Human Rotator Cuff Tears Reveal an Age-Dependent Increase in Markers of Cellular Senescence and Selective Removal of Senescent Cells With Dasatinib + Quercetin Increases Genetic Expression of COL1A1 In Vitro.
Human Rotator Cuff Tears Reveal an Age-Dependent Increase in Markers of Cellular Senescence and Selective Removal of Senescent Cells With Dasatinib + Quercetin Increases Genetic Expression of COL1A1 In Vitro.
复制标题
人类肩袖撕裂揭示了细胞衰老标志物的年龄依赖性增加，并且用达沙替尼槲皮素选择性去除衰老细胞可增加体外 COL1A1 的基因表达。
DOI：
10.1016/j.arthro.2023.05.036
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Mazzocca,August
中科院分区：
文献类型：
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作者：
Hawthorne,BenjaminC;Wellington,IanJ;Sabitsky,JoshuaT;Murphy,KyleV;Karsmarski,OwenP;Thomas,RohinO;LeVasseur,MatthewR;Mancini,MichaelR;Trudeau,MaxwellT;Gulati,Sagar;McCarthy,MaryBethR;Cote,MarkP;Xu,Ming;Mazzocca,August
PurposeTo量化细胞衰老冈上肌腱和肩峰下囊的人肩袖撕裂和探讨体外疗效的senolytic达沙替尼+槲皮素（D+Q），以消除衰老细胞和改变tenogenic differentiation. MethodsTissues从41例（平均年龄，62岁）进行关节镜下肩袖修复收获。在第1部分（n = 35）中，使用免疫组织化学和衰老细胞标志物（p16和p21）和衰老相关分泌表型（SASP）（白细胞介素[IL] 6，IL-8，基质金属蛋白酶[MMP] 3，单核细胞趋化蛋白[MCP] 1）的基因表达定量衰老。比较<60岁和≥60岁患者的衰老情况。在第2部分（n = 6）中，用D+Q或对照品处理肩袖撕裂的体外模型。D+Q，化疗药物和植物黄烷醇，分别杀死衰老细胞。基因表达分析评估D+Q杀死衰老细胞和改变tenogenicdifferentiation.ResultsPart 1的标记物的能力揭示了年龄依赖性的p21，IL-6，IL-8的相对表达量显着增加肌腱和p21，p16，IL-6，IL-8，MMP-3在囊（P< .05）。法氏囊p21的免疫组化染色显著增加（P= 0.028）。第二部分D+Q显著降低肌腱中p21、IL-6和IL-8的表达以及法氏囊中p21和IL-8的表达（P<0.05）。酶联免疫吸附分析显示SASP的释放减少（IL-6，MMP-3，MCP-1;分别为P=.002，P =.024，P < .001）。D+Q处理的肌腱（P= 0.022）和法氏囊（P= 0.027）增加了COL 1A 1的表达。结论虽然细胞衰老标志物存在年龄依赖性增加，但这种关系在所有标志物和组织中并不一致。达沙替尼+槲皮素在降低这些组织的衰老和增加COL 1A 1 expression.Clinical RelevanceThis研究揭示了细胞衰老可能是改变肩袖生物老化的治疗靶点，并确定D+Q作为一种潜在的治疗方法。
PurposeTo quantify cellular senescence in supraspinatus tendon and subacromial bursa of humans with rotator cuff tears and to investigate the in vitro efficacy of the senolytic dasatinib + quercetin (D+Q) to eliminate senescent cells and alter tenogenic differentiation.MethodsTissue was harvested from 41 patients (mean age, 62 years) undergoing arthroscopic rotator cuff repairs. In part 1 (n = 35), senescence was quantified using immunohistochemistry and gene expression for senescent cell markers (p16 and p21) and the senescence-associated secretory phenotype (SASP) (interleukin [IL] 6, IL-8, matrix metalloproteinase [MMP] 3, monocyte chemoattractant protein [MCP] 1). Senescence was compared between patients <60 and ≥60 years old. In part 2 (n = 6) , an in vitro model of rotator cuff tears was treated with D+Q or control. D+Q, a chemotherapeutic and plant flavanol, respectively, kill senescent cells. Gene expression analysis assessed the ability of D+Q to kill senescent cells and alter markers of tenogenic differentiation.ResultsPart 1 revealed an age-dependent significant increase in the relative expression of p21, IL-6, and IL-8 in tendon and p21, p16, IL-6, IL-8, and MMP-3 in bursa (P< .05). A significant increase was seen in immunohistochemical staining of bursa p21 (P= .028). In part 2, D+Q significantly decreased expression of p21, IL-6, and IL-8 in tendon and p21 and IL-8 in bursa (P< .05). Enzyme-linked immunosorbent assay analysis showed decreased release of the SASP (IL-6, MMP-3, MCP-1;P= .002,P= .024,P< .001, respectively). Tendon (P= .022) and bursa (P= .027) treated with D+Q increased the expression of COL1A1.ConclusionsWhile there was an age-dependent increase in markers of cellular senescence, this relationship was not consistently seen across all markers and tissues. Dasatinib + quercetin had moderate efficacy in decreasing senescence in these tissues and increasing COL1A1 expression.Clinical RelevanceThis study reveals that cellular senescence may be a therapeutic target to alter the biological aging of rotator cuffs and identifies D+Q as a potential therapy.