1. Academic Validation
  2. Isoquercitrin attenuates the osteoclast-mediated bone loss in rheumatoid arthritis via the Nrf2/ROS/NF-κB pathway

Isoquercitrin attenuates the osteoclast-mediated bone loss in rheumatoid arthritis via the Nrf2/ROS/NF-κB pathway

  • Biochim Biophys Acta Mol Basis Dis. 2023 Dec 6:166977. doi: 10.1016/j.bbadis.2023.166977.
Yan Liu 1 Tian-Qi Li 2 Jin Bai 2 Wei-Li Liu 2 Zi-Rou Wang 2 Chong Feng 2 Ling-Ling Pu 3 Xin-Xing Wang 4 Hui Liu 5
Affiliations

Affiliations

  • 1 Lanzhou University, Lanzhou 730000, China; Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
  • 2 Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
  • 3 Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China. Electronic address: pulingling@163.com.
  • 4 Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China. Electronic address: wxxemail@sina.cn.
  • 5 Lanzhou University, Lanzhou 730000, China. Electronic address: liuhui@lzu.edu.cn.
Abstract

An excess of osteoclastogenesis significantly contributes to the development of rheumatoid arthritis (RA). Activation of the nuclear factor erythroid-2 related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) ligand (RANKL)-induced Reactive Oxygen Species (ROS)-to-NF-κB signaling cascade are important mechanisms regulating osteoclastogenesis; however, whether Nrf2 is involved in RANKL-induced NF-κB activation is controversial. Isoquercitrin, a natural flavonoid compound, has been shown to have Nrf2-dependent antioxidant effects inprevious studies. We sought to verify whether isoquercitrin could modulate RANKL-induced NF-κB activation by activating Nrf2, thereby affecting osteoclastogenesis. Tartrate-resistant Acid Phosphatase staining, F-actin ring staining and resorption pit assay suggested that isoquercitrin significantly inhibited osteoclastogenesis and osteolytic function. Mitosox staining showed that RANKL-induced ROS generation was significantly inhibited by isoquercitrin from day 3 of the osteoclast differentiation cycle. Quantitative Real-Time PCR, Western blot, and immunofluorescence indicated that isoquercitrin activated the Nrf2 signaling pathway and inhibited NF-κB expression. And when we used the Nrf2-specific inhibitor ML385, the inhibition of NF-κB by isoquercitrin disappeared. Moreover, we found that Nrf2 is not uninvolved in RANKL-induced NF-κB activation and may be related to the timing of ROS regulation. When we limited isoquercitrin administration to 2 days, Nrf2 remained activated and the inhibition of NF-κB disappeared. In vivo experiments suggested that isoquercitrin attenuated RA modeling-induced bone loss. Overall, isoquercitrin-activated Nrf2 blocked the RANKL-induced ROS-to-NF-κB signaling cascade response, thereby inhibiting osteoclastogenesis and bone loss. These findings provide new ideas for the treatment of RA.

Keywords

Antioxidant; NF-κB; Nrf2; Osteoclast; Rheumatoid arthritis.

Figures
Products