Targeting endoplasmic reticulum stress‐induced lymphatic dysfunction for mitigating bisphosphonate‐related osteonecrosis

作者：Ziyue Qin, Hanyu Xie, Pengcheng Su, Zesheng Song, Rongyao Xu, Songsong Guo, Yu Fu, Ping Zhang, Hongbing Jiang · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.70082 · 被引用次数：10 · 研究领域：Bone health and treatments、Oral health in cancer treatment、Bone and Joint Diseases

Abstract Background Bisphosphonates (BPs) are the first‐line treatment to stop bone resorption in diseases, including osteoporosis, Paget's disease, multiple myeloma and bone metastases of cancer. However, BPs‐related osteonecrosis of the jaw (BRONJ), characterized by local inflammation and jawbone necrosis, is a severe intractable complication. The cumulative inflammatory burden often accompanies impaired lymphatic drainage, but its specific impact on BRONJ and the underlying mechanisms remain unclear. Methods The mouse BRONJ model was established to assess the integrity and drainage function of lymphatic vessels by tissue clearing techniques, injected indocyanine green lymphatic clearance assay, flow cytometry analysis and histopathological staining. RNA sequencing, metabolome analysis, transmission electron microscopy and Western blotting were utilized to analyze the impacts of Zoledronate acid (ZA) on endoplasmic reticulum stress (ERS) and function of lymphatic endothelial cells (LECs). By constructing Lyve1 creERT ; SIRT6 f/f and Lyve1 creERT ; ATG5 f/f mice, we evaluated the role of ERS‐induced LECs apoptosis in the progression of BRONJ. Additionally, we developed a nanoparticle‐loaded ZA and rapamycin (ZDPR) to enhance autophagy and evaluated its potential in mitigating BRONJ. Results The mouse BRONJ model displayed impaired lymphatic drainage, accompanied by significant local inflammation and bone necrosis. The prolonged stimulation of ZA resulted in the extension of ...