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

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.