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James et al. NELL-1 warrants further study as a treatment for osteoporosis

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DOI:10.1038/ibmsbonekey.2015.135

In this study, aged mice unable to produce normal amounts of NELL-1, a secreted protein that regulates ossification and is particularly important in human craniofacial development, were shown to have significant signs of osteoporosis (bone fragility, reduced Wnt/β-catenin signaling and a lower osteoblast to osteoclast ratio). The mice were used to further study the mechanism of action of NELL-1, which, in mice and humans causes craniosynostosis when over-expressed and skeletal undermineralisation when under-expressed.

NELL-1 was shown to be a positive regulator of the Wnt/β-catenin signaling pathway, via integrin β1. Its effects on this signaling pathway in osteoclast precursors had a negative impact on bone resorption while its impact on the same pathway in osteoblast precursors served to increase bone formation. Most interestingly from a clinical viewpoint was the finding that ovariectomized mice with osteoporosis showed an improvement in bone mineral density after systemic treatment with NELL-1. Similar benefits were demonstrated in sheep with spinal osteoporosis.

Editor’s comment: NELL1, a gene that encodes this member of the TGF-β pathway, has been shown to repress adipogenic differentiation. These findings suggest that NELL-1 might have a role in osteoporosis and probably have also have potential as a therapy for both bone loss and adiposity.

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