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. 2020 Oct 19;18:162. doi: 10.1186/s12964-020-00656-0

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© The Author(s) 2020

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 5 — Role of sensory neurons in osteogenic differentiation and vascular remodelling. SNs enhance the osteogenic differentiation of MSCs through the upregulation of genes such as Runx2 (runt-related transcription factor 2), Sp7 (osterix) or Bglap (osteocalcin) [according to Silva et al., 2017 [46]]. Through the secretion of CGRP and SP, SNs also play a role in vascular remodeling by upregulating the expression of some angiogenic markers in ECs. More specifically, they strongly upregulate the expression of Mmp2 as well as MMP2/MMP9 protein level and enzymatic activity, suggesting a role in angiogenesis through extracellular matrix remodeling. Besides, ECs are known to have an osteoinductive effect on MSC through the release of bone morphogenetic proteins (BMPs) [according to Grellier et al., 2009 [2]], thus the interplay between these three cell types should be considered for the development of bone regeneration strategies