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Nat Commun ; 6: 7362, 2015 Jun 17.
Article in English | MEDLINE | ID: mdl-26082355

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 ß1 and consequently induces Wnt/ß-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.


Subject(s)
Bone and Bones/pathology , Nerve Tissue Proteins/administration & dosage , Nerve Tissue Proteins/deficiency , Osteoporosis/drug therapy , Adult , Aged , Aged, 80 and over , Animals , Calcium-Binding Proteins , Cells, Cultured , Drug Evaluation, Preclinical , Female , Haploinsufficiency , Humans , Integrin beta Chains/metabolism , Male , Mice , Middle Aged , Osteoporosis/etiology , Osteoporosis/metabolism , Osteoporosis/pathology , Phenotype , Sheep , Wnt Proteins/metabolism , Young Adult , beta Catenin/metabolism
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