Department of Orthopaedic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Guangzhou Saliai Stem Cell Science and Technology Co., LTD, Guangzhou, China.
Orthop Surg. 2023 Mar;15(3):888-898. doi: 10.1111/os.13608. Epub 2023 Jan 31.
Wear particles induce inflammation and the further osteolysis around the prosthesis, has been proven to be the main cause of aseptic hip joint loosening. In this research, we aimed to clarify whether human umbilical cord mesenchymal stem cells (HUCMSCs) could inhibit the titanium particles-induced osteolysis and shed light upon its mechanism.
The expression of chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5) were examinjed in clinical specimens of aseptic hip prosthesis loosening patients. Local injection of lentivirus that knocked down CCL2 or CCL3 in a cranial osteolysis mice model were used to exam the effect of CCL2 and CCL3 on titanium particles-induced osteolysis in vivo. Transwell assay was used to examine the effect of CCL2 and CCL3 on titanium particles-induced activation of macrophage in vitro. Furthermore, the therapeutic effect of HUCMSCs, and exosomes from HUCMSCs were also examed in vivo and vitro. Immunohistochemical and real-time PCR were used to examine the expression of relative pathways. Analysis of variance (ANOVA) and Student-Newman-Keuls post hoc t test were used to analyze the results and determine the statistical significance of the differences.
Results showed that titanium particles caused the osteolysis at the mice cranial in vivo and a large number of macrophages that migrated, while local injection of HUCMSCs and exosomes did inhibit the cranial osteolysis and migration. An exosome inhibitor GW4869 significantly increased the osteolysis area in the mice cranium osteolysis model, and increased the number of migrated macrophages. Immunohistochemical results suggested that the expression of CCL2, CCL3 and CD68 in the cranial in Titanium particles mice increased significantly, but was significantly reduced by HUCMSCs or exosomes. HUCMSC and exosomes down-regulate the expression of CCL3 in vitro and in vivo.
HUCMSCs and HUCMSC-derived exosomes could suppress the titanium particles-induced osteolysis in mice through inhibiting chemokine (C-C motif) ligand 2, chemokine (C-C motif) ligand 3.
磨损颗粒会引发炎症，进一步导致假体周围的骨溶解，这已被证明是无菌性髋关节松动的主要原因。本研究旨在阐明人脐带间充质干细胞（HUCMSCs）是否能抑制钛颗粒诱导的骨溶解，并探讨其机制。
检测无菌性髋关节假体松动患者临床标本中趋化因子（C-C 基序）配体 2（CCL2）、趋化因子（C-C 基序）配体 3（CCL3）和趋化因子（C-C 基序）配体 5（CCL5）的表达。利用颅骨骨溶解小鼠模型中敲低 CCL2 或 CCL3 的慢病毒局部注射，观察 CCL2 和 CCL3 对钛颗粒诱导骨溶解的体内作用。Transwell 检测 CCL2 和 CCL3 对钛颗粒诱导巨噬细胞体外激活的作用。此外，还在体内和体外研究了 HUCMSCs 和 HUCMSCs 来源的外泌体的治疗效果。免疫组化和实时 PCR 用于检测相关通路的表达。采用方差分析（ANOVA）和 Student-Newman-Keuls 事后 t 检验分析结果，确定差异的统计学意义。
结果显示，钛颗粒在体内引起小鼠颅骨骨溶解，并导致大量巨噬细胞迁移，而 HUCMSCs 和外泌体局部注射可抑制颅骨骨溶解和迁移。外泌体抑制剂 GW4869 显著增加了小鼠颅骨骨溶解模型中的骨溶解面积，并增加了迁移的巨噬细胞数量。免疫组化结果表明，钛颗粒小鼠颅骨中 CCL2、CCL3 和 CD68 的表达明显增加，但 HUCMSCs 或外泌体明显减少。HUCMSC 和外泌体在体外和体内均下调 CCL3 的表达。
HUCMSCs 和 HUCMSC 来源的外泌体可通过抑制趋化因子（C-C 基序）配体 2 和趋化因子（C-C 基序）配体 3 抑制钛颗粒诱导的小鼠骨溶解。
