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.
Authors	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 Iii, Benjamin M Wu, Karen Lyons, John S Adams, Kang Ting, Chia Soo
Journal	Nature communications (Nat Commun) Vol. 6 Pg. 7362 (Jun 17 2015) ISSN: 2041-1723 [Electronic] England
PMID	26082355 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Calcium-Binding Proteins Integrin beta Chains NELL1 protein, human Nerve Tissue Proteins Wnt Proteins beta Catenin
Topics	Adult Aged Aged, 80 and over Animals Bone and Bones (pathology) Calcium-Binding Proteins Cells, Cultured Drug Evaluation, Preclinical Female Haploinsufficiency Humans Integrin beta Chains (metabolism) Male Mice Middle Aged Nerve Tissue Proteins (administration & dosage, deficiency) Osteoporosis (drug therapy, etiology, metabolism, pathology) Phenotype Sheep Wnt Proteins (metabolism) Young Adult beta Catenin (metabolism)

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