Fig. 5

The diagram shows the possible signaling pathways of three representative neuropeptides (CGRP, BDNF, and Sema3A) that regulate bone formation. a Calcitonin gene‐related peptide (CGRP) is the main neuropeptide secreted by sensory nerves whose receptor is a G‐protein coupled receptor (GPCR). CGRP binds to the RAMP1-CALCRL complex and activates coupled Gαs subunits, which elevates the intracellular cAMP concentration and subsequently activates PKA. PKA inhibits the phosphorylation of β-catenin by GSK-3β. Unphosphorylated β-catenin translocates into the nucleus, where it associates with TCF/LEF transcription factors. Meanwhile, PKA activates CREB, which translocates into the nucleus and forms a homodimer or heterodimer that binds to the target gene. b Brain-derived neurotrophic factor (BDNF) is an important member of the neurotrophin family. BDNF binding to TrkB leads to the autophosphorylation of TrkB, which activates the PI3K/AKT and MEK/ERK pathways. RUNX2 is activated by the latter signaling pathway and upregulates the downstream molecule osterix to promote bone formation. The activation of ERK or AKT may contribute to the increased expression of integrin-β1, which is associated with migration. c Sema3A inhibits osteoclastogenesis in macrophages. Semaphorin 3A (Sema3A) is a secreted protein in the axon guidance protein family. Sema3A binds to its receptor PlxnA1–Nrp1 to inhibit the formation of the PlxnA1–TREM2–DAP12 complex, which can respond to ligands, such as Sema6D, to dephosphorylate NFATc1, thus inducing the transcription of osteoclast-specific genes. On the other hand, Sema3A activates RhoA, inhibiting BMM migration to prevent osteoclastogenesis. “?” indicates that more direct evidence is needed