Ji Wei, Lu Yueyang, Ma Zhuoyi, Gan Ke, Liu Yan, Cheng Yue, Xu Junliang, Liu Shijia, Guo Yunke, Han Shanhang, Zhao Zengyan, Xu Hanmei, Qi Weiyan
Department of Rheumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210033, Jiangsu, China.
J Orthop Translat. 2022 Sep 16;36:132-144. doi: 10.1016/j.jot.2022.05.007. eCollection 2022 Sep.
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.
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.
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.
Our study confirmed that triptolide targets circ-0110634 to ease the burden of AS patients.
This study suggests triptolide targets circ-0110634 to regulate osteoclastogenesis, which provides a novel potential target in triptolide treatment for AS patients.
强直性脊柱炎（AS）的特征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展的关键部分。环状RNA（circRNAs）是RNA领域最近的研究热点，而在破骨细胞生成中鲜有报道。
将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检测不同外泌体中circ-0110634的表达水平。进行抗酒石酸酸性磷酸酶（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，以探索circ-0110634的下游分子机制。
ASMSCs对PBMCs破骨细胞生成的影响弱于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与肿瘤坏死因子受体相关因子2（TRAF2）和肿瘤坏死因子受体II（TNFRII）均结合。Circ-0110634还加速TRAF2的二聚化以诱导TRAF2泛素化和降解。Circ-0110634抑制TRAF2与TNFRII之间的相互作用，从而使核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）通路失活。雷公藤甲素通过以剂量依赖的方式减少circ-0110634的外泌体转运，促进ASMSCs外泌体处理的PBMCs的破骨细胞生成。同样，雷公藤甲素治疗通过抑制circ-0110634刺激破骨细胞生成，以减轻DBA/1小鼠的关节炎。
我们的研究证实雷公藤甲素靶向circ-0110634以减轻AS患者的负担。
本研究表明雷公藤甲素靶向circ-0110634以调节破骨细胞生成，这为雷公藤甲素治疗AS患者提供了一个新的潜在靶点。
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