Resolution of inflammation in bone regeneration: From understandings to therapeutic applications

Newman, Hunter; Shih, Yu‐Ru V.; Varghese, Shyni

doi:10.1016/j.biomaterials.2021.121114

Cited by 131 publications

(111 citation statements)

References 186 publications

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“…Second, there is now overwhelming evidence indicating that BMSCs play a critical role in the inflammatory reaction following trauma, and are especially important in bone regeneration. 38 Investigating the effect of chrysin on the immunomodulatory property of BMSCs is therefore also necessary. Third, only one drug administration mode was evaluated in the present study, and additional animal experiments are required to determine the optimal dosage and timing of administration.…”

Section: Discussionmentioning

confidence: 99%

Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway

Li¹,

Wang²

2022

DDDT

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Purpose: High glucose environment in diabetes mellitus induces the dysfunction of bone marrow-derived mesenchymal stromal cells (BMSCs) and impairs bone regeneration. Chrysin is a natural polyphenol with outstanding anti-inflammation and anti-oxidation ability. However, whether and how chrysin affects BMSCs in high glucose conditions remain poorly understood. The present study aimed to explore the effects and underlying mechanisms of chrysin on the BMSCs exposed to high glucose environment. Materials and Methods: Cell viability was detected by cell counting kit 8 assay and 5ethynyl-2'-deoxyuridine staining, while cell apoptosis was determined through flow cytometry using Annexin V-FITC/PI kit. The oxidative stress in BMSCs was evaluated by detecting the reactive oxygen species production, malondialdehyde content, and superoxide dismutase activity. Alkaline phosphatase staining, Alizarin Red staining, and quantitative real-time PCR were performed to determine the osteogenic differentiation. Western blot was used to examine the expression of the PI3K/ATK/Nrf2 signaling pathway. Furthermore, chrysin was injected into calvarial defects of type 1 diabetic SD rats to assess its in vivo bone formation capability. Results: Chrysin reduced oxidative stress, increased cell viability, and promoted osteogenic differentiation in BMSCs exposed to high glucose. Blocking PI3K/ATK/Nrf2 signaling pathway weakened the beneficial effects of chrysin, indicating that chrysin at least partly worked through the PI3K/ATK/Nrf2 pathway. Conclusion: Chrysin can protect BMSCs from high glucose-induced oxidative stress via the activation of the PI3K/AKT/Nrf2 pathway, and promote bone regeneration in type 1 diabetic rats.

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Section: Discussionmentioning

confidence: 99%

Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway

Li¹,

Wang²

2022

DDDT

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“…This could lead to an increased rate of cell death and a consequent release of damage-associated molecular pattern (DAMP) from necrotic cells [54]. Released DAMPs may result in further activation of the inflammatory processes, thus contributing to a deterioration of bone healing [55]. However, the exact processes are currently purely speculative and they require further analysis.…”

Section: Discussionmentioning

confidence: 99%

The Induced Membrane Technique—The Filling Matters: Evaluation of Different Forms of Membrane Filling with and without Bone Marrow Mononuclear Cells (BMC) in Large Femoral Bone Defects in Rats

et al. 2022

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The Masquelet technique is used to treat large bone defects; it is a two-stage procedure based on an induced membrane. To improve the induced membrane process, demineralized bone matrix in granular (GDBM) and fibrous form (f-DBM) was tested with and without bone marrow mononuclear cells (BMC) as filling of the membrane against the gold standard filling with syngeneic cancellous bone (SCB). A total of 65 male Sprague–Dawley rats obtained a 5 mm femoral defect. These defects were treated with the induced membrane technique and filled with SCB, GDBM, or f-DBM, with or without BMC. After a healing period of eight weeks, the femurs were harvested and submitted for histological, radiological, and biomechanical analyses. The fracture load in the defect zone was lower compared to SCB in all groups. However, histological analysis showed comparable new bone formation, bone mineral density, and cartilage proportions and vascularization. The results suggest that f-DBM in combination with BMC and the induced membrane technique cannot reproduce the very good results of this material in large, non-membrane coated bone defects, nevertheless it supports the maturation of new bone tissue locally. It can be concluded that BMC should be applied in lower doses and inflammatory cells should be removed from the cell preparation before implantation.

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“…Recently, extensive studies have focused on the key role of inflammation in bone regeneration and bone related disease. Acute inflammation is the first step in bone regeneration and repair ( Goodman and Maruyama, 2020 ; Newman et al, 2021 ). However, when the endogenous adverse stimuli persist or the normal homeostatic mechanisms cannot resolve the injury, chronic inflammation occurs at the site of injury ( Goodman and Maruyama, 2020 ; Newman et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Acute inflammation is the first step in bone regeneration and repair ( Goodman and Maruyama, 2020 ; Newman et al, 2021 ). However, when the endogenous adverse stimuli persist or the normal homeostatic mechanisms cannot resolve the injury, chronic inflammation occurs at the site of injury ( Goodman and Maruyama, 2020 ; Newman et al, 2021 ). Chronic inflammation is detrimental to all tissues and organs, and it is a major driver of osteonecrosis ( Goodman and Maruyama, 2020 ; Chen et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Macrophages are heterogeneous cells that circulate in the blood or are concatenated in different organs and tissues; they constitute the first barrier against disease ( Loi et al, 2016 ; Garcia-Garcia and Martin, 2019 ; Yang et al, 2019 ; Goodman and Maruyama, 2020 ). Among immune cells, macrophages are the vital modulators of inflammation and can be programmed to pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes that allow them to fine-tune the regeneration and repair of tissues ( Ono and Takayanagi, 2017 ; Locati et al, 2020 ; Newman et al, 2021 ). Proinflammatory M1 macrophages secrete inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, which trigger an inflammatory cascade and establish a inflammatory microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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The Dynamic Feature of Macrophage M1/M2 Imbalance Facilitates the Progression of Non-Traumatic Osteonecrosis of the Femoral Head

Tan

Wang

Chen

et al. 2022

Front. Bioeng. Biotechnol.

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Non-traumatic osteonecrosis of the femoral head (NONFH) remains a common refractory disease with poorly understood pathogenesis. Macrophage M1/M2 imbalance and chronic inflammatory microenvironment have been suggested to be closely related to osteonecrosis. Here we describe direct visual evidence for the involvement of dynamic changes in macrophages and the chronic inflammatory microenvironment in human NONFH. Osteonecrosis induces inflammatory responses and macrophage enrichment in the reparative area, and the number of inflammatory cells and macrophages falls during progressive-to end-stage NONFH. Multiplex immunohistochemistry demonstrated that macrophage M1/M2 ratio increased from 3 to 10 during progressive-to end-stage. During the progressive-stage, new blood vessels formed in the reparative area, M2 macrophages accumulated in perivascular (M1/M2 ratio ∼0.05), while M1 macrophages were enriched in avascular areas (M1/M2 ratio ∼12). Furthermore, inflammatory cytokines were detected in synovial fluid and plasma using cytometric bead arrays. Interleukin (IL)-6 and IL-1β were persistently enriched in synovial fluid compared to plasma in patients with NONFH, and this difference was confirmed by immunohistochemistry staining. However, only IL-6 levels in plasma were higher in patients with progressive-stage NONFH than in osteoarthritis. Moreover, fibrosis tissues were observed in the necrotic area in progressive-stage and end-stage NONFH based on Sirius Red staining. Together, these findings indicate that macrophage M1/M2 imbalance facilitates the progression of NONFH, a chronic inflammatory disease characterized by chronic inflammation, osteonecrosis and tissue fibrosis in the local lesion. Inhibiting inflammation, promoting the resolution of inflammation, switching macrophages to an M2 phenotype, or inhibiting their adoption of an M1 phenotype may be useful therapeutic strategies against NONFH.

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Resolution of inflammation in bone regeneration: From understandings to therapeutic applications

Cited by 131 publications

References 186 publications

Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway

Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway

The Induced Membrane Technique—The Filling Matters: Evaluation of Different Forms of Membrane Filling with and without Bone Marrow Mononuclear Cells (BMC) in Large Femoral Bone Defects in Rats

The Dynamic Feature of Macrophage M1/M2 Imbalance Facilitates the Progression of Non-Traumatic Osteonecrosis of the Femoral Head

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