Journal of Cellular Biochemistry

Substance P signaling mediates BMP-dependent heterotopic ossification

Authors

  • Lixin Kan,

    Corresponding author
    1. Department of Neurology, Northwestern University Feinberg Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611
    • Department of Neurology, Northwestern University's Feinberg School of Medicine, Ward Building 10-233, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA.
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  • Vitali Y Lounev,

    1. Department of Orthopaedic Surgery, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    2. The Center for Research in FOP and Related Disorders, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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  • Robert J. Pignolo,

    1. Department of Orthopaedic Surgery, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    2. The Center for Research in FOP and Related Disorders, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    3. Department of Medicine, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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  • Lishu Duan,

    1. Department of Neurology, Northwestern University Feinberg Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611
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  • Yijie Liu,

    1. Department of Neurology, Northwestern University Feinberg Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611
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  • Stuart R. Stock,

    1. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611
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  • Tammy L. McGuire,

    1. Department of Neurology, Northwestern University Feinberg Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611
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  • Bao Lu,

    1. Children's Hospital, 300 Longwood Avenue, Enders-14, Boston, Massachusetts 02215
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  • Norma P. Gerard,

    1. Children's Hospital, 300 Longwood Avenue, Enders-14, Boston, Massachusetts 02215
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  • Eileen M. Shore,

    1. Department of Orthopaedic Surgery, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    2. The Center for Research in FOP and Related Disorders, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    3. Department of Genetics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania19104
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  • Frederick S. Kaplan,

    1. Department of Orthopaedic Surgery, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    2. The Center for Research in FOP and Related Disorders, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    3. Department of Medicine, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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  • John A. Kessler

    1. Department of Neurology, Northwestern University Feinberg Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611
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Abstract

Heterotopic ossification (HO) is a disabling condition associated with neurologic injury, inflammation, and overactive bone morphogenetic protein (BMP) signaling. The inductive factors involved in lesion formation are unknown. We found that the expression of the neuro-inflammatory factor Substance P (SP) is dramatically increased in early lesional tissue in patients who have either fibrodysplasia ossificans progressiva (FOP) or acquired HO, and in three independent mouse models of HO. In Nse-BMP4, a mouse model of HO, robust HO forms in response to tissue injury; however, null mutations of the preprotachykinin (PPT) gene encoding SP prevent HO. Importantly, ablation of SP+ sensory neurons, treatment with an antagonist of SP receptor NK1r, deletion of NK1r gene, or genetic down-regulation of NK1r-expressing mast cells also profoundly inhibit injury-induced HO. These observations establish a potent neuro-inflammatory induction and amplification circuit for BMP-dependent HO lesion formation, and identify novel molecular targets for prevention of HO. J. Cell. Biochem. 112: 2759–2772, 2011. © 2011 Wiley-Liss, Inc.

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