Exogenous adenosine activates A2A adenosine receptor to inhibit RANKL-induced osteoclastogenesis via AP-1 pathway to facilitate bone repair.
Exogenous adenosine activates A2A adenosine receptor to inhibit RANKL-induced osteoclastogenesis via AP-1 pathway to facilitate bone repair.
复制标题
外源性腺苷激活A2A腺苷受体，通过AP-1途径抑制RANKL诱导的破骨细胞生成，促进骨修复。
DOI：
10.1007/s11033-021-07017-1
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发表时间：
2021
影响因子：
2.8
通讯作者：
Li Zubing
中科院分区：
文献类型：
--
作者：
Cheng Xin;Yin Chengcheng;Deng Yongqiang;Li Zubing
背景腺苷是一种嘌呤核苷，通过与A1、A2 A、A2 B和A3腺苷受体（分别为A1 R、A2 AR、A2 BR和A3 R）结合参与调节骨稳态。然而，腺苷和受体亚型调节破骨细胞分化的潜在机制仍然不确定。本研究旨在评估外源性腺苷及其受体亚型在NF-κB配体受体激活因子（RANKL）诱导的破骨细胞形成中的作用，并探讨其潜在的分子机制.Methods and resultsThe nanofibrical mat incorporated with adenosine showed robust ability to facilitate rat critical size calvarial defect healthy with reduced number of osteoclasts.此外，外源性腺苷显著增强A2 AR的表达，抑制抗酒石酸酸性磷酸酶阳性破骨细胞的形成和破骨细胞相关基因Ctsk、NFATc 1、MMP 9和ACP 5的表达。在RAW264.7细胞中加入A2 AR拮抗剂ZM 241385可逆转这种增强和抑制作用。最后，RNA测序显示，在RANKL处理的RAW 264. 7细胞中，通过腺苷刺激，Fos相关抗原2（Fra 2）的表达明显下调。根据实时PCR，Western blot，和免疫荧光analyses.ConclusionsThese研究结果表明，外源性腺苷结合A2 AR衰减破骨细胞分化通过抑制活化蛋白-1（AP-1，包括Fra 2亚基）途径在体外和体内。
BackgroundAdenosine is a purine nucleoside involved in regulating bone homeostasis through binding to A1, A2A, A2B, and A3 adenosine receptors (A1R, A2AR, A2BR, and A3R, respectively). However, the underlying mechanisms by which adenosine and receptor subtypes regulate osteoclast differentiation remain uncertain. This study aims to assess the role of exogenous adenosine and receptor subtypes in receptor activator of NF-κB ligand (RANKL)-induced osteoclast formation and explore the underlying molecular mechanisms.Methods and resultsThe nanofibrous mats incorporated with adenosine exhibited robust ability to facilitate rat critical-size calvarial defect healing with decreased number of osteoclasts. Moreover, exogenous adenosine substantially enhanced the expression of A2AR and suppressed tartrate-resistant acid phosphatase-positive osteoclast formation and expression of osteoclast-related genes Ctsk, NFATc1, MMP9, and ACP5. This enhancement and suppression could be reversed by adding an A2AR antagonist, ZM241385, in RAW264.7 cells. Finally, RNA sequencing showed that the expression of Fos-related antigen 2 (Fra2) was distinctly downregulated through stimulation of adenosine in RAW264.7 cells treated with RANKL. This downregulation was reversed by ZM241385 according to real-time PCR, Western blot, and immunofluorescence analyses.ConclusionsThese findings demonstrated that exogenous adenosine binding to A2AR attenuated osteoclast differentiation via the inhibition of activating protein-1 (AP-1, including Fra2 subunit) pathway both in vitro and in vivo.