Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification

L J Raggatt; M E Wullschleger; K A Alexander; A C K Wu; S M Millard; S Kaur; Michelle Maugham; L S Gregory; R Steck; A R Pettit

doi:10.1016/j.ajpath.2014.08.017

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Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification

Journal article

Peer reviewed

Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification

L J Raggatt, M E Wullschleger, K A Alexander, A C K Wu, S M Millard, S Kaur, Michelle Maugham, L S Gregory, R Steck and A R Pettit

American Journal of Pathology, Vol.184(12), pp.3192-3204

2014

DOI: https://doi.org/10.1016/j.ajpath.2014.08.017

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Abstract

Medical and Health Sciences

The distribution, phenotype, and requirement of macrophages for fracture-associated inflammation and/or early anabolic progression during endochondral callus formation were investigated. A murine femoral fracture model [internally fixed using a flexible plate (MouseFix)] was used to facilitate reproducible fracture reduction. IHC demonstrated that inflammatory macrophages (F4/80þMac-2þ) were localized with initiating chondrification centers and persisted within granulation tissue at the expanding soft callus front. They were also associated with key events during soft-to-hard callus transition. Resident macrophages (F4/ 80þMac-2neg), including osteal macrophages, predominated in the maturing hard callus. Macrophage Fasinduced apoptosis transgenic mice were used to induce macrophage depletion in vivo in the femoral fracture model. Callus formation was completely abolished when macrophage depletion was initiated at the time of surgery and was significantly reduced when depletion was delayed to coincide with initiation of early anabolic phase. Treatment initiating 5 days after fracture with the pro-macrophage cytokine colony stimulating factor-1 significantly enhanced soft callus formation. The data support that inflammatory macrophages were required for initiation of fracture repair, whereas both inflammatory and resident macrophages promoted anabolic mechanisms during endochondral callus formation. Overall, macrophages make substantive and prolonged contributions to fracture healing and can be targeted as a therapeutic approach for enhancing repair mechanisms. Thus, macrophages represent a viable target for the development of pro-anabolic fracture treatments with a potentially broad therapeutic window.

Details

Title: Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification
Authors: L J Raggatt (Author)
M E Wullschleger (Author)
K A Alexander (Author)
A C K Wu (Author)
S M Millard (Author)
S Kaur (Author)
Michelle Maugham (Author) - University of Queensland
L S Gregory (Author)
R Steck (Author)
A R Pettit (Author)
Publication details: American Journal of Pathology, Vol.184(12), pp.3192-3204
Publisher: Elsevier Inc.
Date published: 2014
DOI: 10.1016/j.ajpath.2014.08.017
ISSN: 0002-9440
Organisation Unit: School of Health - Biomedicine; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99451104302621
Output Type: Journal article

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Collaboration types: Domestic collaboration
Web Of Science research areas: Pathology

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