Inhibition of Nf-ҝb prevents trauma-induced heterotopic ossification in rat model

Ju, Jinyong; Yu, Du; Xue, Feng; Zhao, Yong; Shi, Weizhe; Pan, Mingxin; Guo, Tan; Xiao, Haijun

doi:10.1080/03008207.2018.1530771

Cited by 10 publications

(11 citation statements)

References 21 publications

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“…However, after SRT1720 HCI treatment, acetylated NFkB p65 expression was largely weakened, paralleled by the reduced macrophage and mast cell presence and consistent with the assumption that the immunomodulatory effects of SIRT1 may be due to altered NFkB signaling. In accordance with this finding, prolonged NFkB pathway activation was found in monocytes and macrophages from FOP patients (16), and pharmacological inhibition of canonical NFkB signaling also abrogated HO in a rat brain-traumatic/burn/tenotomy model (54). Altogether, we showed that impaired SIRT1/NFkB signaling was responsible for aberrant immunity during HO development.…”

Section: Discussionsupporting

confidence: 84%

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

Sun

Luo

et al. 2021

Front. Immunol.

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Heterotopic ossification (HO) is one of the most intractable disorders following musculoskeletal injury and is characterized by the ectopic presence of bone tissue in the soft tissue leading to severe loss of function in the extremities. Recent studies have indicated that immune cell infiltration and inflammation are involved in aberrant bone formation. In this study, we found increased monocyte/macrophage and mast cell accumulation during early HO progression. Macrophage depletion by clodronate liposomes and mast cell stabilization by cromolyn sodium significantly impeded HO formation. Therefore, we proposed that the dietary phytochemical quercetin could also suppress immune cell recruitment and related inflammatory responses to prevent HO. As expected, quercetin inhibited the monocyte-to-macrophage transition, macrophage polarization, and mast cell activation in vitro in a dose-dependent manner. Using a murine burn/tenotomy model, we also demonstrated that quercetin attenuated inflammatory responses and HO in vivo. Furthermore, elevated SIRT1 and decreased acetylated NFκB p65 expression were responsible for the mechanism of quercetin, and the beneficial effects of quercetin were reversed by the SIRT1 antagonist EX527 and mimicked by the SIRT agonist SRT1720. The findings in this study suggest that targeting monocyte/macrophage and mast cell activities may represent an attractive approach for therapeutic intervention of HO and that quercetin may serve as a promising therapeutic candidate for the treatment of trauma-induced HO by modulating SIRT1/NFκB signaling.

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Section: Discussionsupporting

confidence: 84%

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

Sun

Luo

et al. 2021

Front. Immunol.

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“…In line with these findings, prior studies also determined NF-𝜅B is signaling to be imperative for the cellular senescence within the degenerative rotator cuff and HO formation within the rat traumatic HO model. [55,56] Certain limitations are involved in this study. First, Though the significance of cellular senescence in HO formation after soft tissue injury was validated in this study, how senescent cells drive the aberrant osteochondral healing and HO formation need to be carefully probed in the future study; Second, HMGB1 might not be the sole effect-mediating molecule of the pyroMϕ-EVs, thus other components of EVs that should be further searched with the help of some high-throughput methods through HMGB1 was also screened and ranked top in the previously reported proteomic results.…”

Section: Discussionmentioning

confidence: 99%

NLRP3‐Dependent Crosstalk between Pyroptotic Macrophage and Senescent Cell Orchestrates Trauma‐Induced Heterotopic Ossification During Aberrant Wound Healing

Li,

Wang,

Yao

et al. 2023

Advanced Science

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Heterotopic ossification (HO) represents an unwanted ossific wound healing response to the soft tissue injury which caused catastrophic limb dysfunction. Recent studies established the involvement of inflammation and cellular senescence in the tissue healing process, though their role in HO still remained to be clarified. Here, a novel crosstalk where the pyroptotic macrophages aroused tendon‐derived stem cells (TDSCs) senescence is revealed to encourage osteogenic healing during trauma‐induced HO formation. Macrophage pyroptosis blockade reduces the senescent cell burden and HO formation in NLRP3 knockout mice. Pyroptosis‐driven IL‐1β and extracellular vesicles (EVs) secretion from macrophages are determined to motivate TDSCs senescence and resultant osteogenesis. Mechanistically, pyroptosis in macrophages enhances the exosomal release of high mobility group protein 1 (HMGB1), which directly bounds TLR9 in TDSCs to trigger morbid signaling. NF‐κB signaling is confirmed to be the converging downstream pathway of TDSCs in response to HMGB1‐containing EVs and IL‐1β. This study adds insights into aberrant regeneration‐based theory for HO formation and boosts therapeutic strategy development.

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“…In additions, the nuclear transcription factor peroxisome-proliferator-activated receptor-gamma (PPAR-γ) has been found expressed in both osteoblasts and adipocytes, as well as in mesenchymal stem cells, suggesting its crucial role in regulating adipocyte formation and osteoblast development. In addition, Ju et al found that in models of heterotopic ossification such as traumatic brain injury/burn/tenotomy, the NF-kB/p53 signaling pathway plays an important role in the occurrence and development of heterotopic ossification, and ammonium pyrrolidine dithiocarbamate Pharmacological inhibition of NF-kB signaling pathway (PDTC) can significantly reduce the expression level of p53 and the size of heterotopic ossification (32).…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Study: Reveal the Mechanisms of Palovarotene Against Heterotopic Ossification

et al. 2022

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Heterotopic ossification (HO) occurs when bone forms within non-ossifying tissues, such as in muscle. Palovarotene, an activator of retinoic acid receptor γ (RAR-γ), has been shown to inhibit the formation of ectopic bone in HO model mice, but its specific mechanism of action remains unclear. This study will explore the target and molecular mechanism of Palovarotene's action on HO by network pharmacology study. We collected the relevant targets of Palovarotene and HO from the database, obtained the potential targets of Palovarotene acting on HO through Venn analysis, and constructed the protein-protein interaction (PPI) network. Then, Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment Analysis and Module-based Network Analysis were performed for potential targets, and in addition, PPI Network Topology Analysis and Gene-Phenotype Correlation Analysis were performed. The results suggested that MAPK1, MDM2, and other targets as well as P53 signaling pathway and PI3K–Akt signaling pathway may be closely related to Palovarotene treatment of HO. We carried out verification experiments to confirm our finding, alkaline phosphatase and alizarin red staining in vitro and Micro-CT as well as hematoxylin-eosin staining in vivo were performed to verify treatment for HO of Palovarotene, reverse transcription polymerase chain reaction was also used to explore the transcription changes of MAPK1, MDM2, and osteogenic genes. This study systematically elucidated the possible mechanism of Palovarotene in the treatment of HO through network pharmacology study, revealing a new direction for the further application of Palovarotene in the treatment of HO.

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Inhibition of Nf-ҝb prevents trauma-induced heterotopic ossification in rat model

Cited by 10 publications

References 21 publications

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

NLRP3‐Dependent Crosstalk between Pyroptotic Macrophage and Senescent Cell Orchestrates Trauma‐Induced Heterotopic Ossification During Aberrant Wound Healing

A Network Pharmacology Study: Reveal the Mechanisms of Palovarotene Against Heterotopic Ossification

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