Targeting endoplasmic reticulum stress-induced lymphatic dysfunction for mitigating bisphosphonate-related...

Area of Science:

• Biomedical research
• Cell biology
• Pathology

Background:

• Bisphosphonates (BPs) are crucial for treating bone resorption disorders.
• Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication characterized by inflammation and jawbone necrosis.
• The role of impaired lymphatic drainage in BRONJ pathogenesis is not well understood.

Purpose of the Study:

• To investigate the impact of impaired lymphatic drainage on BRONJ.
• To elucidate the mechanisms underlying Zoledronate acid (ZA)-induced damage to lymphatic endothelial cells (LECs).
• To evaluate a novel nanoparticle therapy for mitigating BRONJ.

Main Methods:

• Established a mouse model of BRONJ to assess lymphatic function.
• Utilized tissue clearing, lymphatic clearance assays, flow cytometry, and histopathology.
• Employed RNA sequencing, metabolomics, electron microscopy, and Western blotting to analyze ZA's effects on LECs.
• Generated conditional knockout mice to study the roles of SIRT6 and ATG5.
• Developed and tested nanoparticle-loaded ZA and rapamycin (ZDPR) for BRONJ treatment.

Main Results:

• BRONJ model exhibited impaired lymphatic drainage, inflammation, and bone necrosis.
• ZA induced endoplasmic reticulum stress (ERS) and inhibited autophagy in LECs, leading to apoptosis.
• ZA activated the NAD+/SIRT6/XBP1s pathway, causing ERS-induced apoptosis in LECs.
• Deletion of SIRT6 or ATG5 exacerbated lymphatic dysfunction and inflammation in BRONJ.
• ZDPR nanoparticles alleviated ERS-apoptosis in LECs and improved lymphatic function, resolving inflammation.

Conclusions:

• The NAD+/SIRT6/XBP1s pathway mediates ERS-induced apoptosis in ZA-treated LECs.
• Impaired lymphatic drainage exacerbates BRONJ.
• ZDPR nanoparticles show therapeutic potential by restoring endothelial function and lymphatic drainage, effectively mitigating BRONJ.