NELL-1 in the treatment of osteoporotic bone loss

Nat Commun. 2015 Jun 17;6:7362. doi: 10.1038/ncomms8362.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*
  • Nerve Tissue Proteins / deficiency*
  • Osteoporosis / drug therapy*
  • Osteoporosis / etiology
  • Osteoporosis / metabolism
  • Osteoporosis / pathology
  • Phenotype
  • Sheep
  • Wnt Proteins / metabolism
  • Young Adult
  • beta Catenin / metabolism

Substances

  • Calcium-Binding Proteins
  • Integrin beta Chains
  • NELL1 protein, human
  • Nerve Tissue Proteins
  • Wnt Proteins
  • beta Catenin