Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
Department of Orthopedics, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, China.
Int J Biochem Cell Biol. 2020 Apr;121:105703. doi: 10.1016/j.biocel.2020.105703. Epub 2020 Jan 31.
The renin-angiotensin system contributes to the pathogenesis of rheumatoid arthritis, but that the mechanism is unclear. This study aims to investigate the effect of angiotensin II (Ang II) on osteogenic differentiation of synoviocytes and the underlying mechanism. Ang II was showed to inhibite osteogenic differentiation of synoviocytes, which was mitigated by a Dickkopf-1 (DKK-1) inhibitor. DKK-1 was upregulated by Ang II, which was weakened by the Ang II type 1 receptor (AT1R) blocker, reactive oxygen species (ROS) scavenger, and p38 inhibitor. Ang II increased the levels of AT1R, ROS, and NADPH oxidase (NOX), and the upregulations were mitigated by the AT1R blocker or NOX inhibitor. Furthermore, Ang II activated the p38 pathway, which was blocked by the AT1R blocker, ROS scavenger, or siRNA-MKK3. In brief, these results indicate that Ang II upregulates NOX expression and ROS production via AT1R, activates the MKK3/p38 signaling, and in turn upregulates DKK-1 expression, participating in the inhibition of osteogenic differentiation of synoviocytes.
肾素-血管紧张素系统（renin-angiotensin system）参与类风湿关节炎（rheumatoid arthritis）的发病机制，但具体机制尚不清楚。本研究旨在探讨血管紧张素 II（angiotensin II，Ang II）对滑膜细胞成骨分化的影响及其潜在机制。结果表明，Ang II 抑制滑膜细胞的成骨分化，而 Dickkopf-1（DKK-1）抑制剂可减轻这种抑制作用。Ang II 上调了 DKK-1 的表达，这种上调作用被 Ang II 型 1 受体（angiotensin II type 1 receptor，AT1R）阻滞剂、活性氧（reactive oxygen species，ROS）清除剂和 p38 抑制剂减弱。Ang II 增加了 AT1R、ROS 和 NADPH 氧化酶（NADPH oxidase，NOX）的水平，而 AT1R 阻滞剂或 NOX 抑制剂可减轻这种上调作用。此外，Ang II 激活了 p38 通路，该通路被 AT1R 阻滞剂、ROS 清除剂或 MKK3 siRNA 阻断。综上所述，这些结果表明，Ang II 通过 AT1R 上调 NOX 表达和 ROS 产生，激活 MKK3/p38 信号通路，进而上调 DKK-1 表达，参与抑制滑膜细胞的成骨分化。
