Abstract W MP82: Role of OPG/RANKL/RANK System in Ischemic Brain in Mice
Background & Purpose: Although recent clinical studies showed that the high serum osteoprotegerin (OPG, decoy receptor for RANKL) level was associated with unfavorable outcome in ischemic stroke, its mechanism is unknown. Since OPG/ RANKL (receptor activator of nuclear factor-β ligand)/ RANK (receptor for RANKL) system has critical roles in immune systems as well as osteoclast biology, we hypothesized the OPG/RANKL/RANK system might play roles in post-ischemic inflammation and immune response. To explore the possibility, we examined their expressions and functions in mice.
Methods: The expression and the functional analysis of OPG/RANKL/RANK system were examined in 70 min-transient cerebral artery occlusion model in C57BL6/J (WT) mice or OPG-/- mice, whose serum RANKL level is higher than that in WT mice. The effects of RANKL/RANK signaling were also examined in mixed glial-neuron cultures stimulated by lipopolysaccharide (LPS).
Results: RANK mRNA was increased from 4 hrs after ischemia, whereas OPG and RANKL mRNA were up-regulated from 5 hrs after ischemia. The RANKL and RANK were expressed in activated macrophage/microglia and OPG was partly expressed in activated macrophage/microglia. OPG-/- mice showed reduced infarct volume 72 hrs after ischemia, whereas the infarct volume was not reduced in OPG-/- mice treated with RANK/Fc chimera. Also, RANKL-treated wild type mice showed the reduction in infarct volume. The expression of IL-6, TNF-α, and IL-1β was less in OPG-/- mice and RANKL-treated mice. Additionally, the LPS-stimulated neuron-glia mixed culture showed less neuronal death in the group of RANKL-treatment cultures through inhibition of inflammatory cytokines production.
Conclusions: These data indicate that RANKL/RANK signaling might work as anti-inflammation in the ischemic brain through inhibiting TLR signaling pathways. High serum OPG level in clinical situations might inhibit RANKL/RANK signaling and exacerbate the post-ischemic inflammation, resulting in poor outcomes. Further studies on the OPG/RANKL/RANK system might shed light on the clarification of molecular mechanisms in post-ischemic inflammation.
Author Disclosures: M. Shimamura: Research Grant; Significant; JSPS KAKENHI Grant Number 25462214, SENSHIN Medical Research Foundation, THE ICHIRO KANEHARA FOUNDATION. H. Nakagami: None. M.K. Osako: None. H. Kurinami: None. K. Wakayama: None. H. Koriyama: None. R. Morishita: None.
- © 2014 by American Heart Association, Inc.