Many bone diseases, such as osteoporosis and rheumatoid arthritis, are attributed to an increase in osteoclast number or activity; therefore, control of osteoclasts has significant clinical implications. This study shows how skullcapflavone II (SFII), a flavonoid with anti-inflammatory activity, regulates osteoclast differentiation, survival, and function. SFII inhibited osteoclastogenesis with decreased activation of MAPKs, Src, and cAMP response element-binding protein (CREB), which have been known to be redox sensitive. SFII decreased reactive oxygen species by scavenging them or activating nuclear factor-erythroid 2-related factor 2 (Nrf2), and its effects were partially reversed by hydrogen peroxide cotreatment or Nrf2 deficiency. In addition, SFII attenuated survival, migration, and bone resorption, with a decrease in the expression of integrin b3, Src, and p130 Crk‐associated substrate, and the activation of RhoA and Rac1 in differentiated osteoclasts. Furthermore, SFII inhibited osteoclast formation and bone loss in an inflammation- or ovariectomy-induced osteolytic mouse model. These findings suggest that SFII inhibits osteoclastogenesis through redox regulation of MAPKs, Src, and CREB and attenuates the survival and resorption function by modulating the integrin pathway in osteoclasts. SFII has therapeutic potential in the treatment and prevention of bone diseases caused by excessive osteoclast activity.
Bibliographical noteFunding Information:
The authors thank Dr. Masayuki Yamamoto (Tohoku University Graduate School of Medicine, Sendai, Japan) for Nrf2 knockout mice. This work was supported by National Research Foundation (NRF) Grants 2017R1A2B2012435, 2016R1A6A3A11931064, and 2012R1A5A1048236, funded by the Korean Ministry of Science, Information and Communications Technology (ICT), and Future Planning. The authors declre no conflicts of interest.
- Bone resorption
- Rho GTPase