Department of Orthopedics, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
Department of Orthopedics, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
Cell Signal. 2022 Jul;95:110353. doi: 10.1016/j.cellsig.2022.110353. Epub 2022 May 5.
Osteolysis caused by wear particles is the main reason for joint replacement failure. Inhibition of osteoclast differentiation relieves wear particle-induced osteolysis. Our study aimed to explore the effect of lncRNA maternally expressed gene 3 (MEG3) on osteoclast differentiation and wear particle-induced osteolysis, and to improve the potential mechanism of interleukin-10 (IL-10) inhibition on osteoclast differentiation.
Polymethylmethacrylate (PMMA) -induced osteolysis mice model and receptor activator of nuclear factor-B ligand (RANKL) -induced osteoclast differentiation model were constructed. Tartrate-resistant acidic phosphatase (TRAP) staining, hematoxylin-eosin (HE) staining, immunohistochemical staining, bone resorption assay, dual-luciferase assay, RNA pull-down assay, RNA immunoprecipitation, and chromatin immunoprecipitation were executed.
MEG3 levels were increased and interferon regulatory factor 8 (IRF8) levels were decreased in PMMA-induced osteolysis mice. IL-10 inhibited RANKL-induced osteoclast differentiation, promoted MEG3 methylation, and inhibited MEG3 expression. Moreover, knockdown of MEG3 inhibited osteoclast differentiation and increased IRF8 levels. Meanwhile, MEG3 combined with signal transducer and activator of transcription 1 (STAT1), STAT1 combined with IRF8, and overexpression of MEG3 inhibited STAT1 binding to IRF8. Further studies have shown that knockdown of MEG3 inhibited osteoclast differentiation and alleviated osteolysis, but knockdown of IRF8 weakened these results.
MEG3 regulated the expression of IRF8 by binding to STAT1, thereby affecting osteoclast differentiation and wear particle-induced osteolysis. IL-10 might inhibit osteoclast differentiation by MEG3/IRF8.
磨损颗粒引起的骨溶解是关节置换失败的主要原因。抑制破骨细胞分化可缓解磨损颗粒诱导的骨溶解。本研究旨在探讨长链非编码 RNA 母系表达基因 3（MEG3）对破骨细胞分化和磨损颗粒诱导的骨溶解的影响，并探讨白细胞介素 10（IL-10）抑制破骨细胞分化的潜在机制。
构建聚甲基丙烯酸甲酯（PMMA）诱导的骨溶解小鼠模型和核因子κB 受体激活剂配体（RANKL）诱导的破骨细胞分化模型。进行抗酒石酸酸性磷酸酶（TRAP）染色、苏木精-伊红（HE）染色、免疫组织化学染色、骨吸收试验、双荧光素酶报告基因实验、RNA 下拉实验、RNA 免疫沉淀实验和染色质免疫沉淀实验。
在 PMMA 诱导的骨溶解小鼠中，MEG3 水平升高，干扰素调节因子 8（IRF8）水平降低。IL-10 抑制 RANKL 诱导的破骨细胞分化，促进 MEG3 甲基化，抑制 MEG3 表达。此外，敲低 MEG3 抑制破骨细胞分化并增加 IRF8 水平。同时，MEG3 与信号转导和转录激活因子 1（STAT1）结合，STAT1 与 IRF8 结合，MEG3 过表达抑制 STAT1 与 IRF8 结合。进一步研究表明，敲低 MEG3 抑制破骨细胞分化并减轻骨溶解，但敲低 IRF8 削弱了这些结果。
MEG3 通过与 STAT1 结合调节 IRF8 的表达，从而影响破骨细胞分化和磨损颗粒诱导的骨溶解。IL-10 可能通过 MEG3/IRF8 抑制破骨细胞分化。
