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.
authors.affiliation: Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California, Los Angeles, California 90095, USA.|Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, California 90095, USA.|Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: James
authors.affiliation: Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California, Los Angeles, California 90095, USA.|Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, California 90095, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.affiliation: Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, California 90095, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, California 90095, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Asatrian
authors.affiliation: Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, California 90095, USA.
authors.forename: Raghav
authors.initials: R
authors.lastname: Goyal
authors.affiliation: Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, California 90095, USA.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Kwak
authors.affiliation: Department of Neurology, Easton Center for Alzheimer's Disease Research, Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California, Los Angeles, California 90095, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bengs
authors.affiliation: Oak Ridge National Laboratory (ORNL), Oak Ridge, Tennessee 37830, USA.
authors.forename: Cymbeline T
authors.initials: CT
authors.lastname: Culiat
authors.affiliation: Department of Veterinary Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: A Simon
authors.initials: AS
authors.lastname: Turner
authors.affiliation: Department of Veterinary Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: Howard B
authors.initials: HB
authors.lastname: Seim Iii
authors.affiliation: Department of Bioengineering and Department of Material Sciences, University of California, Los Angeles, California 90095, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Wu
authors.affiliation: Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California, Los Angeles, California 90095, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Lyons
authors.affiliation: Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California, Los Angeles, California 90095, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Adams
authors.affiliation: Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California, Los Angeles, California 90095, USA.|Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, California 90095, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.affiliation: Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California, Los Angeles, California 90095, USA.|Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001842:Bone and Bones / Q000473:pathology*; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000172:deficiency*; D010024:Osteoporosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012756:Sheep; D051153:Wnt Proteins / Q000378:metabolism; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D039641:Integrin beta Chains; C104144:NELL1 protein, human; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; D051176:beta Catenin