BoneKEy Reports | BoneKEy Watch
Semaphorin 3A and its role in osteoprotection
DOI:10.1038/bonekey.2012.156
In a search for local factors that regulate bone homeostasis, Hayashi et al. focused on the axon guidance factor semaphorin 3A (Sema3A). Experiments using Sema3a knockout mice (Sema3a−/−), which are severely osteopenic in the trabecular and cortical bones, revealed that expression of Sema3A in osteoblasts inhibits osteoclastogenesis by binding to a subunit of Nrp1, a class A plexin. RANKL stimulation prevented Sema3A inhibitory activity through downregulation of Nrp1. Sema3A was shown to reduce osteoblast formation and so lower the rate of bone formation, also by acting through Nrp1.
Gene expression profiling in Sema3a−/− mice showed that gene sets involved in the Wnt pathway were significantly downregulated, with reduced expression of the mRNA of many of the targets of β-catenin and clear suppression of Wnt3a-induced accumulation of β-catenin in the nucleus of calvarial cells.
After treatment with Sema3A, normal mice showed a decrease in osteoclastogenesis and an increase on osteoblastic factors, mice with induced bone injury showed a greater regeneration of cortical bone, and ovariectomized mice showed a decrease in bone loss, all suggesting exciting therapeutic possibilities.
Editor's comment: Previously these authors reported that semaphorin 4D expressed by osteoclasts inhibits bone formation. Now, through an amazing series of in vivo and in vitro experiments, they report that Sema3A not only does the opposite, i.e. activates osteoblasts, it also simultaneously inhibits RANKL-induced osteoclastogenesis. These findings add to our understanding of the coupling mechanisms in bone and provide a new target for therapeutic developments.
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