Background: Recent physiological and experimental data highlight the role of the sensory nervous system in bone repair, but its precise role on angiogenesis in a bone regeneration context is still unknown. Our previous work demonstrated that sensory neurons (SNs) induce the osteoblastic differentiation of mesenchymal stem cells, but the influence of SNs on endothelial cells (ECs) was not studied.Methods: Here, in order to study in vitro the interplay between SNs and ECs, we used microfluidic devices as an indirect co-culture model. Gene expression analysis of angiogenic markers, as well as measurements of metalloproteinases protein levels and enzymatic activity, were performed.Results: We were able to demonstrate that two sensory neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), were involved in the transcriptional upregulation of angiogenic markers (vascular endothelial growth factor, angiopoietin 1, type 4 collagen, matrix metalloproteinase 2) in ECs. Co-cultures of ECs with SNs also increased the protein level and enzymatic activity of matrix metalloproteinases 2 and 9 (MMP2/MMP9) in ECs.Conclusions: Our results suggest a role of sensory neurons, and more specifically of CGRP and SP, in the remodelling of endothelial cells extracellular matrix, thus supporting and enhancing the angiogenesis process.

Electron micrographs revealed the presence of gap junctions in osteoblastic cells over 40 years ago. These intercellular channels formed from connexins are present in bone forming osteoblasts, bone resorbing osteoclasts, and osteocytes (mature osteoblasts embedded in the mineralized bone matrix). More recently, genetic and pharmacologic studies revealed the role of connexins, and in particular Cx43, in the differentiation and function of all bone types. Furthermore, mutations in the gene encoding Cx43 were found to be causally linked to oculodentodigital dysplasia, a condition that results in an abnormal skeleton. Pannexins, molecules with similar structure and single-membrane channel forming potential as connexins when organized as hemichannels, are also expressed in osteoblastic cells. The function of pannexins in bone and cartilage is beginning to be uncovered, but more research is needed to determine the role of pannexins in bone development, adult bone mass and skeletal homeostasis. We describe here the current knowledge on the role of connexins and pannexins on skeletal health and disease.