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Title: NELL-1 in the treatment of osteoporotic bone loss

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. Furthermore, 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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [3];  [1];  [1];  [1];  [1];  [1]
  1. Univ. of California, Los Angeles, CA (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  3. Colorado State Univ., Fort Collins, CO (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1333652
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

James, Aaron W., Shen, Jia, Zhang, Xinli, Asatrian, Greg, Goyal, Raghav, Kwak, Jin H., Jiang, Lin, Bengs, Benjamin, Culiat, Cymbeline T., Turner, A. Simon, Seim, III, Howard B., Wu, Benjamin M., Lyons, Karen, Adams, John S., Ting, Kang, and Soo, Chia. NELL-1 in the treatment of osteoporotic bone loss. United States: N. p., 2015. Web. doi:10.1038/ncomms8362.
James, Aaron W., Shen, Jia, Zhang, Xinli, Asatrian, Greg, Goyal, Raghav, Kwak, Jin H., Jiang, Lin, Bengs, Benjamin, Culiat, Cymbeline T., Turner, A. Simon, Seim, III, Howard B., Wu, Benjamin M., Lyons, Karen, Adams, John S., Ting, Kang, & Soo, Chia. NELL-1 in the treatment of osteoporotic bone loss. United States. doi:10.1038/ncomms8362.
James, Aaron W., Shen, Jia, Zhang, Xinli, Asatrian, Greg, Goyal, Raghav, Kwak, Jin H., Jiang, Lin, Bengs, Benjamin, Culiat, Cymbeline T., Turner, A. Simon, Seim, III, Howard B., Wu, Benjamin M., Lyons, Karen, Adams, John S., Ting, Kang, and Soo, Chia. Wed . "NELL-1 in the treatment of osteoporotic bone loss". United States. doi:10.1038/ncomms8362. https://www.osti.gov/servlets/purl/1333652.
@article{osti_1333652,
title = {NELL-1 in the treatment of osteoporotic bone loss},
author = {James, Aaron W. and Shen, Jia and Zhang, Xinli and Asatrian, Greg and Goyal, Raghav and Kwak, Jin H. and Jiang, Lin and Bengs, Benjamin and Culiat, Cymbeline T. and Turner, A. Simon and Seim, III, Howard B. and Wu, Benjamin M. and Lyons, Karen and Adams, John S. and Ting, Kang and Soo, Chia},
abstractNote = {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. Furthermore, 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.},
doi = {10.1038/ncomms8362},
journal = {Nature Communications},
number = ,
volume = 6,
place = {United States},
year = {Wed Jun 17 00:00:00 EDT 2015},
month = {Wed Jun 17 00:00:00 EDT 2015}
}

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Works referenced in this record:

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journal, July 2011

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The osteoinductive properties of Nell-1 in a rat spinal fusion model
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