The multifaceted roles of macrophages in bone regeneration: A story of polarization, activation and time
Abstract
To present knowledge, macrophages are found in all tissues of the human body. They are a cell population with high plasticity which come with a multitude of functions which appear to be adapted to the respective tissue niche and micro-environment in which they reside. Bone harbors multiple macrophage subpopulations, with the osteoclasts as classical representative of a bone resorbing cells and osteomacs as a bone tissue resident macrophage first described by the expression of F4/80. Both subtypes are found throughout all phases in bone healing. In vivo data on bone regeneration have demonstrated their essential role in initiating the healing cascade (inflammatory phase) but also of the later phases of healing (e.g. endochondral and intramembranous bone formation). To participate in such diverse processes macrophages have to be highly plastic in their functionality. Thus, the widely used M1/M2 paradigm to distinguish macrophage subpopulations may not mirror the comprehensive role of the dynamics of macrophage plasticity. From a clinical perspective it is especially relevant to distinguish what drives macrophages in impaired healing scenarios, implant loosening or infections, where their specific role of a misbalanced inflammatory setting is so far only partially known. With this review we aim at illustrating current knowledge and gaps of knowledge on macrophage plasticity and function during the cascades of regeneration and reconstitution of bone tissue. We propose aspects of the known biological mechanisms of macrophages and their specific subsets that might serve as targets to control their function in impaired healing and eventually support a scar-free regeneration. STATEMENT OF SIGNIFICANCE: Macrophages are essential for successful regeneration. In scar-free healing such as in bone, a complete failure of healing was shown if macrophages were depleted; the M1/M2 switch appears to be key to the progression from pro-inflammation to regeneration. However, experimental data illustrate that the classical M1/M2 paradigm does not completely mirror the complexity of observed macrophage functions during bone healing and thus demands a broader perspective. Within this review we discuss the high degree of plasticity of macrophages and the relevant contribution of the different and more specific M2 subtypes (M2a-M2f) during (bone) regeneration. It summarizes the versatile roles of macrophages in skeletal regeneration and thereby highlights potential target points for immunomodulatory approaches to enable or even foster bone repair.
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M2 macrophages secrete IL-10 to inhibit osteoclast function during later stages of healing.
“Conversely, M2 macrophages secrete IL-10 to inhibit osteoclast function during later stages of healing [21, 22].”
From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [21]
The switch between the M1/M2 macrophage subtype is crucial for successful fracture healing.
“This switch between the M1/M2 subtype is crucial for successful fracture healing [21].”
From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [21]
Prior to the M1/M2 switch, M1 macrophages induce RANKL expression by osteoblasts and T cells, causing osteoclastogenesis that is necessary for remodeling of the healing fracture callus.
“Prior to this switch, M1 macrophages induce RANKL expression by osteoblasts and T cells causing osteoclastogenesis that is necessary for remodeling of the healing fracture callus.”
From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [21]
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- Authors
- Schlundt, C., Fischer, H., Bucher, C. H., Rendenbach, C., Duda, G. N., & Schmidt-Bleek, K.
- Affiliations
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Berlin-Brandenburger Centrum für Regenerative Therapien (DE)
- Corresponding author
- Duda, Georg N.
- Venue
- Acta Biomaterialia
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 133
- Pages
- 46-57
- ISSN
- 1742-7061 (ISSN-L)
- OpenAlex
- W3161474660
- Cited by
- 415
- References
- 15
- Citations by year
- 2026: 94 · 2025: 123 · 2024: 99 · 2023: 66 · 2022: 30 · 2021: 3
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Biomaterialia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- German Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- macrophages, bone regeneration, macrophage polarization, M2 subtype, macrophage plasticity, osteoclasts, F4/80, scarless wound healing, implant loosening, bone infection, immunomodulation, endochondral ossification, intramembranous ossification
- MeSH terms
- Bone and Bones, Bone Regeneration, Humans, Macrophages, Osteogenesis, Wound Healing
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