Journal Article

NELL-1 in the treatment of osteoporotic bone loss

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

2015

Overview

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. The growth factor NELL-1 induces bone formation during development, but its role in osteoporosis is unknown. This study shows that NELL-1 binding to integrin ß1 induces Wnt/ß-catenin signalling in the bone and restores bone mineral density in osteoporotic mice and sheep, suggesting the therapeutic potential of NELL-1 for the treatment of bone loss.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 692/308 / 692/698/690/797 / 692/699/2743/316/801 / 692/700/565/1331 / Adult / Age / Aged / Aged, 80 and over / Animal models / Animals / BASIC BIOLOGICAL SCIENCES / beta Catenin - metabolism / Biomedical materials / Bone and Bones - pathology / Bone density / Bone growth / Bone loss / Bone mineral density / Bone resorption / Calcium-Binding Proteins / Cells, Cultured / Cranial sutures / Craniosynostosis / Drug Evaluation, Preclinical / Female / Fragility / Gonadectomy / Growth factors / Haploinsufficiency / Humanities and Social Sciences / Humans / Integrin beta Chains - metabolism / Male / Mice / Middle Aged / multidisciplinary / Nerve Tissue Proteins - administration & dosage / Nerve Tissue Proteins - deficiency / Ossification / Osteogenesis / Osteoporosis / Osteoporosis - drug therapy / Osteoporosis - etiology / Osteoporosis - metabolism / Osteoporosis - pathology / Phenotype / Science / Sheep / Signaling / Spine / Wnt protein / Wnt Proteins - metabolism / Young Adult / β-Catenin