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NELL-1 in the treatment of osteoporotic bone loss.

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

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