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Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing

Following severe trauma, fracture healing is impaired because of overwhelming systemic and local inflammation. Glucocorticoids (GCs), acting via the glucocorticoid receptor (GR), influence fracture healing by modulating the trauma-induced immune response. GR dimerization-dependent gene regulation is...

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Autores principales: Hachemi, Yasmine, Rapp, Anna E., Lee, Sooyeon, Dorn, Ann-Kristin, Krüger, Benjamin T., Kaiser, Kathrin, Ignatius, Anita, Tuckermann, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927427/
https://www.ncbi.nlm.nih.gov/pubmed/33679723
http://dx.doi.org/10.3389/fimmu.2020.628287
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author Hachemi, Yasmine
Rapp, Anna E.
Lee, Sooyeon
Dorn, Ann-Kristin
Krüger, Benjamin T.
Kaiser, Kathrin
Ignatius, Anita
Tuckermann, Jan
author_facet Hachemi, Yasmine
Rapp, Anna E.
Lee, Sooyeon
Dorn, Ann-Kristin
Krüger, Benjamin T.
Kaiser, Kathrin
Ignatius, Anita
Tuckermann, Jan
author_sort Hachemi, Yasmine
collection PubMed
description Following severe trauma, fracture healing is impaired because of overwhelming systemic and local inflammation. Glucocorticoids (GCs), acting via the glucocorticoid receptor (GR), influence fracture healing by modulating the trauma-induced immune response. GR dimerization-dependent gene regulation is essential for the anti-inflammatory effects of GCs. Therefore, we investigated in a murine trauma model of combined femur fracture and thoracic trauma, whether effective GR dimerization influences the pathomechanisms of trauma-induced compromised fracture healing. To this end, we used mice with decreased GR dimerization ability (GR(dim)). The healing process was analyzed by cytokine/chemokine multiplex analysis, flow cytometry, gene-expression analysis, histomorphometry, micro-computed tomography, and biomechanical testing. GR(dim) mice did not display a systemic or local hyper-inflammation upon combined fracture and thorax trauma. Strikingly, we discovered that GR(dim) mice were protected from fracture healing impairment induced by the additional thorax trauma. Collectively and in contrast to previous studies describing the beneficial effects of intact GR dimerization in inflammatory models, we report here an adverse role of intact GR dimerization in trauma-induced compromised fracture healing.
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spelling pubmed-79274272021-03-04 Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing Hachemi, Yasmine Rapp, Anna E. Lee, Sooyeon Dorn, Ann-Kristin Krüger, Benjamin T. Kaiser, Kathrin Ignatius, Anita Tuckermann, Jan Front Immunol Immunology Following severe trauma, fracture healing is impaired because of overwhelming systemic and local inflammation. Glucocorticoids (GCs), acting via the glucocorticoid receptor (GR), influence fracture healing by modulating the trauma-induced immune response. GR dimerization-dependent gene regulation is essential for the anti-inflammatory effects of GCs. Therefore, we investigated in a murine trauma model of combined femur fracture and thoracic trauma, whether effective GR dimerization influences the pathomechanisms of trauma-induced compromised fracture healing. To this end, we used mice with decreased GR dimerization ability (GR(dim)). The healing process was analyzed by cytokine/chemokine multiplex analysis, flow cytometry, gene-expression analysis, histomorphometry, micro-computed tomography, and biomechanical testing. GR(dim) mice did not display a systemic or local hyper-inflammation upon combined fracture and thorax trauma. Strikingly, we discovered that GR(dim) mice were protected from fracture healing impairment induced by the additional thorax trauma. Collectively and in contrast to previous studies describing the beneficial effects of intact GR dimerization in inflammatory models, we report here an adverse role of intact GR dimerization in trauma-induced compromised fracture healing. Frontiers Media S.A. 2021-02-17 /pmc/articles/PMC7927427/ /pubmed/33679723 http://dx.doi.org/10.3389/fimmu.2020.628287 Text en Copyright © 2021 Hachemi, Rapp, Lee, Dorn, Krüger, Kaiser, Ignatius and Tuckermann http://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 Immunology
Hachemi, Yasmine
Rapp, Anna E.
Lee, Sooyeon
Dorn, Ann-Kristin
Krüger, Benjamin T.
Kaiser, Kathrin
Ignatius, Anita
Tuckermann, Jan
Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing
title Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing
title_full Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing
title_fullStr Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing
title_full_unstemmed Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing
title_short Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing
title_sort intact glucocorticoid receptor dimerization is deleterious in trauma-induced impaired fracture healing
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927427/
https://www.ncbi.nlm.nih.gov/pubmed/33679723
http://dx.doi.org/10.3389/fimmu.2020.628287
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