Macrophages in bone fracture healing: Their essential role in endochondral ossification

Claudia Schlundt, Thaqif el Khassawna, Alessandro Serra, Anke Dienelt, Sebastian Wendler, Hanna Schell, Nico van Rooijen, Andreas Radbruch, Richard Lucius, Susanne Hartmann, Georg N. Duda, Katharina Schmidt-Bleek

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

In fracture healing, skeletal and immune system are closely interacting through common cell precursors and molecular mediators. It is thought that the initial inflammatory reaction, which involves migration of macrophages into the fracture area, has a major impact on the long term outcome of bone repair. Interestingly, macrophages reside during all stages of fracture healing. Thus, we hypothesized a critical role for macrophages in the subsequent phases of bone regeneration. This study examined the impact of in vivo induced macrophage reduction, using clodronate liposomes, on the different healing phases of bone repair in a murine model of a standard closed femoral fracture. A reduction in macrophages had no obvious effect on the early fracture healing phase, but resulted in a delayed hard callus formation, thus severely altering endochondral ossification. Clodronate treated animals clearly showed delayed bony consolidation of cartilage and enhanced periosteal bone formation. Therefore, we decided to backtrack macrophage distribution during fracture healing in non-treated mice, focusing on the identification of the M1 and M2 subsets. We observed that M2 macrophages were clearly prevalent during the ossification phase. Therefore enhancement of M2 phenotype in macrophages was investigated as a way to further bone healing. Induction of M2 macrophages through interleukin 4 and 13 significantly enhanced bone formation during the 3 week investigation period. These cumulative data illustrate their so far unreported highly important role in endochondral ossification and the necessity of a fine balance in M1/M2 macrophage function, which appears mandatory to fracture healing and successful regeneration.
Original languageEnglish
Pages (from-to)78-89
JournalBone
Volume106
DOIs
Publication statusPublished - 2018

Cite this

Schlundt, C., el Khassawna, T., Serra, A., Dienelt, A., Wendler, S., Schell, H., ... Schmidt-Bleek, K. (2018). Macrophages in bone fracture healing: Their essential role in endochondral ossification. Bone, 106, 78-89. https://doi.org/10.1016/j.bone.2015.10.019
Schlundt, Claudia ; el Khassawna, Thaqif ; Serra, Alessandro ; Dienelt, Anke ; Wendler, Sebastian ; Schell, Hanna ; van Rooijen, Nico ; Radbruch, Andreas ; Lucius, Richard ; Hartmann, Susanne ; Duda, Georg N. ; Schmidt-Bleek, Katharina. / Macrophages in bone fracture healing: Their essential role in endochondral ossification. In: Bone. 2018 ; Vol. 106. pp. 78-89.
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abstract = "In fracture healing, skeletal and immune system are closely interacting through common cell precursors and molecular mediators. It is thought that the initial inflammatory reaction, which involves migration of macrophages into the fracture area, has a major impact on the long term outcome of bone repair. Interestingly, macrophages reside during all stages of fracture healing. Thus, we hypothesized a critical role for macrophages in the subsequent phases of bone regeneration. This study examined the impact of in vivo induced macrophage reduction, using clodronate liposomes, on the different healing phases of bone repair in a murine model of a standard closed femoral fracture. A reduction in macrophages had no obvious effect on the early fracture healing phase, but resulted in a delayed hard callus formation, thus severely altering endochondral ossification. Clodronate treated animals clearly showed delayed bony consolidation of cartilage and enhanced periosteal bone formation. Therefore, we decided to backtrack macrophage distribution during fracture healing in non-treated mice, focusing on the identification of the M1 and M2 subsets. We observed that M2 macrophages were clearly prevalent during the ossification phase. Therefore enhancement of M2 phenotype in macrophages was investigated as a way to further bone healing. Induction of M2 macrophages through interleukin 4 and 13 significantly enhanced bone formation during the 3 week investigation period. These cumulative data illustrate their so far unreported highly important role in endochondral ossification and the necessity of a fine balance in M1/M2 macrophage function, which appears mandatory to fracture healing and successful regeneration.",
author = "Claudia Schlundt and {el Khassawna}, Thaqif and Alessandro Serra and Anke Dienelt and Sebastian Wendler and Hanna Schell and {van Rooijen}, Nico and Andreas Radbruch and Richard Lucius and Susanne Hartmann and Duda, {Georg N.} and Katharina Schmidt-Bleek",
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Schlundt, C, el Khassawna, T, Serra, A, Dienelt, A, Wendler, S, Schell, H, van Rooijen, N, Radbruch, A, Lucius, R, Hartmann, S, Duda, GN & Schmidt-Bleek, K 2018, 'Macrophages in bone fracture healing: Their essential role in endochondral ossification' Bone, vol. 106, pp. 78-89. https://doi.org/10.1016/j.bone.2015.10.019

Macrophages in bone fracture healing: Their essential role in endochondral ossification. / Schlundt, Claudia; el Khassawna, Thaqif; Serra, Alessandro; Dienelt, Anke; Wendler, Sebastian; Schell, Hanna; van Rooijen, Nico; Radbruch, Andreas; Lucius, Richard; Hartmann, Susanne; Duda, Georg N.; Schmidt-Bleek, Katharina.

In: Bone, Vol. 106, 2018, p. 78-89.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Serra, Alessandro

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AU - Lucius, Richard

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AU - Duda, Georg N.

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N2 - In fracture healing, skeletal and immune system are closely interacting through common cell precursors and molecular mediators. It is thought that the initial inflammatory reaction, which involves migration of macrophages into the fracture area, has a major impact on the long term outcome of bone repair. Interestingly, macrophages reside during all stages of fracture healing. Thus, we hypothesized a critical role for macrophages in the subsequent phases of bone regeneration. This study examined the impact of in vivo induced macrophage reduction, using clodronate liposomes, on the different healing phases of bone repair in a murine model of a standard closed femoral fracture. A reduction in macrophages had no obvious effect on the early fracture healing phase, but resulted in a delayed hard callus formation, thus severely altering endochondral ossification. Clodronate treated animals clearly showed delayed bony consolidation of cartilage and enhanced periosteal bone formation. Therefore, we decided to backtrack macrophage distribution during fracture healing in non-treated mice, focusing on the identification of the M1 and M2 subsets. We observed that M2 macrophages were clearly prevalent during the ossification phase. Therefore enhancement of M2 phenotype in macrophages was investigated as a way to further bone healing. Induction of M2 macrophages through interleukin 4 and 13 significantly enhanced bone formation during the 3 week investigation period. These cumulative data illustrate their so far unreported highly important role in endochondral ossification and the necessity of a fine balance in M1/M2 macrophage function, which appears mandatory to fracture healing and successful regeneration.

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Schlundt C, el Khassawna T, Serra A, Dienelt A, Wendler S, Schell H et al. Macrophages in bone fracture healing: Their essential role in endochondral ossification. Bone. 2018;106:78-89. https://doi.org/10.1016/j.bone.2015.10.019