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TLR4 Inactivation in Myeloid Cells Accelerates Bone Healing of a Calvarial Defect Model in Mice

BACKGROUND: Toll-like receptor 4 (TLR4) has been implicated in inflammation-induced bone destruction in various chronic bone diseases; however, its direct influence on bone healing is not well understood. The authors’ previous study showed accelerated bone healing with higher osteoclastogenesis gene...

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Autores principales: Wang, Dan, Gilbert, James R., Taylor, Gwen M., Sodhi, Chhinder P., Hackam, David J., Losee, Joseph E., Billiar, Timothy R., Cooper, Gregory M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542792/
https://www.ncbi.nlm.nih.gov/pubmed/28746278
http://dx.doi.org/10.1097/PRS.0000000000003541
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author Wang, Dan
Gilbert, James R.
Taylor, Gwen M.
Sodhi, Chhinder P.
Hackam, David J.
Losee, Joseph E.
Billiar, Timothy R.
Cooper, Gregory M.
author_facet Wang, Dan
Gilbert, James R.
Taylor, Gwen M.
Sodhi, Chhinder P.
Hackam, David J.
Losee, Joseph E.
Billiar, Timothy R.
Cooper, Gregory M.
author_sort Wang, Dan
collection PubMed
description BACKGROUND: Toll-like receptor 4 (TLR4) has been implicated in inflammation-induced bone destruction in various chronic bone diseases; however, its direct influence on bone healing is not well understood. The authors’ previous study showed accelerated bone healing with higher osteoclastogenesis gene expression in toll-like receptor 4 knockout mice (TLR4(-/-)). This study aimed to further elucidate the underlying cellular mechanisms during fracture healing by generating a myeloid cell-specific toll-like receptor 4 knockout model (Lyz-TLR4(-/-) mice). METHODS: Calvarial defects, 1.8 mm in diameter, were created in wild-type, TLR4(-/-), and Lyz-TLR4(-/-) mice. Bone healing was investigated using micro–computed tomography and histologic, histomorphometric, and immunohistochemistry analyses. Primary bone marrow–derived cells were also isolated from wild-type, TLR4(-/-), and Lyz-TLR4(-/-) mice to measure their osteoclast differentiation and resorption properties. RESULTS: A similar faster bone healing response, with active intramembranous bone formation, intense osteopontin staining, and more osteoblast infiltration, was observed in TLR4(-/-) and Lyz-TLR4(-/-) mice. Tartrate-resistant acid phosphatase staining showed more osteoclast infiltration in Lyz-TLR4(-/-) mice than in wild-type mice at day 7. Primary bone marrow–derived cells isolated from TLR4(-/-) and Lyz-TLR4(-/-) mice presented enhanced osteoclastogenesis and resorption activity compared with those from wild-type mice. Comparable M0, M1, and M2 macrophage infiltration was found among all groups at days 1, 4, and 7. CONCLUSIONS: This study revealed that inactivation of toll-like receptor 4 in myeloid cells enhanced osteoclastogenesis and accelerated healing response during skull repair. Together with the role of toll-like receptor 4 in inflammation-mediated bone destruction, it suggests that toll-like receptor 4 might regulate inflammation-induced osteoclastogenesis under different clinical settings.
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spelling pubmed-55427922017-08-09 TLR4 Inactivation in Myeloid Cells Accelerates Bone Healing of a Calvarial Defect Model in Mice Wang, Dan Gilbert, James R. Taylor, Gwen M. Sodhi, Chhinder P. Hackam, David J. Losee, Joseph E. Billiar, Timothy R. Cooper, Gregory M. Plast Reconstr Surg Experimental: Original Articles BACKGROUND: Toll-like receptor 4 (TLR4) has been implicated in inflammation-induced bone destruction in various chronic bone diseases; however, its direct influence on bone healing is not well understood. The authors’ previous study showed accelerated bone healing with higher osteoclastogenesis gene expression in toll-like receptor 4 knockout mice (TLR4(-/-)). This study aimed to further elucidate the underlying cellular mechanisms during fracture healing by generating a myeloid cell-specific toll-like receptor 4 knockout model (Lyz-TLR4(-/-) mice). METHODS: Calvarial defects, 1.8 mm in diameter, were created in wild-type, TLR4(-/-), and Lyz-TLR4(-/-) mice. Bone healing was investigated using micro–computed tomography and histologic, histomorphometric, and immunohistochemistry analyses. Primary bone marrow–derived cells were also isolated from wild-type, TLR4(-/-), and Lyz-TLR4(-/-) mice to measure their osteoclast differentiation and resorption properties. RESULTS: A similar faster bone healing response, with active intramembranous bone formation, intense osteopontin staining, and more osteoblast infiltration, was observed in TLR4(-/-) and Lyz-TLR4(-/-) mice. Tartrate-resistant acid phosphatase staining showed more osteoclast infiltration in Lyz-TLR4(-/-) mice than in wild-type mice at day 7. Primary bone marrow–derived cells isolated from TLR4(-/-) and Lyz-TLR4(-/-) mice presented enhanced osteoclastogenesis and resorption activity compared with those from wild-type mice. Comparable M0, M1, and M2 macrophage infiltration was found among all groups at days 1, 4, and 7. CONCLUSIONS: This study revealed that inactivation of toll-like receptor 4 in myeloid cells enhanced osteoclastogenesis and accelerated healing response during skull repair. Together with the role of toll-like receptor 4 in inflammation-mediated bone destruction, it suggests that toll-like receptor 4 might regulate inflammation-induced osteoclastogenesis under different clinical settings. Lippincott Williams & Wilkins 2017-08 2017-07-27 /pmc/articles/PMC5542792/ /pubmed/28746278 http://dx.doi.org/10.1097/PRS.0000000000003541 Text en Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Experimental: Original Articles
Wang, Dan
Gilbert, James R.
Taylor, Gwen M.
Sodhi, Chhinder P.
Hackam, David J.
Losee, Joseph E.
Billiar, Timothy R.
Cooper, Gregory M.
TLR4 Inactivation in Myeloid Cells Accelerates Bone Healing of a Calvarial Defect Model in Mice
title TLR4 Inactivation in Myeloid Cells Accelerates Bone Healing of a Calvarial Defect Model in Mice
title_full TLR4 Inactivation in Myeloid Cells Accelerates Bone Healing of a Calvarial Defect Model in Mice
title_fullStr TLR4 Inactivation in Myeloid Cells Accelerates Bone Healing of a Calvarial Defect Model in Mice
title_full_unstemmed TLR4 Inactivation in Myeloid Cells Accelerates Bone Healing of a Calvarial Defect Model in Mice
title_short TLR4 Inactivation in Myeloid Cells Accelerates Bone Healing of a Calvarial Defect Model in Mice
title_sort tlr4 inactivation in myeloid cells accelerates bone healing of a calvarial defect model in mice
topic Experimental: Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542792/
https://www.ncbi.nlm.nih.gov/pubmed/28746278
http://dx.doi.org/10.1097/PRS.0000000000003541
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