NELL-1 in the treatment of osteoporotic bone loss

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

doi:10.1038/ncomms8362

NELL-1 in the treatment of osteoporotic bone loss

Journal Article · Wed Jun 17 00:00:00 EDT 2015 · Nature Communications

DOI:https://doi.org/10.1038/ncomms8362· OSTI ID:1333652

James, Aaron W. ^[1]; Shen, Jia ^[1]; Zhang, Xinli ^[1]; Asatrian, Greg ^[1]; Goyal, Raghav ^[1]; Kwak, Jin H. ^[1]; Jiang, Lin ^[1]; Bengs, Benjamin ^[1]; Culiat, Cymbeline T. ^[2]; Turner, A. Simon ^[3]; Seim, III, Howard B. ^[3]; Wu, Benjamin M. ^[1]; Lyons, Karen ^[1]; Adams, John S. ^[1]; Ting, Kang ^[1]; Soo, Chia ^[1]

Univ. of California, Los Angeles, CA (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Colorado State Univ., Fort Collins, CO (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1333652

Journal Information:: Nature Communications, Journal Name: Nature Communications Vol. 6; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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