Alk2 Regulates Early Chondrogenic Fate in Fibrodysplasia Ossificans Progressiva Heterotopic Endochondral Ossification

Authors

  • Andria L. Culbert,

    1. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Salin A. Chakkalakal,

    1. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Edwin G. Theosmy,

    1. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Tracy A. Brennan,

    1. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Frederick S. Kaplan,

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

    Corresponding author
    1. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    2. Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    3. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    • Correspondence: Eileen M. Shore, Ph.D., University of Pennsylvania, Department of Orthopaedic Surgery, 424 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, Pennsylvania 19104-6081, USA. Telephone: 215-898-2331; Fax: 215-573-2133; e-mail: shore@mail.med.upenn.edu

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Abstract

Bone morphogenetic protein (BMP) signaling is a critical regulator of cartilage differentiation and endochondral ossification. Gain-of-function mutations in ALK2, a type I BMP receptor, cause the debilitating disorder fibrodysplasia ossificans progressiva (FOP) and result in progressive heterotopic (extraskeletal) endochondral ossification within soft connective tissues. Here, we used murine mesenchymal progenitor cells to investigate the contribution of Alk2 during chondrogenic differentiation and heterotopic endochondral ossification (HEO). Alk2R206H/+ (gain-of-function), Alk2CKO (loss-of-function), and wild-type mouse embryonic fibroblasts were evaluated for chondrogenic potential. Chondrogenic differentiation was accelerated in Alk2R206H/+ cells, due in part to enhanced sensitivity to BMP ligand. In vivo, Alk2R206H/+ cells initiated robust HEO and recruited wild-type cell contribution. Despite expression of other type I BMP receptors (Alk3 and Alk6), chondrogenesis of Alk2CKO cells was severely impaired by absence of Alk2 during early differentiation. Alk2 is therefore a direct regulator of cartilage formation and mediates chondrogenic commitment of progenitor cells. These data establish that at least one effect of ALK2 gain-of-function mutations in FOP patients is enhanced chondrogenic differentiation which supports formation of heterotopic endochondral bone. This establishes ALK2 as a plausible therapeutic target during early chondrogenic stages of lesion formation for preventing heterotopic bone formation in FOP and other conditions. Stem Cells 2014;32:1289–1300

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