Institute for Rheumatology Research, Hanyang University, Seoul 04763, Korea.
Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea.
Cells. 2021 Dec 10;10(12):3498. doi: 10.3390/cells10123498.
Aryl-hydrocarbon receptor (AhR) is a ligand-activated transcription factor and regulates differentiation and function of various immune cells such as dendritic cells, Th17, and regulatory T cells. In recent studies, it was reported that AhR is involved in bone remodeling through regulating both osteoblasts and osteoclasts. However, the roles and mechanisms of AhR activation in human osteoclasts remain unknown. Here we show that AhR is involved in human osteoclast differentiation. We found that AhR expressed highly in the early stage of osteoclastogenesis and decreased in mature osteoclasts. Kynurenine (Kyn), formylindolo[3,4-b] carbazole (FICZ), and benzopyrene (BaP), which are AhR agonists, inhibited osteoclast formation and Kyn suppressed osteoclast differentiation at an early stage. Furthermore, blockade of AhR signaling through CH223191, an AhR antagonist, and knockdown of AhR expression reversed Kyn-induced inhibition of osteoclast differentiation. Overall, our study is the first report that AhR negatively regulates human osteoclast differentiation and suggests that AhR could be good therapeutic molecule to prevent bone destruction in chronic inflammatory diseases such as rheumatoid arthritis (RA).
芳香烃受体 (AhR) 是一种配体激活的转录因子，可调节树突状细胞、Th17 和调节性 T 细胞等各种免疫细胞的分化和功能。最近的研究表明，AhR 通过调节成骨细胞和破骨细胞参与骨重塑。然而，AhR 激活在人类破骨细胞中的作用和机制尚不清楚。在这里，我们显示 AhR 参与人类破骨细胞分化。我们发现 AhR 在破骨细胞发生的早期阶段表达量高，而在成熟破骨细胞中表达量降低。AhR 激动剂色氨酸 (Kyn)、吲唑并[3,4-b]咔唑 (FICZ) 和苯并芘 (BaP) 抑制破骨细胞形成，Kyn 在早期抑制破骨细胞分化。此外，通过 AhR 拮抗剂 CH223191 阻断 AhR 信号通路和 AhR 表达的敲低可逆转 Kyn 诱导的破骨细胞分化抑制。总的来说，我们的研究首次报道 AhR 负调节人类破骨细胞分化，并表明 AhR 可能是预防类风湿关节炎 (RA) 等慢性炎症性疾病中骨破坏的良好治疗分子。
