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NELL-1 in the treatment of osteoporotic bone loss

Author

Listed:
  • Aaron W. James

    (UCLA and Orthopaedic Hospital, University of California
    Section of Orthodontics, School of Dentistry, University of California
    David Geffen School of Medicine, University of California)

  • Jia Shen

    (UCLA and Orthopaedic Hospital, University of California
    Section of Orthodontics, School of Dentistry, University of California)

  • Xinli Zhang

    (Section of Orthodontics, School of Dentistry, University of California)

  • Greg Asatrian

    (Section of Orthodontics, School of Dentistry, University of California)

  • Raghav Goyal

    (Section of Orthodontics, School of Dentistry, University of California)

  • Jin H. Kwak

    (Section of Orthodontics, School of Dentistry, University of California)

  • Lin Jiang

    (Easton Center for Alzheimer’s Disease Research, Molecular Biology Institute, University of California)

  • Benjamin Bengs

    (UCLA and Orthopaedic Hospital, University of California)

  • Cymbeline T. Culiat

    (Oak Ridge National Laboratory (ORNL))

  • A. Simon Turner

    (Colorado State University)

  • Howard B. Seim III

    (Colorado State University)

  • Benjamin M. Wu

    (University of California)

  • Karen Lyons

    (UCLA and Orthopaedic Hospital, University of California)

  • John S. Adams

    (UCLA and Orthopaedic Hospital, University of California)

  • Kang Ting

    (UCLA and Orthopaedic Hospital, University of California
    Section of Orthodontics, School of Dentistry, University of California)

  • Chia Soo

    (UCLA and Orthopaedic Hospital, University of California
    David Geffen School of Medicine, University of California, Los Angeles)

Abstract

NELL-1 is a secreted, osteoinductive protein whose expression rheostatically controls skeletal ossification. Overexpression of NELL-1 results in craniosynostosis in humans and mice, whereas lack of Nell-1 expression is associated with skeletal undermineralization. Here we show that Nell-1-haploinsufficient mice have normal skeletal development but undergo age-related osteoporosis, characterized by a reduction in osteoblast:osteoclast (OB:OC) ratio and increased bone fragility. Recombinant NELL-1 binds to integrin β1 and consequently induces Wnt/β-catenin signalling, associated with increased OB differentiation and inhibition of OC-directed bone resorption. Systemic delivery of NELL-1 to mice with gonadectomy-induced osteoporosis results in improved bone mineral density. When extended to a large animal model, local delivery of NELL-1 to osteoporotic sheep spine leads to significant increase in bone formation. Altogether, these findings suggest that NELL-1 deficiency plays a role in osteoporosis and demonstrate the potential utility of NELL-1 as a combination anabolic/antiosteoclastic therapeutic for bone loss.

Suggested Citation

  • Aaron W. James & Jia Shen & Xinli Zhang & Greg Asatrian & Raghav Goyal & Jin H. Kwak & Lin Jiang & Benjamin Bengs & Cymbeline T. Culiat & A. Simon Turner & Howard B. Seim III & Benjamin M. Wu & Karen , 2015. "NELL-1 in the treatment of osteoporotic bone loss," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8362
    DOI: 10.1038/ncomms8362
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