<br>Senolytics 通过细胞衰老相关的炎症信号通路改善骨再生失败,Biomedicine & Pharmacotherapy

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Senolytics 通过细胞衰老相关的炎症信号通路改善骨再生失败
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2024-04-25 , DOI: 10.1016/j.biopha.2024.116606
Xinchen Wang ₁ , Yue Zhou ₂ , Chuyi Luo ₃ , Jianxin Zhao ₃ , Yuna Ji ₄ , Zheng Wang ₄ , Pengchao Zheng ₄ , Dingji Li ₄ , Yuhan Shi ₄ , Aki Nishiura ₃ , Naoyuki Matsumoto ₃ , Yoshitomo Honda ₅ , Baoshan Xu ₄ , Fang Huang ₄

Affiliation

由各种压力诱导的应激诱导的早衰（SIPS）细胞会使细胞功能恶化。达沙替尼和槲皮素（DQ）可以通过消除衰老细胞来缓解多种疾病。α-磷酸三钙（α-TCP）是一种广泛使用的骨修复治疗方法，但诱导骨形成的时间相对较长。此外，由于口腔细菌和无意污染，骨感染加剧了材料植入手术期间骨形成的不良预后。在外科手术过程中减轻对骨形成的抑制作用至关重要。在颌面骨缺损研究中，DQ 可改善脂多糖（LPS）污染的植入物及其内在机制，知之甚少。本研究旨在探讨 DQ 的给药是否通过消除 SIPS 细胞来改善骨骼修复、炎症和污染的损害。将 α-TCP 和 LPS 污染的 α-TCP 植入 Sprague-Dawley 大鼠颅骨缺损中。同时，在有或没有口服 DQ 的情况下研究骨缺损中的骨形成。显微计算机断层扫描和苏木精-伊红染色显示，senolytics 显着增强了缺损部位的骨形成。组织学和免疫荧光染色显示，DQ 后 p21 和 p16 阳性衰老细胞、炎症、巨噬细胞、活性氧和抗酒石酸盐酸性磷酸酶阳性细胞水平下降。DQ 可以在体外部分缓解衰老标志物和衰老相关分泌表型的产生。这项研究表明，LPS 污染的基于 α-TCP 的生物材料可以诱导细胞衰老并阻碍骨骼再生。Senolytics 在减少生物材料相关感染的不良成骨作用和提高骨形成能力方面具有显着的治疗潜力。

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

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 acid phosphatase-positive cells declined after administering DQ. DQ could partially alleviate the production of senescent markers and senescence-associated secretory phenotypes in vitro. This study indicates that LPS-contaminated α-TCP-based biomaterials can induce cellular senescence and hamper bone regeneration. Senolytics have significant therapeutic potential in reducing the adverse osteogenic effects of biomaterial-related infections and improving bone formation capacity.

更新日期：2024-04-25

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