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. 2023 Feb 21;11:1104709. doi: 10.3389/fcell.2023.1104709

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Copyright © 2023 Burkhardt, Bucher, Löffler, Rinne, Duda, Geissler, Schulz and Schmidt-Bleek.

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.

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Overview of the five distinct fracture healing phases: (A) Stage 1: Hematoma formation and pro-inflammatory signalling; Stage 2: Anti-inflammatory hematoma; Stage 3: Soft callus development; Stage 4: Hard callus development; Stage 5: Remodelling of the newly formed bone; modified from Ono, et al. (2017) and Maruyama, et al. (2020). (B) Distinct cytokines affecting the pro- and anti-inflammatory phase during the early healing stage, callus formation and remodelling. (C) MSCs change their metabolic features from glycolysis towards OXPHOS during osteogenic differentiation. Monocytes, M1 macrophages and T cells prominently use the glycolytic pathways when differentiation and activation happens and change their metabolism towards OXPHOS when the anti-inflammatory phase is induced (Tregs/M2 macrophages) (Fretz et al., 2010; Scheller and Rosen, 2014; Loeffler et al., 2018).