Targeting APJ drives BNIP3-PINK1-PARKIN induced mitophagy and improves systemic inflammatory bone loss

Wentao Wang; Qing Wang; Wenming Li; Hao Xu; Xiaolong Liang; Wei Wang; Ning Li; Huilin Yang; Yaozeng Xu; Jiaxiang Bai; Shuli Yang; Dechun Geng

doi:10.1016/j.jare.2024.12.033

Targeting APJ drives BNIP3-PINK1-PARKIN induced mitophagy and improves systemic inflammatory bone loss

J Adv Res. 2024 Dec 24:S2090-1232(24)00611-8. doi: 10.1016/j.jare.2024.12.033. Online ahead of print.

Authors

Wentao Wang¹, Qing Wang¹, Wenming Li¹, Hao Xu¹, Xiaolong Liang¹, Wei Wang¹, Ning Li², Huilin Yang¹, Yaozeng Xu¹, Jiaxiang Bai³, Shuli Yang⁴, Dechun Geng⁵

Affiliations

¹ Department of Orthopaedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China.
² Department of Orthopedics, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230022, China.
³ Department of Orthopedics, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230022, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, China. Electronic address: jxbai1995@ustc.edu.cn.
⁴ College of Clinical Medicine, Suzhou Vocational Health College, 215009, No.28 Kehua Road, Suzhou city, China. Electronic address: shlyang@szhct.edu.cn.
⁵ Department of Orthopaedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China. Electronic address: szgengdc@suda.edu.cn.

PMID: 39725007
DOI: 10.1016/j.jare.2024.12.033

Abstract

Introduction: Inflammatory diseases, such as diabetes mellitus, rheumatoid arthritis, and inflammatory bowel disease, lead to systemic immune microenvironment disturbances, contributing to bone loss, yet the mechanisms by which specific receptors regulate this process in inflammatory bone loss remain poorly understood. As a G-protein-coupled receptor, the Apelin receptor plays a crucial role in the regulation of inflammation and immune microenvironment. However, the precise mechanisms governing its role in inflammatory bone loss remain incompletely understood.

Objective: This study aims to investigate how APJ regulates macrophage polarization to mitigate inflammatory bone loss.

Methods: Lipopolysaccharide induced systemic inflammatory bone loss model in mice was used to explore the relationship between bone loss and osteoclast activation, macrophage polarization and APJ. In vitro studies, Bone marrow derived macrophages and siRNA were used to elucidate the regulatory influence of APJ on the immune microenvironment and osteoclast differentiation, while high-throughput sequencing is leveraged to uncover the underlying mechanisms through which APJ modulates macrophage polarization.

Results: Our study established a link between APJ and macrophage M1 polarization in systemic inflammatory bone loss mice. The activation of APJ effectively mitigated M1 polarization in macrophages, suppressed excessive osteoclast activation, and alleviated systemic inflammatory bone loss. In vitro high-throughput sequencing analysis revealed that APJ modulates macrophage polarization, linking to mitochondrial autophagy and the NOD-like receptor signaling pathway and the involvement of the AMPK and MAPK signaling pathways in signal transduction after APJ activation was also suggested. Subsequent experiments substantiated that APJ predominantly enhances mitophagy and diminishes the accumulation of reactive oxygen species by regulating the AMPK/BNIP3/PINK1/PARKIN axis, thereby suppressing the activation of macrophage M1 polarization and osteoclastogenesis.

Conclusion: This study elucidated the underlying mechanism by which APJ modulates macrophage polarization, thereby proposing a new therapeutic target for addressing inflammatory bone loss.

Keywords: APJ; Bone immune microenvironment; Macrophage polarization; Mitophagy.