Osteoclasts control sensory neurons axonal growth through epidermal growth factor receptor signaling

Dense ectopic sprouting of nerve fibers was reported in several bone pathologies featuring high osteoclast number and/or activity. Osteoclasts play a critical role on nociceptors activation; however, their contribution to nerve fibers outgrowth is unknown. This study provides compelling evidence that osteoclastic lineage has an intrinsic capacity to promote axonal outgrowth of dorsal root ganglia (DRG), surpassing the neurotrophic potential of bone marrow stromal cells. Using microfluidic devices, we showed that osteoclast-secreted molecules induced nerve growth via local action on nerve terminals. Interestingly, the axonal outgrowth mediated by osteoclast is neurotrophin-independent but implicate epidermal growth factor receptor (EGFR)/ErbB2 signaling. Ligand search studies showed lack of EGFR agonists in osteoclast secretome, however, demonstrated an increase of endogenous EGF in DRG under osteoclast stimulation. Moreover, proteomic analysis revealed molecules able to trigger EGFR signaling to induce osteoclast-mediated axonal outgrowth, as fibronectin, low-density lipoprotein receptor-related protein 1 and periostin.