Background Ankylosing spondylitis (AS) is featured by chronic inflammation of the sacroiliac joints and spine as well as pathological new bone formation. Osteoclastogenesis is a critical part in the development of bone formation. Circular RNAs (circRNAs) are recent research hotspot in the RNA field while rarely reported in osteoclastogenesis. Methods AS mesenchymal stem cells (ASMSCs) and healthy donor mesenchymal stem cells (HDMSCs) were co-cultured with peripheral blood mononuclear cells (PBMCs). RT-qPCR was applied to detect the expression level of circ-0110634 in different exosomes. TRAP staining and TRAP activity detection were performed to identify the effect of circ-0110634 overexpression on osteoclastogenesis. Bioinformatics analysis and mechanism investigation were conducted to explore the downstream molecular mechanism of circ-0110634. Results The effect of ASMSCs on PBMCs osteoclastogenesis is weaker than that of HDMSCs. Circ-0110634 had higher expression in ASMSCs exosomes than HDMSCs exosomes. Circ-0110634 overexpression suppressed the osteoclastogenesis. Circ-0110634 bound to both TNF receptor associated factor 2 (TRAF2) and tumor necrosis factor receptor II (TNFRII). Circ-0110634 also accelerated the dimerization of TRAF2 to induce TRAF2 ubiquitination and degradation. Circ-0110634 repressed the interplay between TRAF2 and TNFRII to inactivate the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) pathways. Triptolide promoted the osteoclastogenesis of ASMSCs exosomes-treated PBMCs via decreasing the exosomal transference of circ-0110634 in a dose-dependent manner. Consistently, triptolide treatment stimulated osteoclastogenesis to alleviate the arthritis of DBA/1 mice through suppressing circ-0110634. Conclusion Our study confirmed that triptolide targets circ-0110634 to ease the burden of AS patients. The Translational potential of this article This study suggests triptolide targets circ-0110634 to regulate osteoclastogenesis, which provides a novel potential target in triptolide treatment for AS patients.

中文翻译：

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雷公藤甲素通过调节 circ-0110634 的外泌体转移减弱强直性脊柱炎衍生的间充质干细胞对破骨细胞生成的抑制作用。

背景强直性脊柱炎（AS）的特点是骶髂关节和脊柱的慢性炎症以及病理性新骨形成。破骨细胞生成是骨形成发育的关键部分。环状RNA（circRNAs）是近年来RNA领域的研究热点，而在破骨细胞生成中却鲜有报道。方法AS间充质干细胞（ASMSCs）和健康供体间充质干细胞（HDMSCs）与外周血单个核细胞（PBMCs）共培养。应用 RT-qPCR 检测 circ-0110634 在不同外泌体中的表达水平。进行 TRAP 染色和 TRAP 活性检测以确定 circ-0110634 过表达对破骨细胞生成的影响。进行生物信息学分析和机制研究，探索circ-0110634的下游分子机制。结果ASMSCs对PBMCs破骨细胞生成的作用弱于HDMSCs。Circ-0110634 在 ASMSCs 外泌体中的表达高于 HDMSCs 外泌体。Circ-0110634 过表达抑制破骨细胞生成。Circ-0110634 与 TNF 受体相关因子 2 (TRAF2) 和肿瘤坏死因子受体 II (TNFRII) 结合。Circ-0110634 还加速了 TRAF2 的二聚化以诱导 TRAF2 泛素化和降解。Circ-0110634 抑制了 TRAF2 和 TNFRII 之间的相互作用，使核因子-κB (NF-κB) 和丝裂原活化蛋白激酶 (MAPK) 通路失活。雷公藤内酯通过以剂量依赖性方式减少 circ-0110634 的外泌体转移来促进 ASMSCs 外泌体处理的 PBMC 的破骨细胞生成。始终如一，雷公藤甲素治疗刺激破骨细胞生成，通过抑制 circ-0110634 来缓解 DBA/1 小鼠的关节炎。结论 我们的研究证实雷公藤甲素靶向 circ-0110634 可减轻 AS 患者的负担。本文的转化潜力 本研究建议雷公藤甲素靶向circ-0110634来调节破骨细胞生成，这为雷公藤甲素治疗AS患者提供了一个新的潜在靶点。