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, Chia Soo

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number7362
JournalNature communications
Volume6
DOIs
StatePublished - Jun 17 2015

    Fingerprint

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

James, A. W., Shen, J., Zhang, X., Asatrian, G., Goyal, R., Kwak, J. H., Jiang, L., Bengs, B., Culiat, C. T., Turner, A. S., Seim, H. B., Wu, B. M., Lyons, K., Adams, J. S., Ting, K., & Soo, C. (2015). NELL-1 in the treatment of osteoporotic bone loss. Nature communications, 6, [7362]. https://doi.org/10.1038/ncomms8362