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Inhibition of angiogenetic macrophages reduces disc degeneration-associated pain

Abnormal angiogenesis and innervation in avascular discs during lumbar disc degeneration (LDD) cause severe back pain. These pathological alterations in the degenerating discs are induced by cytokines partially produced and secreted by inflammatory cells, among which macrophages are the most frequen...

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Autores principales: Hou, Yang, Shi, Jiangang, Guo, Yongfei, Shi, Guodong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9592909/
https://www.ncbi.nlm.nih.gov/pubmed/36304897
http://dx.doi.org/10.3389/fbioe.2022.962155
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author Hou, Yang
Shi, Jiangang
Guo, Yongfei
Shi, Guodong
author_facet Hou, Yang
Shi, Jiangang
Guo, Yongfei
Shi, Guodong
author_sort Hou, Yang
collection PubMed
description Abnormal angiogenesis and innervation in avascular discs during lumbar disc degeneration (LDD) cause severe back pain. These pathological alterations in the degenerating discs are induced by cytokines partially produced and secreted by inflammatory cells, among which macrophages are the most frequently ones detected at the legion site. However, the role of macrophages as well as their polarization in regulation of innervation and angiogenesis in the degenerating discs is unclear. In this study, we analyzed macrophages in the degenerating discs from patients and detected a specific macrophage subtype that expresses high levels of vascular endothelial growth factor A (VEGF-A). Co-expression of M2 macrophage markers in this macrophage subtype suggested that they were a M2d-like subtype. High levels of VEGF-A and genes associated with angiogenesis were also detected in LDD specimens compared to control heathy discs from a public database, consistent with our finding. Moreover, the levels of VEGF-A in disc macrophages were strongly correlated to the pain score of the examined patients, but not to the Thompson classification of the degeneration level of the patients. In vitro, overexpressing VEGF-A in macrophages increased the tube formation, proliferation and migration of co-cultured endothelial cells, and increased the innervation of embryonic spinal cord explant into the co-cultured area for macrophages and skeletal myocytes. In vivo, an orthotopic injection of adeno-associated virus carrying siRNA for VEGF-A under a macrophage-specific CD68 promoter significantly reduced the number of VEGF-A-positive disc macrophages and alleviated the pain in LDD-mice. Together, these data suggest that inhibition of angiogenetic potential of macrophages may reduce disc degeneration-associated pain through suppression of angiogenesis and innervation, as a promising therapy for LDD-associated pain.
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spelling pubmed-95929092022-10-26 Inhibition of angiogenetic macrophages reduces disc degeneration-associated pain Hou, Yang Shi, Jiangang Guo, Yongfei Shi, Guodong Front Bioeng Biotechnol Bioengineering and Biotechnology Abnormal angiogenesis and innervation in avascular discs during lumbar disc degeneration (LDD) cause severe back pain. These pathological alterations in the degenerating discs are induced by cytokines partially produced and secreted by inflammatory cells, among which macrophages are the most frequently ones detected at the legion site. However, the role of macrophages as well as their polarization in regulation of innervation and angiogenesis in the degenerating discs is unclear. In this study, we analyzed macrophages in the degenerating discs from patients and detected a specific macrophage subtype that expresses high levels of vascular endothelial growth factor A (VEGF-A). Co-expression of M2 macrophage markers in this macrophage subtype suggested that they were a M2d-like subtype. High levels of VEGF-A and genes associated with angiogenesis were also detected in LDD specimens compared to control heathy discs from a public database, consistent with our finding. Moreover, the levels of VEGF-A in disc macrophages were strongly correlated to the pain score of the examined patients, but not to the Thompson classification of the degeneration level of the patients. In vitro, overexpressing VEGF-A in macrophages increased the tube formation, proliferation and migration of co-cultured endothelial cells, and increased the innervation of embryonic spinal cord explant into the co-cultured area for macrophages and skeletal myocytes. In vivo, an orthotopic injection of adeno-associated virus carrying siRNA for VEGF-A under a macrophage-specific CD68 promoter significantly reduced the number of VEGF-A-positive disc macrophages and alleviated the pain in LDD-mice. Together, these data suggest that inhibition of angiogenetic potential of macrophages may reduce disc degeneration-associated pain through suppression of angiogenesis and innervation, as a promising therapy for LDD-associated pain. Frontiers Media S.A. 2022-10-11 /pmc/articles/PMC9592909/ /pubmed/36304897 http://dx.doi.org/10.3389/fbioe.2022.962155 Text en Copyright © 2022 Hou, Shi, Guo and Shi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Bioengineering and Biotechnology
Hou, Yang
Shi, Jiangang
Guo, Yongfei
Shi, Guodong
Inhibition of angiogenetic macrophages reduces disc degeneration-associated pain
title Inhibition of angiogenetic macrophages reduces disc degeneration-associated pain
title_full Inhibition of angiogenetic macrophages reduces disc degeneration-associated pain
title_fullStr Inhibition of angiogenetic macrophages reduces disc degeneration-associated pain
title_full_unstemmed Inhibition of angiogenetic macrophages reduces disc degeneration-associated pain
title_short Inhibition of angiogenetic macrophages reduces disc degeneration-associated pain
title_sort inhibition of angiogenetic macrophages reduces disc degeneration-associated pain
topic Bioengineering and Biotechnology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9592909/
https://www.ncbi.nlm.nih.gov/pubmed/36304897
http://dx.doi.org/10.3389/fbioe.2022.962155
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