NELL-1 in the treatment of osteoporotic bone loss

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, Benjamin M. Wu, Karen Lyons, John S. Adams, Kang Ting () and Chia Soo ()
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Aaron W. James: UCLA and Orthopaedic Hospital, University of California
Jia Shen: UCLA and Orthopaedic Hospital, 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: 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
Chia Soo: UCLA and Orthopaedic Hospital, University of California

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8362

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