

    1. The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    2. The Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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  • Jennifer L Fiori,

    1. The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    2. The Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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  • Jennifer L Bentwood,

    1. The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    2. The Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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  • Michael P O'Connell,

    1. The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    2. The Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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  • Xiangyang Jiao,

    1. The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    2. The Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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  • Burton Nussbaum,

    1. The Department of Preventive and Restorative Sciences, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA
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  • Robert J Caron,

    1. The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    2. The Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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  • Eileen M Shore,

    1. The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    2. The Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    3. The Department of Genetics, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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    • These authors contributed equally to this work

  • Frederick S Kaplan MD

    Corresponding author
    1. The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    2. The Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    3. The Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    • The University of Pennsylvania School of Medicine, Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Silverstein 2, 3400 Spruce Street, Philadelphia, PA 19104, USA
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    • These authors contributed equally to this work


  • The authors state that they have no conflicts of interest.

Abstract

The study of FOP, a disabling genetic disorder of progressive heterotopic ossification, is hampered by the lack of readily available connective tissue progenitor cells. We isolated such cells from discarded primary teeth of patients with FOP and controls and discovered dysregulation of BMP signaling and rapid osteoblast differentiation in FOP cells compared with control cells.

Introduction: Fibrodysplasia ossificans progressiva (FOP), the most disabling condition of progressive heterotopic ossification in humans, is caused by a recurrent heterozygous missense mutation in activin receptor IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor, in all classically affected individuals. A comprehensive understanding of FOP has been limited, in part, by a lack of readily available connective tissue progenitor cells in which to study the molecular pathology of this disorder.

Materials and Methods: We derived connective tissue progenitor cells from discarded primary teeth (SHED cells) of patients with FOP and controls and examined BMP signaling and osteogenic differentiation in these cells.

Results: SHED cells transmitted BMP signals through both the SMAD and p38 mitogen-activated protein kinase (MAPK) pathways and responded to BMP4 treatment by inducing BMP responsive genes. FOP cells showed ligand-independent BMP signaling and ligand-dependent hyper-responsiveness to BMP stimulation. Furthermore, FOP cells showed more rapid differentiation to an osteogenic phenotype than control cells.

Conclusions: This is the first study of BMP signaling and osteogenic differentiation in connective tissue progenitor cells from patients with FOP. Our data strongly support both basal and ligand-stimulated dysregulation of BMP signaling consistent with in silico studies of the mutant ACVR1 receptor in this condition. This study substantially extends our understanding of dysregulated BMP signaling in a progenitor cell population relevant to the pathogenesis of this catastrophic disorder of progressive ectopic ossification.

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