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

doi:10.1038/ncomms8362

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 journal › Article › peer-review

67 Scopus citations

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 language	English (US)
Article number	7362
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8362
State	Published - Jun 17 2015
Externally published	Yes

ASJC Scopus subject areas

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

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@article{262f4c09e7e344a49de8591fe68bcfba,

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. 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.",

author = "James, {Aaron W.} and Jia Shen and Xinli Zhang and Greg Asatrian and Raghav Goyal and Kwak, {Jin H.} and Lin Jiang and Benjamin Bengs and Culiat, {Cymbeline T.} and Turner, {A. Simon} and Seim, {Howard B.} and Wu, {Benjamin M.} and Karen Lyons and Adams, {John S.} and Kang Ting and Chia Soo",

note = "Funding Information: We thank the following individuals and offices for their expertise: TPCL and Surgical Pathology divisions of the UCLA Department of Pathology and Laboratory Medicine, the UCLA Statistical Consulting Center, the Crump Institute for Molecular Imaging, the BioDent testing facility, Drs Ender, Lassman, Nelson, Said, Pang, Lusis, Davis, Stout, Pereira, Prikhodko and Tetradis. We thank the following individuals for their excellent technical assistance: Drs Chiang, Chung, Kim, Hu, Park, Scott, Valesco, Zara and Zhang, and Mr/Ms Askarinam, Chang, Chawan, Covarrubias, Ghiam, Hakim, James, Khadarian, Kim, Le, A. Nguyen, V. Nguyen, Pan, Schnitzer and Siu. This work was supported by the CIRM Early Translational II Research Award TR2-01821, NIH/NIDCR (grants R01 AR066782-01 and R01 AR061399-01A1), and T32 training fellowship to A.W.J. (5T32DE007296-14). Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = jun,

day = "17",

doi = "10.1038/ncomms8362",

language = "English (US)",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - NELL-1 in the treatment of osteoporotic bone loss

AU - James, Aaron W.

AU - Shen, Jia

AU - Zhang, Xinli

AU - Asatrian, Greg

AU - Goyal, Raghav

AU - Kwak, Jin H.

AU - Jiang, Lin

AU - Bengs, Benjamin

AU - Culiat, Cymbeline T.

AU - Turner, A. Simon

AU - Seim, Howard B.

AU - Wu, Benjamin M.

AU - Lyons, Karen

AU - Adams, John S.

AU - Ting, Kang

AU - Soo, Chia

N1 - Funding Information: We thank the following individuals and offices for their expertise: TPCL and Surgical Pathology divisions of the UCLA Department of Pathology and Laboratory Medicine, the UCLA Statistical Consulting Center, the Crump Institute for Molecular Imaging, the BioDent testing facility, Drs Ender, Lassman, Nelson, Said, Pang, Lusis, Davis, Stout, Pereira, Prikhodko and Tetradis. We thank the following individuals for their excellent technical assistance: Drs Chiang, Chung, Kim, Hu, Park, Scott, Valesco, Zara and Zhang, and Mr/Ms Askarinam, Chang, Chawan, Covarrubias, Ghiam, Hakim, James, Khadarian, Kim, Le, A. Nguyen, V. Nguyen, Pan, Schnitzer and Siu. This work was supported by the CIRM Early Translational II Research Award TR2-01821, NIH/NIDCR (grants R01 AR066782-01 and R01 AR061399-01A1), and T32 training fellowship to A.W.J. (5T32DE007296-14). Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/6/17

Y1 - 2015/6/17

N2 - 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.

AB - 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.

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DO - 10.1038/ncomms8362

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SN - 2041-1723

VL - 6

JO - Nature communications

JF - Nature communications

M1 - 7362

ER -

NELL-1 in the treatment of osteoporotic bone loss

Abstract

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