Abstract：
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.
摘要：
由各种应激诱导的应激诱导的过早衰老(SIPS)细胞使细胞功能恶化。达沙替尼和槲皮素促性腺激素（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，但在相当长的时间内诱导骨形成。此外，由于口腔细菌和无意污染，骨感染会加剧材料植入手术中骨形成的不良预后。在外科手术过程中，必须减轻对骨形成的抑制作用。在颌面部骨缺损的研究中，鲜为人知的是，DQ可以改善脂多糖（LPS）污染的植入物中的骨形成及其内在机制。本研究旨在研究DQ的给药是否通过消除SIPS细胞来改善对骨修复炎症和污染的损害。将α-TCP和LPS污染的α-TCP植入Sprague-Dawley大鼠颅骨骨缺损中。同时,在口服或不口服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p21和p16阳性衰老细胞的水平，炎症,巨噬细胞，活性氧，服用DQ后，抗酒石酸酸性磷酸酶阳性细胞下降。DQ可以部分缓解体外衰老标记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再生。Senolyics在减少生物材料相关感染的不良成骨作用和改善骨形成能力方面具有显着的治疗潜力。
