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Angiopoietin 1 Relieves Osteolysis by Promoting Macrophage Mitophagy Through the TBK1-SQSTM1 Pathway to Inhibit AIM2 Inflammasome-Mediated Pyroptosis

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Abstract

Osteolysis resulting from wear particles and subsequent aseptic loosening is a leading cause of revision surgery of artificial joints. The underlying pathogenesis of particle-induced osteolysis (PPO) has remained largely uncertain. Addressing how to mitigate osteolysis caused by wear particles presents a significant challenge for orthopedic surgeons. This study aimed to explore the molecular mechanism by which Angiopoietin (Ang-1) inhibits osteoclast activation to alleviate osteolysis. RAW264.7 mouse macrophages were stimulated with LPS or RANKL to induce osteoclast formation. Additionally, titanium (Ti) particles (50 mg) were subperiosteally implanted around the cranial suture of mice to establish a calvarial osteolysis model. Ang-1, a member of the pro-angiogenic factor protein family and an important inflammatory regulator molecule, was utilized in this model. TRAP staining was utilized to detect osteoclast activation, while a western blot was conducted to identify key proteins associated with mitophagy and pyroptosis. Scanning electron microscopy was employed to observe the morphology and dimensions of Ti particles. Additionally, a combination of micro-CT, H&E, Masson’s trichrome, and immunohistochemical staining techniques were applied to analyze the calvarial samples. Results indicated that Ang-1 could inhibit LPS- or RANKL-induced osteoclastogenesis and alleviate Ti particle–induced calvarial osteolysis in mice. TBK-1, a key signaling molecule involved in initiating mitophagy, was found to be mechanistically enhanced by Ang-1 through promoting TBK-1 phosphorylation in macrophages. This process inhibited AIM2 inflammasome-mediated pyroptosis and impeded osteoclastogenesis. Overall, this research uncovers a novel mechanism by which Ang-1 can attenuate inflammatory osteolysis, potentially offering a new therapeutic approach for PPO.

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Data Availability

The data that support the findings of this study are available from the corresponding author, (Jinzhong Ma), upon reasonable request.

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Funding

This work is supported by grants from the National Natural Science Foundation of China (grant numbers 81871795 and 82172411).

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  1. Jian Yin and Peng Lai contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, Shanghai General Hospital of Nanjing Medical University, Songjiang, Shanghai, 201600, China

    Jian Yin & Jinzhong Ma

  2. Department of Orthopedics, the Affiliated Jiangning Hospital With Nanjing Medical University, Nanjing, 211100, China

    Jian Yin & Jinzhong Ma

  3. Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Songjiang, Shanghai, 201600, China

    Peng Lai, Libo Zhu & Jinzhong Ma

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Contributions

All authors contributed to the study’s conception and design. Jian Yin: software, methodology, conceptualization, validation, and writing—original draft and review and editing. Peng Lai: investigation, conceptualization, visualization, and writing—original draft and review and editing. Libo Zhu: writing—review and editing. Jinzhong Ma: conceptualization, supervision, writing—review and editing, project administration, and funding acquisition.

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Correspondence to Jinzhong Ma.

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The animal study protocol was approved by the Ethics Committee of Nanjing Medical University (Nanjing, China) and Shanghai General Hospital (Shanghai, China) and was conducted under the guidelines of the National Institute of Health Guide for the Care and Use of Laboratory Animals.

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Yin, J., Lai, P., Zhu, L. et al. Angiopoietin 1 Relieves Osteolysis by Promoting Macrophage Mitophagy Through the TBK1-SQSTM1 Pathway to Inhibit AIM2 Inflammasome-Mediated Pyroptosis. Appl Biochem Biotechnol (2024). https://doi.org/10.1007/s12010-024-04961-z

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