The multifaceted roles of macrophages in bone regeneration: A story of polarization, activation and time

Schlundt, Claudia; Fischer, Heilwig; Bucher, Christian H.; Rendenbach, Carsten; Duda, Georg N.; Schmidt‐Bleek, Katharina

doi:10.1016/j.actbio.2021.04.052

Cited by 165 publications

(115 citation statements)

References 114 publications

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“…The control of macrophage plasticity ranging from M1 to M2 phenotypes is a critical process in the immunomodulatory control of bone regeneration ( 43 ). In the present investigation, TNFα EVs treatment of calvaria wounds was associated with a marked switch from an M1 predominant to an M2 predominant regenerative environment at the early times of healing.…”

Section: Discussionmentioning

confidence: 99%

“…In the present investigation, TNFα EVs treatment of calvaria wounds was associated with a marked switch from an M1 predominant to an M2 predominant regenerative environment at the early times of healing. M1 macrophage-elaborated factors such as OSM assist in promoting osteogenesis ( 29 , 43 ) and M2 macrophage-elaborated factors promote ongoing osseous regeneration ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

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Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration

et al. 2022

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Mesenchymal stem cells show remarkable versatility and respond to extracellular and micro environmental cues by altering their phenotype and behavior. In this regard, the MSC’s immunomodulatory properties in tissue repair are well documented. The paracrine effects of MSCs in immunomodulation are, in part, attributable to their secreted extracellular vesicles (EVs). When MSCs migrate to the wound bed, they are exposed to a myriad of inflammatory signals. To understand their response to an inflammatory environment from an EV perspective, we sought to evaluate the effects of the inflammatory cytokine TNFα on MSC EV mediated immunomodulation. Our results indicate that while the physical characteristics of the EVs remain unchanged, the TNFα preconditioned MSC EVs possess enhanced immunomodulatory properties. In vitro experiments using polarized (M1 and M2) primary mouse macrophages indicated that the preconditioned MSC EVs suppressed pro-inflammatory (M1) markers such as IL-1β and iNOS and elevated reparatory (M2) markers such as Arg1 and CD206. When evaluated in vivo in a rat calvarial defect model, the TNFα preconditioned MSC EVs reduced inflammation at 1-, 3- and 7-days post wounding resulting in the subsequent enhanced bone formation at 4- and 8-weeks post wounding possibly by modulation of oncostatin M (OSM) expression. An analysis of EV miRNA composition revealed significant changes to anti-inflammatory miRNAs in the preconditioned MSC EVs hinting at a possible role for EV derived miRNA in the enhanced immunomodulatory activity. Overall, these results indicate that MSC exposure to inflammatory signals influence the MSC EV’s immunomodulatory function in the context of tissue repair. The specific function of TNFα preconditioned MSC EV miRNAs in immunomodulatory control of bone regeneration merits further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration

et al. 2022

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“…In addition, lots of studies revealed that polarized macrophages serve as important constituent of immune environment for bone homeostasis. In general, M1 macrophages were found to be associated with bone destruction and M2 macrophages with bone construction, in which macrophages secreted cytokines plays an important role ( Schlundt et al, 2021 ). Proinflammatory factors such as TNF-α and IL-1β derived from M1 phenotype macrophages inhibit the expression of osteogenic genes including Runx2 and Alp in BMSCs, while significantly enhance osteoclastogenesis by NF-κB and MAPK activation ( Chen et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Naringenin is a Potential Anabolic Treatment for Bone Loss by Modulating Osteogenesis, Osteoclastogenesis, and Macrophage Polarization

et al. 2022

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Bone undergoes constant remodeling of formation by osteoblasts and resorption by osteoclasts. In particular, macrophages have been reported to play an essential role in the regulation of bone homeostasis and regeneration. Naringenin, the predominant flavanone in citrus fruits, is reported to exert anti-inflammatory, anti-osteoclastic, and osteogenic effects. However, whether naringenin could modulate the crosstalk between macrophages and osteoblasts/osteoclasts remains to be investigated. In this study, we confirmed that naringenin enhanced osteogenesis and inhibited osteoclastogenesis directly. Naringenin promoted M2 transition and the secretion of osteogenic cytokines including IL-4, IL-10, BMP2, and TGF-β, while suppressing LPS-induced M1 polarization and the production of proinflammatory factors such as TNF-α and IL-1β. In addition, the coculture of primary bone mesenchymal stem cells (BMSCs)/bone marrow monocytes (BMMs) with macrophages showed that the naringenin-treated medium significantly enhanced osteogenic differentiation and impeded osteoclastic differentiation in both inflammatory and non-inflammatory environment. Moreover, in vivo experiments demonstrated that naringenin remarkably reversed LPS-induced bone loss and assisted the healing of calvarial defect. Taken together, naringenin serves as a potential anabolic treatment for pathological bone loss.

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“…Osteocytes are regulated by macrophages that secrete inflammatory mediators to control the coupling of bone resorption and bone formation (Supplementary Table S3). Macrophages are vital modulators of inflammation that rapidly change their phenotypes and functions in response to local microenvironmental signals and also play various roles in both the induction and resolution of inflammation, such as clearing dead cells and debris, presenting antigens, and recruiting, and activating other immune cells (7,(32)(33)(34). Skeletal homeostasis depends on the balance between the classically active M1 type and the alternatively active M2 type (35,36).…”

Section: Uncoupling Of Bone Resorption and Bone Formation: Cytokines ...mentioning

confidence: 99%

Roles of Altered Macrophages and Cytokines: Implications for Pathological Mechanisms of Postmenopausal Osteoporosis, Rheumatoid Arthritis, and Alzheimer’s Disease

Yan

Zhang

et al. 2022

Front. Endocrinol.

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Postmenopausal osteoporosis (PMOP) is characterized by the uncoupling of bone resorption and bone formation induced by estrogen deficiency, which is a complex outcome related to estrogen and the immune system. The interaction between bone and immune cells is regarded as the context of PMOP. Macrophages act differently on bone cells, depending on their polarization profile and secreted paracrine factors, which may have implications for the development of PMOP. PMOP, rheumatoid arthritis (RA), and Alzheimer’s disease (AD) might have pathophysiological links, and the similarity of their pathological mechanisms is partially visible in altered macrophages and cytokines in the immune system. This review focuses on exploring the pathological mechanisms of PMOP, RA, and AD through the roles of altered macrophages and cytokines secretion. First, the multiple effects on cytokines secretion by bone-bone marrow (BM) macrophages in the pathological mechanism of PMOP are reviewed. Then, based on the thought of “different tissue-same cell type-common pathological molecules-disease pathological links-drug targets” and the methodologies of “molecular network” in bioinformatics, highlight that multiple cytokines overlap in the pathological molecules associated with PMOP vs. RA and PMOP vs. AD, and propose that these overlaps may lead to a pathological synergy in PMOP, RA, and AD. It provides a novel strategy for understanding the pathogenesis of PMOP and potential drug targets for the treatment of PMOP.

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The multifaceted roles of macrophages in bone regeneration: A story of polarization, activation and time

Cited by 165 publications

References 114 publications

Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration

Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration

Naringenin is a Potential Anabolic Treatment for Bone Loss by Modulating Osteogenesis, Osteoclastogenesis, and Macrophage Polarization

Roles of Altered Macrophages and Cytokines: Implications for Pathological Mechanisms of Postmenopausal Osteoporosis, Rheumatoid Arthritis, and Alzheimer’s Disease

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