Senolytics ameliorate the failure of bone regeneration through the cell senescence-related inflammatory signalling pathway

作者：Xinchen Wang, Yue Zhou, Chuyi Luo, Jianxin Zhao, Yuna Ji, Zheng Wang, Pengchao Zheng, Dingji Li, Yuhan Shi, Aki Nishiura, Naoyuki Matsumoto, Yoshitomo Honda, Baoshan Xu, Fang Huang · 发表于：Biomedicine & Pharmacotherapy · 年份：2024 · DOI：10.1016/j.biopha.2024.116606 · 被引用次数：15 · 研究领域：Telomeres, Telomerase, and Senescence、Advanced biosensing and bioanalysis techniques、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Stress-induced premature senescent (SIPS) cells induced by various stresses deteriorate cell functions. Dasatinib and quercetin senolytics (DQ) can alleviate several diseases by eliminating senescent cells. α-tricalcium phosphate (α-TCP) is a widely used therapeutic approach for bone restoration but induces bone formation for a comparatively long time. Furthermore, bone infection exacerbates the detrimental prognosis of bone formation during material implant surgery due to oral cavity bacteria and unintentional contamination. It is essential to mitigate the inhibitory effects on bone formation during surgical procedures. Little is known that DQ improves bone formation in Lipopolysaccharide (LPS)-contaminated implants and its intrinsic mechanisms in the study of maxillofacial bone defects. This study aims to investigate whether the administration of DQ ameliorates the impairments on bone repair inflammation and contamination by eliminating SIPS cells. α-TCP and LPS-contaminated α-TCP were implanted into Sprague-Dawley rat calvaria bone defects. Simultaneously, bone formation in the bone defects was investigated with or without the oral administration of DQ. Micro-computed tomography and hematoxylin-eosin staining showed that senolytics significantly enhanced bone formation at the defect site. Histology and immunofluorescence staining revealed that the levels of p21- and p16-positive senescent cells, inflammation, macrophages, reactive oxygen species, and tartrate-resistant aci...