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Sema3A regulates bone-mass accrual by controlling sensory nerve development



DOI:10.1038/bonekey.2013.162

Fukuda et al. demonstrate that bone expresses abundant quantities of semaphorin 3A (Sema3A), a well-characterized chemorepellent that stimulates outgrowth of axons and cell migration during development. Furthermore, the protein has a direct impact on osteoblast differentiation in mice.

The authors went on to investigate the function of the protein in bone by looking at knockout mice. Sema3a−/− mice, with a knockout in all cells, showed reduced bone formation and low bone mass. Mice with a specific knockout in osteoblasts, surprisingly, had normal bone mass, even though they showed lower than normal bone levels of Sema3A, while mice with a neuron-specific knockout had the same low bone mass as Sema3a−/− mice.

The absence of expression of Sema3A derived from neurons also caused a reduction in the level of sensory innervation to trabecular bone, but the level of sympathetic innervation was normal. The authors conclude that bone remodelling is controlled by Sema3A, not through its action on osteoblasts as previously suspected, but by affecting the development of sensory nerves.

Editor’s comment: A previous report demonstrated that osteoblast-derived Sema3A suppressed osteoclast formation by inhibiting RANKL and macrophage colony-stimulating factor signaling, and stimulated osteoblast differentiation by enhancing Wnt/β-catenin signaling. This study, which shows that Sema3A enhances sensory neuron innervation to bone but does not affect sympathetic innervation, is the first to provide evidence that Sema3A derived from neurons, but not osteoblasts, stimulates bone formation.


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